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Sample records for acute quadriplegic myopathy

  1. Myopathy in acute hypothyroidism.

    PubMed Central

    Kung, A. W.; Ma, J. T.; Yu, Y. L.; Wang, C. C.; Woo, E. K.; Lam, K. S.; Huang, C. Y.; Yeung, R. T.

    1987-01-01

    Hypothyroid myopathy has so far been reported in long standing cases of hypothyroidism. We describe two adult patients with myopathy associated with acute transient hypothyroidism. Both presented with severe muscle aches and cramps, stiffness and spasms. Muscle enzymes were markedly elevated and electromyography in one patient showed myopathic features. Histological changes were absent in muscle biopsy, probably because of the short duration of metabolic disturbance. The myopathy subsided promptly when the hypothyroid state was reversed. PMID:3422868

  2. Delayed acute capture myopathy in three roe deer.

    PubMed

    Montané, J; Marco, I; Manteca, X; López, J; Lavín, S

    2002-03-01

    Delayed acute capture myopathy is the term used to describe the clinical syndrome observed in three roe deer captured by drive-nets and transported to an enclosure for scientific purposes. The animals died 48 h, 60 h and 8 days after being captured. The simultaneous deaths coincided with a previous episode of deliberate human disturbance. The histopathological findings were indicative of acute myopathy and myoglobinaemic nephrosis. These could be related to an ataxic myoglobinuric syndrome brought on by capture and transport operations. The lack of clinical signs and negative prognosis indicators in the period between capture and just before death. the absence of gross muscular lesions in the animal that died after 8 days post-capture, the simultaneous deaths of animals captured at different times and the evidence of deliberate human disturbance in the enclosure are suggestive of death triggered by a second stress episode.

  3. A study of acute muscle dysfunction with particular reference to dengue myopathy

    PubMed Central

    Verma, Rajesh; Holla, Vikram V.; Kumar, Vijay; Jain, Amita; Husain, Nuzhat; Malhotra, Kiran Preet; Garg, Ravindra Kumar; Malhotra, Hardeep Singh; Sharma, Praveen Kumar; Kumar, Neeraj

    2017-01-01

    Background: Acute myopathy is a common cause of acute motor quadriparesis which has various etiologies with different courses of illness and prognosis depending on the cause. Understanding this diversity helps us in proper approach toward diagnosis, predicting the prognosis, and possible complications and in improving the treatments that are being provided. This study was planned to study the clinical, electrophysiological, and etiological profile of patients presenting with acute myopathy. We also studied how dengue-related acute myopathy differs from other causes and also difference between myopathy due to myositis and hypokalemia in cases of dengue. Materials and Methods: This was a prospective, observational study involving all clinically suspected cases of acute myopathy of not more than 4 weeks duration with raised serum creatine kinase (CK) level. They were subjected to detailed clinical evaluation along with hematological, biochemical, microbiological, and electrophysiological studies and followed-up for outcome at 1 and 3 months. Muscle biopsy and histopathological examination were done in selected patients after taking informed consent. Statistical analysis was performed by appropriate methods using SPSS version 16.0 (Chicago, IL, USA). Results: We evaluated thirty patients of acute myopathy with raised CK level. Seventeen patients had fever, 11 had myalgia, and 5 had skin lesions. All presented with symmetric weakness, 17 (56.7%) patients having predominantly proximal weakness, neck or truncal weakness in 6 (20%), hyporeflexia in 12 (40%), with mean Medical Research Council (MRC) sum score of 46.67 ± 6.0. Eight (mean modified Barthel index [MBI] at presentation - 15 ± 3.7) patients had poor functional status according to MBI and 15 according to modified Rankin scale (MRS) (mean MRS score - 2.5 ± 1.2). Etiology was dengue viral infection in 14 patients; hypokalemia due to various causes other than dengue in 8; pyomyositis in 3; dermatomyositis

  4. Acute Hemorrhagic Myositis in Inflammatory Myopathy and Review of the Literature

    PubMed Central

    Van Gelder, Howard; Wu, Kim M.; Gharibian, Nayiri; Patel, Dharmi B.; Clements, Philip J.; Heinze, Emil R.; Morris, Robert I.; Wong, Andrew L.

    2014-01-01

    We describe two patients with dermatomyositis that presented with interstitial lung disease, positive V and Shawl sign who developed acute spontaneous abdominal/retroperitoneal bleed. Both patients expired despite aggressive treatment and resuscitation. Hemorrhagic myositis in these two patients with inflammatory myopathy is a very rare complication. The association of anti-Ro52 with this potentially very serious complication remains unclear. This potential relationship should be further evaluated in future studies. PMID:25379317

  5. Acute forearm compressive myopathy syndrome secondary to upper limb entrapment: an unusual cause of renal failure.

    PubMed

    Tachtsi, Maria D; Kalogirou, Thomas E; Atmatzidis, Stefanos K; Papadimitriou, Dimitrios K; Atmatzidis, Konstantinos S

    2011-05-01

    Compressive myopathy syndrome (SCM) is a syndrome characterized by the lesion of skeletal muscle resulting in subsequent release of intracellular contents (myoglobin, creatine phosphokinase, potassium, etc.) into the circulatory system, which can cause potentially lethal complications. There are numerous causes that can lead to SCM resulting to acute rhabdomyolysis, and many patients present with multiple causes. The most common potentially lethal complication is acute renal failure. The occurrence of acute rhabdomyolysis should be considered as a possibility in any patient who can remain stationary for long periods, or is in a coma, or is intoxicated in any form. We report the rare case of a 26-year-old patient who developed SCM caused by ischemia reperfusion, with subsequent acute rhabdomyolysis and acute renal failure after prolonged compression of the right upper extremity.

  6. Acute myoedema: an unusual presenting manifestation of hypothyroid myopathy

    PubMed Central

    Bhansali, A; Chandran, V; Ramesh, J; Kashyap, A; Dash, R

    2000-01-01

    We describe a patient with primary hypothyroidism due to autoimmune thyroiditis, presenting with acute myoedema and spontaneous rhabdomyolysis. During his hospital stay, he developed altered sensorium due to hypo-osmolal hyponatraemia and later developed bilateral foot drop that responded to appropriate treatment.


Keywords: hypothyroidism; myoedema; rhabdomyolysis PMID:10644388

  7. Enhanced muscle shortening and impaired Ca2+ channel function in an acute septic myopathy model.

    PubMed

    Friedrich, Oliver; Hund, Ernst; von Wegner, Frederic

    2010-04-01

    Myopathies in critically ill patients are increasingly documented. Various animal models of chronic sepsis have been employed to investigate reduced membrane excitability or altered isometric contractility of skeletal muscle. In contrast, immediate changes occurring during acute sepsis are significantly under-characterised; L-type Ca(2+) channel function or isotonic shortening are examples. We recorded slowly activating L-type Ca(2+) currents (I (Ca)) in voltage-clamped single intact mouse skeletal muscle fibres and tested the effects of acute challenge with serum fractions from critical illness myopathy patients (CIM). Using a high-speed camera system, we simultaneously recorded unloaded fibre shortening during isotonic contractions with unprecedented temporal resolution (approximately 1,600 frames/s). Time courses of fibre lengths and shortening velocity were determined from automated imaging algorithms. CIM fractions acutely induced depression of I (Ca) amplitudes with no shifts in I (Ca)-V-relations. Voltage-dependent inactivation was unaltered and I (Ca) activation and inactivation kinetics were prolonged compared to controls. Unexpectedly, maximum unloaded speed of shortening was slightly faster following CIM serum applications, suggesting a direct action of CIM serum on weak-binding-state cross-bridges. Our results are compatible with a model where CIM serum might acutely reduce a fraction of functional L-type Ca(2+) channels and could account for reduced SR Ca(2+) release and force production in CIM patients. Acute increase in isotonic shortening velocity might be an early diagnostic feature suitable for testing in clinical studies. The acute challenge model is also robust against atrophy or fibre type changes that ordinarily would have to be considered in chronic sepsis models.

  8. Isotretinoin-induced acute severe myopathy involving pelvic girdle muscles: A case report

    PubMed Central

    Sameem, Farah; Semira

    2016-01-01

    Oral isotretinoin has been in widespread use for more than three decades. It causes numerous side effects; skin and mucous membrane being commonly involved. Musculoskeletal adverse effects are also known to occur, but pelvic girdle myopathy is rarely reported. We report myopathy involving pelvic girdle muscles in a young male who received oral isotretinoin for folliculitis decalvans. PMID:27721552

  9. Statin-associated myopathy.

    PubMed

    Hamilton-Craig, I

    2001-11-05

    Myopathy occurs in 0.1%-0.2% of patients receiving statins in clinical trials. This adverse effect is shared by all statins, but is more common with cerivastatin, especially in combination with gemfibrozil. The risk of myopathy is increased by: the use of high doses of statins, concurrent use of fibrates, concurrent use of hepatic cytochrome P450 inhibitors, acute viral infections, major trauma, surgery, hypothyroidism and other conditions. Statin-associated myopathy should be suspected when a statin-treated patient complains of unexplained muscle pain, tenderness or weakness. Statin therapy should be stopped in cases of suspected myopathy, and serum creatine kinase levels should be checked and monitored. No specific therapies other than statin withdrawal and supportive measures for rhabdomyolysis are currently available.

  10. DISTAL MYOPATHIES

    PubMed Central

    Dimachkie, Mazen M.; Barohn, Richard J.

    2014-01-01

    Over a century ago, Gowers described two young patients in whom distal muscles weakness involved the hand, foot, sternocleidomastoid, and facial muscles in the other case the shoulder and distal leg musculature. Soon after, , similar distal myopathy cases were reported whereby the absence of sensory symptoms and of pathologic changes in the peripheral nerves and spinal cord at postmortem examination allowed differentiation from Charcot-Marie-Tooth disease. In 1951, Welander described autosomal dominant (AD) distal arm myopathy in a large Scandanavian cohort. Since then the number of well-characterized distal myopathies has continued to grow such that the distal myopathies have formed a clinically and genetically heterogeneous group of disorders. Affected kindred commonly manifest weakness that is limited to foot and toe muscles even in advanced stages of the disease, with variable mild proximal leg, distal arm, neck and laryngeal muscle involvement in selected individuals. An interesting consequence of the molecular characterization of the distal myopathies has been the recognition that mutation in a single gene can lead to more than one clinical disorder. For example, Myoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) type 2B are allelic disorders due to defects in the gene that encodes dysferlin. The six well described distal myopathy syndromes are shown in Table 1. Table 2 lists advances in our understanding of the myofibrillar myopathy group and Table 3 includes more recently delineated and less common distal myopathies. In the same manner, the first section of this review pertains to the more traditional six distal myopathies followed by discussion of the myofibrillar myopathies. In the third section, we review other clinically and genetically distinctive distal myopathy syndromes usually based upon single or smaller family cohorts. The fourth section considers other neuromuscular disorders that are important to recognize as they display prominent

  11. Statin-induced myopathies.

    PubMed

    Tomaszewski, Michał; Stępień, Karolina M; Tomaszewska, Joanna; Czuczwar, Stanisław J

    2011-01-01

    Statins are considered to be safe, well tolerated and the most efficient drugs for the treatment of hypercholesterolemia, one of the main risk factor for atherosclerosis, and therefore they are frequently prescribed medications. The most severe adverse effect of statins is myotoxicity, in the form of myopathy, myalgia, myositis or rhabdomyolysis. Clinical trials commonly define statin toxicity as myalgia or muscle weakness with creatine kinase (CK) levels greater than 10 times the normal upper limit. Rhabdomyolysis is the most severe adverse effect of statins, which may result in acute renal failure, disseminated intravascular coagulation and death. The exact pathophysiology of statin-induced myopathy is not fully known. Multiple pathophysiological mechanisms may contribute to statin myotoxicity. This review focuses on a number of them. The prevention of statin-related myopathy involves using the lowest statin dose required to achieve therapeutic goals and avoiding polytherapy with drugs known to increase systemic exposure and myopathy risk. Currently, the only effective treatment of statin-induced myopathy is the discontinuation of statin use in patients affected by muscle aches, pains and elevated CK levels.

  12. Typewriter Modifications for Persons Who Are High-Level Quadriplegics.

    ERIC Educational Resources Information Center

    O'Reagan, James R.; And Others

    Standard, common electric typewriters are not completely suited to the needs of a high-level quadriplegic typing with a mouthstick. Experiences show that for complete control of a typewriter a mouthstick user needs the combined features of one-button correction, electric forward and reverse indexing, and easy character viewing. To modify a…

  13. Congenital Myopathy

    MedlinePlus

    ... arms and legs, droopy eyelids, and problems with eye movements. Weakness often gets worse with time. Central core ... difficulties occur as well. Some children have weakened eye movements. Congenital fiber-type disproportion myopathy is a rare ...

  14. Stepwise Approach to Myopathy in Systemic Disease

    PubMed Central

    Chawla, Jasvinder

    2011-01-01

    Muscle diseases can constitute a large variety of both acquired and hereditary disorders. Myopathies in systemic disease results from several different disease processes including endocrine, inflammatory, paraneoplastic, infectious, drug- and toxin-induced, critical illness myopathy, metabolic, and myopathies with other systemic disorders. Patients with systemic myopathies often present acutely or sub acutely. On the other hand, familial myopathies or dystrophies generally present in a chronic fashion with exceptions of metabolic myopathies where symptoms on occasion can be precipitated acutely. Most of the inflammatory myopathies can have a chance association with malignant lesions; the incidence appears to be specifically increased only in patients with dermatomyositis. In dealing with myopathies associated with systemic illnesses, the focus will be on the acquired causes. Management is beyond the scope of this chapter. Prognosis is based upon the underlying cause and, most of the time, carries a good prognosis. In order to approach a patient with suspected myopathy from systemic disease, a stepwise approach is utilized. PMID:21886637

  15. [Inflammatory myopathies].

    PubMed

    Maurer, Britta

    2017-02-01

    Inflammatory myopathies comprise heterogeneous, often multisystemic autoimmune diseases with muscle involvement as a common feature. The prognosis largely depends on a timely diagnosis and initiation of therapy. Given the complexity of these rare diseases, when an inflammatory myopathy is suspected patients should be referred to an expert center with established algorithms for the diagnostic work-up. The differential diagnostic exclusion of myositis mimics should ideally be carried out in close collaboration with neurologists and neuropathologists. The choice of immunosuppressive treatment should primarily depend on disease severity and organ involvement but age and comorbidities also have to be taken into account.

  16. Toxic Myopathies

    PubMed Central

    Pasnoor, Mamatha; Barohn, Richard J.; Dimachkie, Mazen M.

    2014-01-01

    Muscle tissue is highly sensitive to many substances. Early recognition of toxic myopathies is important, as they potentially are reversible on removal of the offending drug or toxin, with greater likelihood of complete resolution the sooner this is achieved. Clinical features range from mild muscle pain and cramps to severe weakness with rhabdomyolysis, renal failure, and even death. The pathogenic bases can be multifactorial. This article reviews some of the common toxic myopathies and their clinical presentation, histopathologic features and possible underlying cellular mechanisms. PMID:25037083

  17. Metabolic myopathies

    NASA Technical Reports Server (NTRS)

    Martin, A.; Haller, R. G.; Barohn, R.; Blomqvist, C. G. (Principal Investigator)

    1994-01-01

    Metabolic myopathies are disorders of muscle energy production that result in skeletal muscle dysfunction. Cardiac and systemic metabolic dysfunction may coexist. Symptoms are often intermittent and provoked by exercise or changes in supply of lipid and carbohydrate fuels. Specific disorders of lipid and carbohydrate metabolism in muscle are reviewed. Evaluation often requires provocative exercise testing. These tests may include ischemic forearm exercise, aerobic cycle exercise, and 31P magnetic resonance spectroscopy with exercise.

  18. Molecular and Genetic Studies of Congenital Myopathies

    ClinicalTrials.gov

    2016-12-08

    Central Core Disease; Centronuclear Myopathy; Congenital Fiber Type Disproportion; Multiminicore Disease; Myotubular Myopathy; Nemaline Myopathy; Rigid Spine Muscular Dystrophy; Undefined Congenital Myopathy

  19. Metabolic neuropathies and myopathies.

    PubMed

    D'Amico, Adele; Bertini, Enrico

    2013-01-01

    Inborn errors of metabolism may impact on muscle and peripheral nerve. Abnormalities involve mitochondria and other subcellular organelles such as peroxisomes and lysosomes related to the turnover and recycling of cellular compartments. Treatable causes are β-oxidation defects producing progressive neuropathy; pyruvate dehydrogenase deficiency, porphyria, or vitamin B12 deficiency causing recurrent episodes of neuropathy or acute motor deficit mimicking Guillain-Barré syndrome. On the other hand, lysosomal (mucopolysaccharidosis, Gaucher and Fabry diseases), mitochondriopathic (mitochondrial or nuclear mutations or mDNA depletion), peroxisomal (adrenomyeloneuropathy, Refsum disease, sterol carrier protein-2 deficiency, cerebrotendinous xanthomatosis, α-methylacyl racemase deficiency) diseases are multisystemic disorders involving also the heart, liver, brain, retina, and kidney. Pathophysiology of most metabolic myopathies is related to the impairment of energy production or to abnormal production of reactive oxygen species (ROS). Main symptoms are exercise intolerance with myalgias, cramps and recurrent myoglobinuria or limb weakness associated with elevation of serum creatine kinase. Carnitine palmitoyl transferase deficiency, followed by acid maltase deficiency, and lipin deficiency, are the most common cause of isolated rhabdomyolysis. Metabolic myopathies are frequently associated to extra-neuromuscular disorders particularly involving the heart, liver, brain, retina, skin, and kidney.

  20. Congenital myopathies

    PubMed Central

    Colombo, Irene; Scoto, Mariacristina; Manzur, Adnan Y.; Robb, Stephanie A.; Maggi, Lorenzo; Gowda, Vasantha; Cullup, Thomas; Yau, Michael; Phadke, Rahul; Sewry, Caroline; Jungbluth, Heinz

    2015-01-01

    Objective: To assess the natural history of congenital myopathies (CMs) due to different genotypes. Methods: Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012. Results: Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p = 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchair-dependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years). Conclusions: We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling. PMID:25428687

  1. Cardiorespiratory fitness and training in quadriplegics and paraplegics.

    PubMed

    Hoffman, M D

    1986-01-01

    With the growing interest in exercise and sport and the significance of cardiovascular disease in the spinal cord injured population, the role of endurance training in improving cardiovascular health is of particular interest. Ordinary daily activities of those with spinal cord injury are usually not adequate to maintain cardiovascular fitness, and lack of participation in a regular activity programme may result in a debilitative cycle. As this occurs, there is a reduction in functional work capacity which may limit independence, and the reduction in cardiovascular fitness may increase the risk for cardiovascular disease. Work capacity in those with spinal cord injury is limited by loss of functional muscle mass and sympathetic control. Sympathetic nervous system impairment limits control of regional blood flow and cardiac output, and maximum heart rate following cervical lesions may be reduced to 110 to 130 beats/min. However, endurance training in quadriplegics and paraplegics can elicit improvements in exercise performance similar to those observed in able-bodied individuals. Review of 13 cardiorespiratory training studies involving spinal cord injured subjects revealed average improvements of 20% in VO2max and 40% in physical work capacity after 4 to 20 weeks of training. Based upon the positive results of these studies, the general endurance training guidelines for the normal population appear to also be appropriate for the spinal cord injured population. These guidelines can be followed during participation in a number of different activities and sports including wheelchair pushing, arm crank ergometry, aerobic swimming, ambulation training, canoeing and wheelchair basketball. There is no evidence that intense training and competition is harmful, but special areas of risk as a result of impairments in sensation, cardiovascular function, autonomic function and temperature regulation must be considered. The long term benefits of endurance training in those with

  2. Critical illness polyneuropathy and myopathy: a systematic review.

    PubMed

    Zhou, Chunkui; Wu, Limin; Ni, Fengming; Ji, Wei; Wu, Jiang; Zhang, Hongliang

    2014-01-01

    Critical illness polyneuropathy and critical illness myopathy are frequent complications of severe illness that involve sensorimotor axons and skeletal muscles, respectively. Clinically, they manifest as limb and respiratory muscle weakness. Critical illness polyneuropathy/myopathy in isolation or combination increases intensive care unit morbidity via the inability or difficulty in weaning these patients off mechanical ventilation. Many patients continue to suffer from decreased exercise capacity and compromised quality of life for months to years after the acute event. Substantial progress has been made lately in the understanding of the pathophysiology of critical illness polyneuropathy and myopathy. Clinical and ancillary test results should be carefully interpreted to differentiate critical illness polyneuropathy/myopathy from similar weaknesses in this patient population. The present review is aimed at providing the latest knowledge concerning the pathophysiology of critical illness polyneuropathy/myopathy along with relevant clinical, diagnostic, differentiating, and treatment information for this debilitating neurological disease.

  3. Central Cardiovascular Responses of Quadriplegic Subjects to Arm Exercise at Varying Levels of Oxygen Uptake.

    ERIC Educational Resources Information Center

    Figoni, Stephen F.

    The purpose of this study was to assess selected central cardiovascular functions of spinal cord injured, quadriplegic subjects at varying levels of oxygen uptake (VO sub 2). Subjects included 11 untrained, male college students with C5, C6, or C7 complete quadriplegia and 11 able-bodied reference subjects. Exercise was performed on a Monark cycle…

  4. Pravastatin-associated myopathy. Report of a case.

    PubMed

    Scalvini, T; Marocolo, D; Cerudelli, B; Sleiman, I; Balestrieri, G P; Giustina, G

    1995-05-01

    A case of acute inflammatory myopathy associated with the use of pravastatin, a new hydrophilic 3-hydroxy-3 methylglutaril coenzyme A reductase inhibitor, is reported. The patient, a 69-year-old man was affected by non-insulin-dependent diabetes mellitus and hypertension. He assumed pravastatin (20 mg/day) because of hypercholesterolemia. He was admitted with acute myopathy of the lower limbs which resolved in a few days after pravastatin discontinuation. A previously unknown hypothyroidism, probably due to chronic autoimmune thyroiditis, was evidenced. Muscle biopsy (left gastrocnemius) revealed a perimysial and endomysial inflammatory infiltrate with a prevalence of CD4+ lymphocytes. While lovastatin and simvastatin have been associated with toxic myopathy, pravastatin-associated myopathy could represent a distinct, inflammatory entity.

  5. Statin-induced Myopathy.

    PubMed

    Fitzgerald, Kara; Redmond, Elizabeth; Harbor, Cathryn

    2012-05-01

    Heart disease (HD) is the number one killer in the United States.(1) In 2006, the direct and indirect costs associated with cardiovascular disease in the United States were estimated at 400 billion dollars.(2) Statin therapy for cholesterol reduction is a mainstay intervention for cardiovascular disease (CVD) as reflected in atorvastatin's status as the number one prescribed medication in the United States.(3) Statin therapy, however, is also associated with side effects that signal mitochondrial distress. A commonly reported statin-induced symptom is myalgia, which is defined as muscle pain without an associated elevation of serum creatine kinase (CK). In clinical trials, the reports of myalgia vary from less than 1% to 25% of patients.(4) Myopathy is a general term defined as an abnormal condition or disease of muscle tissue. Myopathy includes myalgia, myositis (inflammation of muscle tissue associated with elevated CK) and the very serious condition rhabdomyolysis (extreme myositis). Histological findings in statin-induced myopathy demonstrate electron chain dysfunction making "mitochondrial myopathy" the more precise term.(5) Mitochondrial myopathy has been associated with statin-induced CoQ10 depletion.(5) Given the density of mitochondria in cardiomyocytes, and CoQ10's role in mitochondrial energy production, depletion has long been associated with increased risk for heart disease.(6-7) In the case below, mitochondrial-specific organic acids, serum CoQ10, vitamin D and clinical history all suggest statin-induced mitochondrial myopathy, despite normal serum CK.

  6. Myopathy in Addison's disease.

    PubMed Central

    Mor, F; Green, P; Wysenbeek, A J

    1987-01-01

    Since the first description of primary adrenocortical insufficiency by Thomas Addison in 1855 several large series of patients with Addison's disease have been published. The common signs and symptoms include: weakness, hyperpigmentation, weight loss, gastrointestinal complaints, and hypotension. It is rare for patients with Addison's disease to present with musculoskeletal symptoms including flexion contractures, hyperkalaemic neuromyopathy, Guillain-Barré syndrome, migratory myalgia, sciatica-like pain, and low back pain. Myopathy has not been previously described in Addison's disease. Herein we report a patient presenting with severe hyponatraemia and myopathy which resolved after steroid replacement therapy. PMID:3813679

  7. Aerobic capacity and peak power output of elite quadriplegic games players

    PubMed Central

    Goosey‐Tolfrey, V; Castle, P; Webborn, N

    2006-01-01

    Background Participation in wheelchair sports such as tennis and rugby enables people with quadriplegia to compete both individually and as a team at the highest level. Both sports are dominated by frequent, intermittent, short term power demands superimposed on a background of aerobic activity. Objective To gain physiological profiles of highly trained British quadriplegic athletes, and to examine the relation between aerobic and sprint capacity. Methods Eight male quadriplegic athletes performed an arm crank exercise using an ergometer fitted with a Schoberer Rad Messtechnik (SRM) powermeter. The sprint test consisted of three maximum‐effort sprints of five seconds duration against a resistance of 2%, 3%, and 4% of body mass. The highest power output obtained was recorded (PPO). Peak oxygen consumption (V̇o2peak), peak heart rate (HRpeak), and maximal power output (POaer) were determined. Results Mean POaer was 67.7 (16.2) W, mean V̇o2peak was 0.96 (0.17) litres/min, and HRpeak was 134 (19) beats/min for the group. There was high variability among subjects. Peak power over the five second sprint for the group was 220 (62) W. There was a significant correlation between V̇o2peak (litres/min) and POaer (W) (r  =  0.74, p<0.05). Conclusions These British quadriplegic athletes have relatively high aerobic fitness when compared with the available literature. Moreover, the anaerobic capacity of these athletes appeared to be relatively high compared with paraplegic participants. PMID:16611721

  8. Genetics Home Reference: inclusion body myopathy 2

    MedlinePlus

    ... Conditions inclusion body myopathy 2 inclusion body myopathy 2 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Inclusion body myopathy 2 is a condition that primarily affects skeletal muscles , ...

  9. Managing statin myopathy.

    PubMed

    Venero, Carmelo V; Thompson, Paul D

    2009-03-01

    Approximately 10% of patients treated with statins experience some form of muscle-related side effects in clinical practice. These can range from asymptomatic creatine kinase (CK) elevation, to muscle pain, weakness, and its most severe form, rhabdomyolysis. Higher risk patients for statin myopathy are those older than 80, with a small body frame, on higher statin doses, on other medications, or with other systemic diseases including hepatic or renal diseases, diabetes mellitus, or hypothyroidism. The cause of statin myopathy is presumed to be the same for its variable presentation but has not been defined. In patients with myopathic symptoms, their symptoms and CK levels determine whether statin therapy can be continued or must be stopped.

  10. Speech-Associated Labiomandibular Movement in Mandarin-Speaking Children with Quadriplegic Cerebral Palsy: A Kinematic Study

    ERIC Educational Resources Information Center

    Hong, Wei-Hsien; Chen, Hsieh-Ching; Yang, Fan-pei Gloria; Wu, Ching-Yi; Chen, Chia-Ling; Wong, Alice May-kuen

    2011-01-01

    The purpose of this study was to investigate the speech-associated labiomandibular movement during articulation production in Mandarin-speaking children with spastic quadriplegic (SQ) cerebral palsy (CP). Twelve children with SQ CP (aged 7-11 years) and 12 age-matched healthy children as controls were enrolled for the study. All children underwent…

  11. Myopathy associated with gluten sensitivity.

    PubMed

    Hadjivassiliou, Marios; Chattopadhyay, Arup K; Grünewald, Richard A; Jarratt, John A; Kandler, Rosalind H; Rao, D G; Sanders, D S; Wharton, S B; Davies-Jones, G A B

    2007-04-01

    Ataxia and peripheral neuropathy are the most common neurological manifestations of gluten sensitivity. Myopathy is a less common and poorly characterized additional neurological manifestation of gluten sensitivity. We present our experience with 13 patients who presented with symptoms and signs suggestive of a myopathy and in whom investigation led to the diagnosis of gluten sensitivity. Three of these patients had a neuropathy with or without ataxia in addition to the myopathy. The mean age at onset of the myopathic symptoms was 54 years. Ten patients had neurophysiological evidence of myopathy. Inflammatory myopathy was the most common finding on neuropathological examination. One patient had basophilic rimmed vacuoles suggestive of inclusion-body myositis. Six patients received immunosuppressive treatment in addition to starting on a gluten-free diet; five improved and one remained unchanged. Among seven patients not on immunosuppressive treatment, four showed clinical improvement of the myopathy with a gluten-free diet. The improvement was also associated with reduction or normalization of serum creatine kinase level. The myopathy progressed in one patient who refused the gluten-free diet. Myopathy may be another manifestation of gluten sensitivity and is likely to have an immune-mediated pathogenesis. A gluten-free diet may be a useful therapeutic intervention.

  12. A rat model of spontaneous myopathy and malignant hyperthermia.

    PubMed Central

    Gonzalez, L. E.; Meléndez-Vásquez, C. V.; Gregson, N. A.; File, S. E.

    1998-01-01

    Malignant hyperthermia is a main cause of death during general anesthesia, particularly in children. However, research has been hampered by the lack of a convenient animal model, the only one available being a special strain of pig. In this study, we describe spontaneous myopathy and a fatal syndrome of generalized muscle rigidity triggered by halothane in an outbred strain of rat. Histological examination of skeletal muscle reveals severe abnormalities indicating chronic underlying myopathy. The association of histological abnormalities with an acute, fatal syndrome clinically resembling malignant hyperthermia provides a strong basis for a new and extremely useful animal model to study this fatal disorder. Images Figure 1 Figure 2 PMID:9546371

  13. Centronuclear (myotubular) myopathy

    PubMed Central

    Jungbluth, Heinz; Wallgren-Pettersson, Carina; Laporte, Jocelyn

    2008-01-01

    Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy. The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available. The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects. Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes. Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made. The main differential

  14. Genetics Home Reference: Miyoshi myopathy

    MedlinePlus

    ... Itoyama Y. Dysferlin mutations in Japanese Miyoshi myopathy: relationship to phenotype. Neurology. 2003 Jun 10;60(11): ... healthcare professional . About Genetics Home Reference Site Map Customer Support Selection Criteria for Links USA.gov Copyright ...

  15. [Spheroid body myopathy: case report].

    PubMed

    Scola, Rosana Hermínia; Trentin, Alcides Júnior; Vaez, Rodrigo; Gignon, Vinicius de Faria; Costa, Thaís Gurgel; Werneck, Lineu Cesar

    2005-06-01

    Spheroid body myopathy is a rare illness classified in the group of the congenital myopathies as a desmin-related neuromuscular disorder, presenting dominant autosomical origin with the beginning of the symptoms in the adult phase. We report on a seven years old girl with facial paresia, generalized muscular hypotrophy and hypotony, generalized deep areflexia, proximal upper and lower limbs muscular strengh and distal upper limbs grade 3 and distal lower limbs grade 1. Needle electromyography evidenced increased conscription and potentials of motor unit of short duration and low amplitude, characterizing a myopathic standard. The muscle biopsy disclosed mixed standard to myopathy, denervation and inclusion bodies that are consistent to spheroid body myopathy. In this case, the patient presented, in advance, early beginning of the symptoms and there are no similar cases in the family.

  16. Adult-onset mitochondrial myopathy.

    PubMed Central

    Fernandez-Sola, J.; Casademont, J.; Grau, J. M.; Graus, F.; Cardellach, F.; Pedrol, E.; Urbano-Marquez, A.

    1992-01-01

    Mitochondrial diseases are polymorphic entities which may affect many organs and systems. Skeletal muscle involvement is frequent in the context of systemic mitochondrial disease, but adult-onset pure mitochondrial myopathy appears to be rare. We report 3 patients with progressive skeletal mitochondrial myopathy starting in adult age. In all cases, the proximal myopathy was the only clinical feature. Mitochondrial pathology was confirmed by evidence of ragged-red fibres in muscle histochemistry, an abnormal mitochondrial morphology in electron microscopy and by exclusion of other underlying diseases. No deletions of mitochondrial DNA were found. We emphasize the need to look for a mitochondrial disorder in some non-specific myopathies starting in adult life. Images Figure 1 Figure 2 PMID:1589382

  17. Genetics Home Reference: nemaline myopathy

    MedlinePlus

    ... Nemaline myopathy is a disorder that primarily affects skeletal muscles , which are muscles that the body uses for ... for producing proteins that play important roles in skeletal muscles . Within skeletal muscle cells, these proteins are found ...

  18. [Autoantibodies of Inflammatory Myopathies: Update].

    PubMed

    Suzuki, Shigeaki

    2016-12-01

    Inflammatory myopathies are a heterogeneous group of immune-mediated diseases that involve the skeletal muscle as well as many other organs. In addition to a histological diagnosis at muscle biopsy, the clinical phenotypes of inflammatory myopathies can be defined by the presence of various autoantibodies that are originally detected by RNA or protein immunoprecipitation. However, the correlation between histological features and autoantibodies has not been fully elucidated. Immune-mediated necrotizing myopathy (IMNM), which is characterized by significant necrotic and regeneration muscle fibers with minimal or no inflammatory cell infiltration, is associated with the presence of autoantibodies. IMNM is now classified as a distinct category of inflammatory myopathies, separate from polymyositis, dermatomyositis, and sporadic inclusion body myositis. Here, we divided the autoantibodies of inflammatory myopathies into the following categories: those associated with IMNM, those with activity against aminoacyl transfer RNA synthetase, those associated with dermatomyositis, and those related to other disorders, including overlap syndrome, inclusion body myositis, and primary biliary cirrhosis. The detection of autoantibodies against signal recognition particle or 3-hydroxy-3-methylglutaryl-coenzyme A reductase is useful for the diagnosis of IMNM. The screening of autoantibodies has clinical relevance for managing patients with inflammatory myopathies.

  19. Idiopathic Inflammatory Myopathies: Clinical Approach and Management

    PubMed Central

    Malik, Asma; Hayat, Ghazala; Kalia, Junaid S.; Guzman, Miguel A.

    2016-01-01

    Idiopathic inflammatory myopathies (IIM) are a group of chronic, autoimmune conditions affecting primarily the proximal muscles. The most common types are dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myopathy (NAM), and sporadic inclusion body myositis (sIBM). Patients typically present with sub-acute to chronic onset of proximal weakness manifested by difficulty with rising from a chair, climbing stairs, lifting objects, and combing hair. They are uniquely identified by their clinical presentation consisting of muscular and extramuscular manifestations. Laboratory investigations, including increased serum creatine kinase (CK) and myositis specific antibodies (MSA) may help in differentiating clinical phenotype and to confirm the diagnosis. However, muscle biopsy remains the gold standard for diagnosis. These disorders are potentially treatable with proper diagnosis and initiation of therapy. Goals of treatment are to eliminate inflammation, restore muscle performance, reduce morbidity, and improve quality of life. This review aims to provide a basic diagnostic approach to patients with suspected IIM, summarize current therapeutic strategies, and provide an insight into future prospective therapies. PMID:27242652

  20. Schistosomiasis and nutritional myopathy in a Brazilian tapir (Tapirus terrestris).

    PubMed

    Yamini, B; Schillhorn van Veen, T W

    1988-10-01

    Gross lesions suggestive of severe hepatoenteropathy and myopathy were noted in a 4.5-yr-old Brazilian tapir (Tapirus terrestris) from a zoo in Michigan (USA). The major microscopic lesions were granulomatous hepatitis and hemorrhagic enteritis associated with non-operculated eggs compatible with those of the Schistosomatidae (Digenea). Skeletal muscle and tongue contained foci of severe acute myodegeneration and necrosis. The hepatic vitamin E value of 1.3 ppm dry weight was considered critically low.

  1. Motor recovery mechanism in a quadriplegic patient with locked-in syndrome.

    PubMed

    Kwon, Hyeok Gyu; Jang, Sung Ho

    2012-01-01

    Locked-in syndrome (LIS) is a rare neurologic condition caused by bilateral pontine lesions. Quadriplegia is one of the most serious clinical manifestations in patients with LIS. However, little is known about the motor recovery mechanism of quadriplegia in patients with LIS. In the current study, we present with a quadriplegic patient with bilateral pontine infarcts, whose motor function appeared to be reorganized into the peri-infarct areas of the infarcted pons, as demonstrated by diffusion tensor tractography (DTT). A 60-year-old was diagnosed as LIS due to bilateral pontine infarcts 6 years ago. The patient presented with complete paralysis of all four extremities at onset. After slow motor recovery, the patient was able to move all joint muscles against gravity and demonstrated some fine motor activity at the time of DTT scanning (6 years after onset). Results of DTTs for the corticospinal tract (CST) in both hemispheres showed that the CSTs originated from the primary motor cortex, descended along the known CST pathway, and passed through lateral areas of infarcts in the pons. Therefore, motor function of the four extremities of this patient appears to have been recovered by the CST, which passed through the lateral areas to the pontine infarcts.

  2. Elbow extension in the C5 quadriplegic using functional neuromuscular stimulation.

    PubMed

    Miller, L J; Peckham, P H; Keith, M W

    1989-07-01

    A system has been designed to provide overhead reach in C5/6 quadriplegic subjects using functional neuromuscular stimulation (FNS) for control of the triceps muscle. The system uses the position of the arm in space as the input command, relieving the user from having to supply a conscious command signal. By measuring the position of the arm, the magnitude of the gravitational and passive torques opposing elbow extension can be calculated. This torque is counteracted by electrical activation of the triceps muscle, with the appropriate stimulus parameters determined from the recruitment characteristics of each electrode. Sufficient stimulus is applied to produce full elbow extension. Intermediate elbow angles are achieved using voluntary elbow flexor torque to counteract the effects of the stimulation. System performance was tested in two subjects. Subjects were asked to reach targets with and without stimulation, with loads up to 500 g in the hand. Using the FNS system, subjects were able to successfully reach the target positions above the horizontal that were inaccessible without stimulation.

  3. Resveratrol and Myopathy

    PubMed Central

    Bastin, Jean; Djouadi, Fatima

    2016-01-01

    Resveratrol is a natural polyphenolic compound produced by plants under various stress conditions. Resveratrol has been reported to exhibit antioxidant, anti-inflammatory, and anti-proliferative properties in mammalian cells and animal models, and might therefore exert pleiotropic beneficial effects in different pathophysiological states. More recently, resveratrol has also been shown to potentially target many mitochondrial metabolic pathways, including fatty acid β-oxidation or oxidative phosphorylation, leading to the up-regulation of the energy metabolism via signaling pathways involving PGC-1α, SIRT1, and/or AMP-kinase, which are not yet fully delineated. Some of resveratrol beneficial effects likely arise from its cellular effects in the skeletal muscle, which, surprisingly, has been given relatively little attention, compared to other target tissues. Here, we review the potential for resveratrol to ameliorate or correct mitochondrial metabolic deficiencies responsible for myopathies, due to inherited fatty acid β-oxidation or to respiratory chain defects, for which no treatment exists to date. We also review recent data supporting therapeutic effects of resveratrol in the Duchenne Muscular Dystrophy, a fatal genetic disease affecting the production of muscle dystrophin, associated to a variety of mitochondrial dysfunctions, which likely contribute to disease pathogenesis. PMID:27136581

  4. Resveratrol and Myopathy.

    PubMed

    Bastin, Jean; Djouadi, Fatima

    2016-04-28

    Resveratrol is a natural polyphenolic compound produced by plants under various stress conditions. Resveratrol has been reported to exhibit antioxidant, anti-inflammatory, and anti-proliferative properties in mammalian cells and animal models, and might therefore exert pleiotropic beneficial effects in different pathophysiological states. More recently, resveratrol has also been shown to potentially target many mitochondrial metabolic pathways, including fatty acid β-oxidation or oxidative phosphorylation, leading to the up-regulation of the energy metabolism via signaling pathways involving PGC-1α, SIRT1, and/or AMP-kinase, which are not yet fully delineated. Some of resveratrol beneficial effects likely arise from its cellular effects in the skeletal muscle, which, surprisingly, has been given relatively little attention, compared to other target tissues. Here, we review the potential for resveratrol to ameliorate or correct mitochondrial metabolic deficiencies responsible for myopathies, due to inherited fatty acid β-oxidation or to respiratory chain defects, for which no treatment exists to date. We also review recent data supporting therapeutic effects of resveratrol in the Duchenne Muscular Dystrophy, a fatal genetic disease affecting the production of muscle dystrophin, associated to a variety of mitochondrial dysfunctions, which likely contribute to disease pathogenesis.

  5. Botulinum toxin type a injections to salivary glands: combination with single event multilevel chemoneurolysis in 2 children with severe spastic quadriplegic cerebral palsy.

    PubMed

    Kim, Heakyung; Lee, Yung; Weiner, Daniel; Kaye, Robin; Cahill, Anne Marie; Yudkoff, Marc

    2006-01-01

    We describe 2 children with severe spastic quadriplegic cerebral palsy (CP) who have significant drooling and frequent aspiration pneumonia. They underwent simultaneous botulinum toxin type A (BTX-A) injections to salivary glands for drooling and prevention of aspiration pneumonia along with single-event multilevel chemoneurolysis (SEMLC) with BTX-A and 5% phenol for severe diffuse spasticity. There was significant improvement in drooling, frequency of aspiration pneumonia, and spasticity without adverse effect. BTX-A injections into the salivary glands, in addition to SEMLC, for these 2 children with medically complicated severe spastic quadriplegic CP, were safe and highly successful procedures, which improved their health-related quality of life.

  6. Evidence-based management of statin myopathy.

    PubMed

    Harper, Charles R; Jacobson, Terry A

    2010-09-01

    Statin-associated muscle symptoms are a relatively common condition that may affect 10% to 15% of statin users. Statin myopathy includes a wide spectrum of clinical conditions, ranging from mild myalgia to rhabdomyolysis. The etiology of myopathy is multifactorial. Recent studies suggest that statins may cause myopathy by depleting isoprenoids and interfering with intracellular calcium signaling. Certain patient and drug characteristics increase risk for statin myopathy, including higher statin doses, statin cytochrome metabolism, and polypharmacy. Genetic risk factors have been identified, including a single nucleotide polymorphism of SLCO1B1. Coenzyme Q10 and vitamin D have been used to prevent and treat statin myopathy; however, clinical trial evidence demonstrating their efficacy is limited. Statin-intolerant patients may be successfully treated with either low-dose statins, alternate-day dosing, or using twice-weekly dosing with longer half-life statins. An algorithm is presented to assist the clinician in managing myopathy in patients with dyslipidemia.

  7. Statin-associated necrotizing autoimmune myopathy.

    PubMed

    Fernandes, Geórgea Hermogenes; Zanoteli, Edmar; Shinjo, Samuel Katsuyuki

    2014-09-01

    Necrotizing autoimmune myopathy (NAM) is a severe adverse effect of statins. We report a 66-year-old Caucasian female who had progressive proximal muscle weakness after treatment with statins. Results of a muscle biopsy showed necrotizing myopathy with minimal inflammatory cell infiltrate and increased major histocompatibility class I antigen expression in muscle fibers. The clinical and laboratory parameters improved significantly with immunosuppressive treatment. Although it is a rare event, statin-induced NAM should be included as a differential diagnosis of myopathies.

  8. Metabolic myopathies: clinical features and diagnostic approach.

    PubMed

    Smith, Edward C; El-Gharbawy, Areeg; Koeberl, Dwight D

    2011-05-01

    The rheumatologist is frequently called on to evaluate patients with complaints of myalgia, muscle cramps, and fatigue. The evaluation of these patients presents a diagnostic challenge given the nonspecific and intermittent nature of their complaints, often leading to inappropriate diagnostic testing. When these symptoms are associated with physical exertion, a metabolic myopathy should be suspected Although inflammatory myopathies may present with similar features, such a pattern should prompt a thorough evaluation for an underlying metabolic myopathy. This review discusses the most common causes of metabolic myopathies and reviews the current diagnostic options available to the clinician.

  9. Fetal akinesia sequence caused by nemaline myopathy.

    PubMed

    Lammens, M; Moerman, P; Fryns, J P; Lemmens, F; van de Kamp, G M; Goemans, N; Dom, R

    1997-04-01

    Nine patients with the characteristic signs of fetal akinesia sequence (polyhydramnion, multiple joint contractures and lung hypoplasia) are described. In 8 of the 9 patients nemaline myopathy could be demonstrated with histology. The ninth patient presented the same phenotype as his 4 affected siblings in whom the nemaline myopathy could be histologically proven. Seven of the patients belonged to 2 families; the other 2 patients were isolated cases. In one fetal case nemaline myopathy was documented at week 22 of gestation. These observations demonstrate that nemaline myopathy can cause the fetal akinesia sequence, with onset of first symptoms as early as the beginning of the second trimester of pregnancy.

  10. Osteopathic approach to sacroiliac dysfunction in a patient with steroid myopathy: case report and literature review.

    PubMed

    Kohns, David J; Fitch, David S

    2014-06-01

    Long-term steroid use has a well-documented risk of myopathy that imposes functional limitations for patients and challenges for health care providers. Proximal weakness from steroid myopathy affects support structures around the pelvic girdle and likely predisposes patients to somatic dysfunction. To the authors' knowledge, there are no prior reports in the literature that describe an osteopathic manipulative medicine (OMM) approach for patients with steroid myopathy. In the present case report, a 59-year-old woman with acute myeloid leukemia received a blood stem cell transplantation and developed gastrointestinal graft-versus-host disease. High-dose steroids were prescribed, and she developed proximal weakness from steroid myopathy. The patient's acute inpatient rehabilitation was impacted by new onset left sacroiliac dysfunction. A patient-focused OMM approach was used to assist the patient in maximizing her sacroiliac function. The proximal weakness seen with steroid myopathy necessitates special considerations for an OMM approach to address somatic dysfunction associated with this disease.

  11. Statin induced necrotizing autoimmune myopathy.

    PubMed

    Babu, Suma; Li, Yuebing

    2015-04-15

    Statin induced necrotizing autoimmune myopathy (SINAM) is a recently characterized entity belonging to the spectrum of statin myotoxicity. It is a more severe form, and is usually associated with significant proximal muscle weakness, strikingly elevated creatine kinase levels and persistent symptoms despite statin discontinuation. The characteristic pathological finding is a marked muscle fiber necrosis with minimal or no inflammation on muscle biopsy. SINAM is an autoimmune disorder associated with an antibody against 3-hydroxy-3-methyglutaryl-coenzyme A reductase (HMGCR), and the antibody titer is a useful marker for assessing treatment response. However, anti-HMGCR positive myopathies are also caused by unknown etiologies other than statin exposure, especially in the younger population. SINAM should be promptly recognized as immunosuppressive therapy can improve its clinical outcome significantly. Further research is needed to elucidate its pathogenesis and provide evidence based guidelines for management.

  12. Immune-mediated statin myopathy.

    PubMed

    Loganathan, Priyadarshini; Oddis, Chester V; Aggarwal, Rohit

    2016-01-01

    Statin-induced necrotizing autoimmune myopathy (SINAM) is associated with a unique clinical 5 phenotype of severe proximal muscle weakness during or after exposure to statins in patients with high creatine kinase (CK) levels. Electromyography (EMG) and muscle biopsy reveal features of a necrotizing myopathy and the anti-HMGCR autoantibody is frequently detected. Treatment requires a combination of statin discontinuation as well as immunomodulatory or immunosuppressive therapy. HLA typing (HLADRB1*1101) is strongly associated with anti-10 HMGCR autoantibody positivity in statin-exposed patients. It is well documented that statin triggers autoimmune disease in those with a genetic susceptibility. With the commercial availability of an accurate ELISA test, the natural history of the disease and its phenotypic features are becoming increasingly understood.

  13. Respiratory assessment in centronuclear myopathies

    PubMed Central

    Smith, Barbara K; Goddard, Melissa; Childers, Martin K.

    2014-01-01

    The centronuclear myopathies (CNMs) are a group of inherited neuromuscular disorders classified as congenital myopathies. While several causative genes have been identified, some patients do not harbor any of the currently known mutations. These diverse disorders have common histological features, which include a high proportion of centrally-nucleated muscle fibers, and clinical attributes of muscle weakness and respiratory insufficiency. Respiratory problems in CNMs may manifest initially during sleep, but daytime symptoms, ineffective airway clearance, and hypoventilation predominate as more severe respiratory muscle dysfunction evolves. Respiratory muscle capacity can be evaluated using a variety of clinical tests selected with consideration for the age and baseline motor function of the patient. Similar clinical tests of respiratory function can also be incorporated into preclinical CNM canine models to offer insight for clinical trials. Since respiratory problems account for significant morbidity in patients, routine assessments of respiratory muscle function are discussed. PMID:24668768

  14. Integrated classification of inflammatory myopathies.

    PubMed

    Allenbach, Y; Benveniste, O; Goebel, H-H; Stenzel, W

    2017-02-01

    Inflammatory myopathies comprise a multitude of diverse diseases, most often occurring in complex clinical settings. To ensure accurate diagnosis, multidisciplinary expertise is required. Here, we propose a comprehensive myositis classification that incorporates clinical, morphological and molecular data as well as autoantibody profile. This review focuses on recent advances in myositis research, in particular, the correlation between autoantibodies and morphological or clinical phenotypes that can be used as the basis for an 'integrated' classification system.

  15. Pathogenic Mechanisms in Centronuclear Myopathies

    PubMed Central

    Jungbluth, Heinz; Gautel, Mathias

    2014-01-01

    Centronuclear myopathies (CNMs) are a genetically heterogeneous group of inherited neuromuscular disorders characterized by clinical features of a congenital myopathy and abundant central nuclei as the most prominent histopathological feature. The most common forms of congenital myopathies with central nuclei have been attributed to X-linked recessive mutations in the MTM1 gene encoding myotubularin (“X-linked myotubular myopathy”), autosomal-dominant mutations in the DNM2 gene encoding dynamin-2 and the BIN1 gene encoding amphiphysin-2 (also named bridging integrator-1, BIN1, or SH3P9), and autosomal-recessive mutations in BIN1, the RYR1 gene encoding the skeletal muscle ryanodine receptor, and the TTN gene encoding titin. Models to study and rescue the affected cellular pathways are now available in yeast, C. elegans, drosophila, zebrafish, mouse, and dog. Defects in membrane trafficking have emerged as a key pathogenic mechanisms, with aberrant T-tubule formation, abnormalities of triadic assembly, and disturbance of the excitation–contraction machinery the main downstream effects studied to date. Abnormal autophagy has recently been recognized as another important collateral of defective membrane trafficking in different genetic forms of CNM, suggesting an intriguing link to primary disorders of defective autophagy with overlapping histopathological features. The following review will provide an overview of clinical, histopathological, and genetic aspects of the CNMs in the context of the key pathogenic mechanism, outline unresolved questions, and indicate promising future lines of enquiry. PMID:25566070

  16. [Autoimmune myopathy associated with statin use].

    PubMed

    Ljøstad, Unn; Mygland, Åse

    2016-09-01

    It is well known that statins can have a toxic effect on musculature, but less widely known that they can also trigger progressive autoimmune myopathy. Statin-associated autoimmune myopathy is characterised by proximal muscle weakness, antibodies to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in serum, and necrosis without lymphocytic infiltration on muscle biopsy.

  17. Unilateral symptomatic intracranial arterial stenosis and myopathy in an adolescent with Graves disease: a case report of an high-resolution magnetic resonance imaging study.

    PubMed

    Yin, Jia; Zhu, Jiajia; Huang, Dongling; Shi, Changzheng; Guan, Yuqing; Zhou, Liang; Pan, Suyue

    2015-01-01

    Vascular and muscular involvements in Graves disease (GD) are rare. Here, we report a case of a 17-year-old patient with unilateral symptomatic middle cerebral artery stenosis concurrent with GD and myopathy. He presented with a 1-day history of acute severe right-sided hemiparesis and aphasia and a 3-week history of high metabolic syndrome. The pathogenesis of the stenosis is most likely vasculitis rather than atherosclerosis, based on contrast-enhanced high-resolution magnetic resonance imaging showing concentric wall enhancement. We suggest that lipid storage myopathy is secondary to GD, and it is likely mitochondrial dysfunction or immune dysfunction induced by GD responsible for the myopathy and that magnetic resonance spectroscopy (MRS) is capable of establishing the diagnosis of myopathy. Thus, MRS can be used for follow-up evaluations of the myopathy along with the pathology biopsy.

  18. Renal Involvement in Idiopathic Inflammatory Myopathies.

    PubMed

    Cucchiari, David; Angelini, Claudio

    2017-02-01

    Renal involvement in idiopathic inflammatory myopathies is not as uncommon as was previously thought, as it develops in about one fifth of patients. Clinical presentation includes either acute kidney injury or chronic glomerulonephritis. The former usually develops abruptly during acute phases of rhabdomyolysis: in this case, kidney injury is caused by the toxic effects that myoglobinuria has on the kidney tubules, including cast formation and iron-induced oxidative stress and the development of a third space into the injured muscles. The latter instead has an autoimmune nature, a pleomorphic histological picture, and a more indolent course, with the exception of crescentic glomerulonephritis. Accurate diagnosis and management is crucial for these patients, as timely evaluation and treatment can prevent most of the complications. In the setting of rhabdomyolysis-induced acute kidney injury, the necessity of dialysis can be avoided through aggressive hydration and alkalinization, in order to force diuresis and avoid acidosis and hyperkalemia. In immune-mediated glomerulonephritis, renal biopsy is of undoubtedly value in the diagnostic process and can add prognostic and therapeutic information. In these forms, the development of chronic kidney disease can be prevented or at least delayed by the institution or modification of immunosuppressive treatment. Moreover, the use of drugs that inhibit the renin-angiotensin-aldosterone system and some lifestyle modifications, such as smoking cessation, weight loss, and salt restriction have also value in reducing proteinuria and the progression of kidney damage. In this review, we have summarized the currently available evidence and the different case series in an attempt to provide the readers with the most complete and practical notions that are needed to handle these delicate patients.

  19. The change in upper tract urolithiasis composition, surgical treatments and outcomes of para and quadriplegic patients over time.

    PubMed

    Clifton, Marisa M; Gettman, Matthew T; Patterson, David E; Rangel, Laureano; Krambeck, Amy E

    2014-10-01

    Stone disease in patients with spinal cord injury is a source of morbidity and mortality. Previous studies have indicated a decrease in infection-based urolithiasis in recent decades. We aimed to identify changes in stone composition and surgical outcomes in patients with para and quadriplegia over time. A retrospective review of para and quadriplegic patients from 1986 to 2011 who underwent surgical intervention for urolithiasis was performed, identifying 95 patients. The Mantel-Haenszel Chi square test was used to compare change in stone composition over time. The mean patient age was 44.0 years (range 18-88) and treatment included percutaneous nephrolithotomy (PCNL) 40 (42.1 %), ureteroscopy 28 (29.5 %), shock wave lithotripsy (SWL) 26 (27.4 %), and nephrectomy 1 (1 %). Overall stone-free status was found in 47.4 % with 19.0 % requiring a repeat procedure. The median hospital stay for patients undergoing SWL was 2.5 days, ureteroscopy 5 days, and PCNL 6 days. Infection-based stone composition was identified in 23 patients (36.5 %). We evaluated the linear change in percent of each stone component over time and identified increasing components of calcium oxalate dihydrate (p = 0.002) and calcium carbonate (p = 0.009). However, over a period of 25 years, the incidence of infection-based stone did not change (p = 0.57). Para and quadriplegic patients with urolithiasis can be difficult to treat surgically with prolonged hospitalizations, low stone-free status, and often require additional procedures. Despite improvements in antibiotic agents and management of neurogenic bladders, infection-based calculi continue to be a significant source of morbidity to this patient population.

  20. A diagnostic algorithm for metabolic myopathies.

    PubMed

    Berardo, Andres; DiMauro, Salvatore; Hirano, Michio

    2010-03-01

    Metabolic myopathies comprise a clinically and etiologically diverse group of disorders caused by defects in cellular energy metabolism, including the breakdown of carbohydrates and fatty acids to generate adenosine triphosphate, predominantly through mitochondrial oxidative phosphorylation. Accordingly, the three main categories of metabolic myopathies are glycogen storage diseases, fatty acid oxidation defects, and mitochondrial disorders due to respiratory chain impairment. The wide clinical spectrum of metabolic myopathies ranges from severe infantile-onset multisystemic diseases to adult-onset isolated myopathies with exertional cramps. Diagnosing these diverse disorders often is challenging because clinical features such as recurrent myoglobinuria and exercise intolerance are common to all three types of metabolic myopathy. Nevertheless, distinct clinical manifestations are important to recognize as they can guide diagnostic testing and lead to the correct diagnosis. This article briefly reviews general clinical aspects of metabolic myopathies and highlights approaches to diagnosing the relatively more frequent subtypes (Fig. 1). Fig. 1 Clinical algorithm for patients with exercise intolerance in whom a metabolic myopathy is suspected. CK-creatine kinase; COX-cytochrome c oxidase; CPT-carnitine palmitoyl transferase; cyt b-cytochrome b; mtDNA-mitochondrial DNA; nDNA-nuclear DNA; PFK-phosphofructokinase; PGAM-phosphoglycerate mutase; PGK-phosphoglycerate kinase; PPL-myophosphorylase; RRF-ragged red fibers; TFP-trifunctional protein deficiency; VLCAD-very long-chain acyl-coenzyme A dehydrogenase.

  1. Narrative review: statin-related myopathy.

    PubMed

    Joy, Tisha R; Hegele, Robert A

    2009-06-16

    Statin-related myopathy is a clinically important cause of statin intolerance and discontinuation. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare. The mechanisms of statin-related myopathy are unclear. Options for managing statin myopathy include statin switching, particularly to fluvastatin or low-dose rosuvastatin; nondaily dosing regimens; nonstatin alternatives, such as ezetimibe and bile acid-binding resins; and coenzyme Q10 supplementation. Few of these strategies have high-quality evidence supporting them. Because statin-related myopathy will probably become more common with greater numbers of persons starting high-dose statin therapy and the increasing stringency of low-density lipoprotein cholesterol level targets, research to better identify patients at risk for statin myopathy and to evaluate management strategies for statin-related myopathy is warranted.

  2. Dementia in a child with myotubular myopathy.

    PubMed

    McCrea, Heather J; Kretz, Christine; Laporte, Jocelyn; Ment, Laura R

    2009-06-01

    An 8-year old boy with genetically confirmed X-linked myotubular myopathy developed progressively worsening dementia and subclinical seizures at age 5-6 years. Previously, seizures or dementia have been noted in only a small number of myotubular myopathy patients, and only in association with significant metabolic disturbances. This patient had no evidence of hypoxemia or other metabolic disturbance. The present case suggests that the clinical spectrum of X-linked myotubular myopathy is broader than previously considered and may include mutation-dependent central nervous system disease.

  3. Mitochondrial DNA polymorphism in mitochondrial myopathy.

    PubMed

    Holt, I J; Harding, A E; Morgan-Hughes, J A

    1988-05-01

    In order to test the hypothesis that mitochondrial myopathy may be caused by mutation of the mitochondrial (mt) genome, restriction fragment length polymorphism in leucocyte mt DNA has been studied in 38 patients with mitochondrial myopathy, 44 of their unaffected matrilineal relatives, and 35 normal control subjects. Previously unreported mt DNA polymorphisms were identified in both patients and controls. No differences in restriction fragment patterns were observed between affected and unaffected individuals in the same maternal line, and there was no evidence of major deletion of mt DNA in patients. This study provides no positive evidence of mitochondrial inheritance in mitochondrial myopathy, but this has not been excluded.

  4. Nemaline myopathy with dilated cardiomyopathy in childhood.

    PubMed

    Gatayama, Ryohei; Ueno, Kentaro; Nakamura, Hideaki; Yanagi, Sadamitsu; Ueda, Hideaki; Yamagishi, Hiroyuki; Yasui, Seiyo

    2013-06-01

    We present a case of a 9-year-old boy with nemaline myopathy and dilated cardiomyopathy. The combination of nemaline myopathy and cardiomyopathy is rare, and this is the first reported case of dilated cardiomyopathy associated with childhood-onset nemaline myopathy. A novel mutation, p.W358C, in ACTA1 was detected in this patient. An unusual feature of this case was that the patient's cardiac failure developed during early childhood with no delay of gross motor milestones. The use of a β-blocker did not improve his clinical course, and the patient died 6 months after diagnosis of dilated cardiomyopathy. Congenital nonprogressive nemaline myopathy is not necessarily a benign disorder: deterioration can occur early in the course of dilated cardiomyopathy with neuromuscular disease, and careful clinical evaluation is therefore necessary.

  5. Genetics Home Reference: Laing distal myopathy

    MedlinePlus

    ... Laing distal myopathy is a condition that affects skeletal muscles, which are muscles that the body uses for ... in heart (cardiac) muscle and in type I skeletal muscle fibers. Type I fibers, which are also known ...

  6. Pulmonary complications of inflammatory myopathy.

    PubMed

    Ascherman, Dana P

    2002-10-01

    Pulmonary manifestations contribute significantly to the morbidity and mortality of the idiopathic inflammatory myopathies, ranging from intrinsic lung disease to secondary complications that include aspiration pneumonia, opportunistic infection, congestive heart failure, and hypoventilation. Newer classification schemes for interstitial lung disease have permitted closer correlation between histologic subtype and clinical outcome, while diagnostic techniques such as bronchoalveolar lavage have begun to define the cellular elements responsible for immune-mediated pulmonary dysfunction. Investigators have identified several serum markers correlating with inflammatory disease activity in the lung that should enhance noninvasive monitoring of therapeutic responses to newer regimens involving agents such as cyclosporine and tacrolimus. Taken together, these advances have contributed to better understanding of the immunopathogenesis of myositis-associated interstitial lung disease that should ultimately translate into more effective treatment.

  7. Mitochondrial dysfunction in myofibrillar myopathy.

    PubMed

    Vincent, Amy E; Grady, John P; Rocha, Mariana C; Alston, Charlotte L; Rygiel, Karolina A; Barresi, Rita; Taylor, Robert W; Turnbull, Doug M

    2016-10-01

    Myofibrillar myopathies (MFM) are characterised by focal myofibrillar destruction and accumulation of myofibrillar elements as protein aggregates. They are caused by mutations in the DES, MYOT, CRYAB, FLNC, BAG3, DNAJB6 and ZASP genes as well as other as yet unidentified genes. Previous studies have reported changes in mitochondrial morphology and cellular positioning, as well as clonally-expanded, large-scale mitochondrial DNA (mtDNA) deletions and focal respiratory chain deficiency in muscle of MFM patients. Here we examine skeletal muscle from patients with desmin (n = 6), ZASP (n = 1) and myotilin (n = 2) mutations and MFM protein aggregates, to understand how mitochondrial dysfunction may contribute to the underlying mechanisms causing disease pathology. We have used a validated quantitative immunofluorescent assay to study respiratory chain protein levels, together with oxidative enzyme histochemistry and single cell mitochondrial DNA analysis, to examine mitochondrial changes. Results demonstrate a small number of clonally-expanded mitochondrial DNA deletions, which we conclude are due to both ageing and disease pathology. Further to this we report higher levels of respiratory chain complex I and IV deficiency compared to age matched controls, although overall levels of respiratory deficient muscle fibres in patient biopsies are low. More strikingly, a significantly higher percentage of myofibrillar myopathy patient muscle fibres have a low mitochondrial mass compared to controls. We concluded this is mechanistically unrelated to desmin and myotilin protein aggregates; however, correlation between mitochondrial mass and muscle fibre area is found. We suggest this may be due to reduced mitochondrial biogenesis in combination with muscle fibre hypertrophy.

  8. Myopathy

    MedlinePlus

    ... Association National Office - 222 S. Riverside Plaza Suite 1500 Chicago IL Chicago, IL 60606 mda@mdausa.org http://www.mda. ... Association National Office - 222 S. Riverside Plaza Suite 1500 Chicago IL Chicago, IL 60606 mda@mdausa.org http:// ...

  9. Myopathies

    MedlinePlus

    ... to an attack, while potassium intake can restore serum potassium levels and stem an oncoming attack. Ask your MDA clinic director for specific recommendations about diet, exercise and medications. Andersen-Tawil syndrome Causes: This disease is caused by defects in a potassium channel ...

  10. Statin-induced myopathy in the rat: relationship between systemic exposure, muscle exposure and myopathy.

    PubMed

    Sidaway, J; Wang, Y; Marsden, A M; Orton, T C; Westwood, F R; Azuma, C T; Scott, R C

    2009-01-01

    Rare instances of myopathy are associated with all statins, but cerivastatin was withdrawn from clinical use due to a greater incidence of myopathy. The mechanism of statin-induced myopathy with respect to tissue disposition was investigated by measuring the systemic, hepatic, and skeletal muscle exposure of cerivastatin, rosuvastatin, and simvastatin in rats before and after muscle damage. The development of myopathy was not associated with the accumulation of statins in skeletal muscle. For each statin exposure was equivalent in muscles irrespective of their fibre-type sensitivity to myopathy. The low amount of each statin in skeletal muscle relative to the liver does not support a significant role for transporters in the disposition of statins in skeletal muscle. Finally, the concentration of cerivastatin necessary to cause necrosis in skeletal muscle was considerably lower than rosuvastatin or simvastatin, supporting the concept cerivastatin is intrinsically more myotoxic than other statins.

  11. Myopathy in hypophosphataemic osteomalacia presenting in adult life.

    PubMed Central

    Schott, G D; Wills, M R

    1975-01-01

    Three cases of hypophosphataemic osteomalacia presenting in adult life, in which a myopathy was a prominent presenting feature, are described. In one, a nasopharyngeal haemangioma was also present. Possible mechanisms underlying the myopathy are discussed briefly. PMID:1151410

  12. Does reduced creatine synthesis protect against statin myopathy?

    PubMed

    Ballard, Kevin D; Thompson, Paul D

    2013-12-03

    Statins, widely used to lower cholesterol levels, cause myopathy in some patients. Mangravite et al. (2013) show that a single nucleotide polymorphism decreasing expression of glycine amidinotransferase (GATM), the enzyme regulating creatine biosynthesis, is associated with reduced statin myopathy. Whether reduced creatine production protects against statin myopathy remains to be determined.

  13. Dropped head presentation of mitochondrial myopathy.

    PubMed

    Rahim, Fazal; Gupta, Devanshi; Bertorini, Tulio E; Ledoux, Mark S

    2003-12-01

    Dropped head secondary to weakness of the neck extensors has been reported in a wide assortment of neuromuscular disorders. Infrequently, dropped head can be the first sign of disease. We describe two patients with dropped head as the presenting manifestation of mitochondrial myopathy. In both patients, serum lactate was elevated and muscle biopsy showed mitochondrial proliferation. Mitochondrial myopathy should be considered in the differential diagnosis of dropped head syndrome, particularly when other, more common causes such as myasthenia gravis, polymyositis, and amyotrophic lateral sclerosis have been excluded by appropriate laboratory and electrophysiological studies.

  14. A TPM3 mutation causing cap myopathy.

    PubMed

    De Paula, Andre Maues; Franques, Jerome; Fernandez, Carla; Monnier, Nicole; Lunardi, Joel; Pellissier, Jean-François; Figarella-Branger, Dominique; Pouget, Jean

    2009-10-01

    Cap disease is a rare congenital myopathy associated with skeletal malformations and respiratory involvement. Abnormally arranged myofibrils taking the appearance of a "cap" are the morphological hallmark of this entity. We report a case of cap disease concerning a 42-year-old man, without any family history and presenting a p.Arg168His mutation on the TPM3 gene. His first biopsy at 7years had only shown selective type I hypotrophy. Mutations of TPM3 gene have been found in nemaline myopathy, congenital fiber type disproportion, but never before in cap disease.

  15. Clinicopathological Features of Telbivudine-Associated Myopathy

    PubMed Central

    2016-01-01

    Telbivudine, a thymidine nucleoside analog, is a common therapeutic option for chronic hepatitis B infection. While raised serum creatine kinase is common, myopathy associated with telbivudine is rare. Reports on its myopathological features are few and immunohistochemical analyses of inflammatory cell infiltrates have not been previously described. We describe the clinical, myopathological and immunohistochemical features of four patients who developed myopathy after telbivudine therapy for chronic hepatitis B infection. All four patients presented with progressive proximal muscle weakness, elevation of serum creatine kinase and myopathic changes on electromyography. Muscle biopsies showed myofiber degeneration/necrosis, regeneration, and fibers with cytoplasmic bodies and cytochrome c oxidase deficiency. There was minimal inflammation associated with strong sarcolemmal overexpression of class I major histocompatibility complex (MHC class I). Upon withdrawal of telbivudine, muscle weakness improved in all patients and eventually completely resolved in three. In our series, telbivudine-associated myopathy is characterized by necrotizing myopathy which improved on drug withdrawal. Although the occasional loss of cytochrome c oxidase is consistent with mitochondrial toxicity, the overexpression of MHC class I in all patients could suggest an underlying immune-mediated mechanism which may warrant further investigation. PMID:27611456

  16. Atypical Miyoshi distal myopathy: A case report

    PubMed Central

    Wang, Meiling; Guo, Yujie; Fu, Yong; Jia, Rui; Chen, Gang

    2016-01-01

    Five distinct predominant distal myopathies have been identified with discrete clinical and genetic patterns. Miyoshi myopathy (MM; early adult-onset, type 2) is a subtype of dysferlinopathy. Furthermore, MM is the most common form of autosomal recessive distal myopathy. MM is typically characterized by muscular weakness, initially affecting the gastrocnemius or soleus muscle from the late teens or early adulthood. The present study reports a case of MM that was confirmed by pathological and immunohistochemical methods, in addition to a review of the relevant literature. A 37-year-old male patient presented with muscular weakness in the left foot. This clinical manifestation was not typical of MM, and the patient was initially diagnosed with inflammatory myopathy. He was treated with dexamethasone at a dose of 10 mg for 5 days followed by gradual tapering, following which the symptoms were alleviated; however, the pathology, immunohistochemistry and electromyography eventually confirmed the diagnosis of MM. The treatment was then terminated and the patient was discharged. The present study further supports the underlying heterogeneity in atypical MM-like phenotypes. Dysferlin protein deficiency can be identified by pathological examination. The pathology of dysferlinopathy is characterized by changes of muscular dystrophy. Inflammatory cellular infiltration is a relatively common finding in the muscle biopsies from numerous patients with dysferlinopathy. Therefore, the detection of dysferlin deficiency or marked reduction on the sarcolemma using immunohistochemical staining is important for the diagnosis of dysferlinopathy. PMID:27882118

  17. Genetics Home Reference: intranuclear rod myopathy

    MedlinePlus

    ... fibers and are important for muscle contraction. Attachment (binding) and release of the overlapping thick and thin filaments allows them to move relative to each other so that the muscles can contract. ACTA1 gene mutations that cause intranuclear rod myopathy ...

  18. Genetics Home Reference: actin-accumulation myopathy

    MedlinePlus

    ... fibers and are important for muscle contraction. Attachment (binding) and release of the overlapping thick and thin filaments allows them to move relative to each other so that the muscles can contract. ACTA1 gene mutations that cause actin-accumulation myopathy ...

  19. Eosinophils in hereditary and inflammatory myopathies.

    PubMed

    Schröder, Thomas; Fuchss, Johann; Schneider, Ilka; Stoltenburg-Didinger, Gisela; Hanisch, Frank

    2013-12-01

    It is not known whether eosinophilic myositis is a specific histopathological feature of limb girdle muscular dystrophy 2A (LGMD2A). Number and location of eosinophils in skeletal muscle biopsies (n=100) was analysed by Giemsa and modified hematoxylin/eosin staining in patients with genetically confirmed myopathies (LGMD2A, LGMD2B, LGMD2L, facioscapulohumeral muscular dystrophy, dystrophinopathy), histologically confirmed idiopathic inflammatory myopathies (sporadic inclusion body myositis (sIBM), dermatomyositis (DM), polymyositis), amyotrophic lateral sclerosis (neurogenic control), and normal controls. The number of eosinophils/mm² was significantly higher in LGMD2A, PM, DM, and sIBM compared to controls but not significantly higher than other myopathies. A large overlap in the number of eosinophils/mm2 between all groups was seen. In all disease groups eosinophils were mainly found endomysially (46- 88%) and intra- and perivascularly (4-37%). There was no correlation between the numbers of eosinophils/mm² and (i) age at biopsy and (ii) the duration of the disease. The extent of myopathic, fibrotic, and inflammatory changes did not differ in samples with high and low eosinophil count. Eosinophils seem to represent an unspecific histological finding in hereditary and inflammatory myopathies, but also amyotrophic lateral sclerosis.

  20. Genetics Home Reference: tubular aggregate myopathy

    MedlinePlus

    ... Krahn M, Eymard B, Bartoli M, Laporte J. Constitutive activation of the calcium sensor STIM1 causes tubular- ... ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca²⁺ channels. Hum Mol ...

  1. Multidisciplinary Approach to the Management of Myopathies

    PubMed Central

    M. King, Wendy; Kissel, John T.

    2013-01-01

    Purpose of Review Aside from some inflammatory myopathies and very few genetic disorders, there are no therapies that make most patients with myopathies stronger. Consequently, the management of these patients can be frustrating for patients and their families as well as the clinicians taking care of them. Treatment of these patients must involve a comprehensive approach focused on limiting the secondary effects of skeletal muscle weakness, managing comorbidities associated with specific diseases, and, most importantly, optimizing patients’ functional abilities and quality of life in terms of their ability to accomplish activities of daily living. While the approach to each patient differs depending on their disease, certain common themes can be addressed in each patient. This review highlights an approach centered on four conceptual themes (“the Four S’s”): Strength therapies, Supportive care, Symptomatic therapies, and pSychological support. Recent Findings Although relatively few well-designed studies have been done that highlight conservative management of patients with various myopathies, an emerging literature helps guide the clinician in certain key areas, especially in relation to cardiac and pulmonary management of these patients. Summary While disease-altering therapies have proven elusive for many muscle diseases, a multimodal approach to the conservative and supportive care of these patients can markedly improve their quality of life. Pharmacologic treatment options for specific myopathies will not be addressed in this article but are covered elsewhere in this issue of CONTINUUM. PMID:24305452

  2. Severe congenital RYR1-associated myopathy

    PubMed Central

    Bharucha-Goebel, Diana Xerxes; Santi, Mariarita; Medne, Līvija; Zukosky, Kristin; Dastgir, Jahannaz; Shieh, Perry B.; Winder, Thomas; Tennekoon, Gihan; Finkel, Richard S.; Dowling, James J.; Monnier, Nicole

    2013-01-01

    Objective: To report a series of 11 patients on the severe end of the spectrum of ryanodine receptor 1 (RYR1) gene–related myopathy, in order to expand the clinical, histologic, and genetic heterogeneity associated with this group of patients. Methods: Eleven patients evaluated in the neonatal period with severe neonatal-onset RYR1-associated myopathy confirmed by genetic testing were ascertained. Clinical features, molecular testing results, muscle imaging, and muscle histology are reviewed. Results: Clinical features associated with the severe neonatal presentation of RYR1-associated myopathy included decreased fetal movement, hypotonia, poor feeding, respiratory involvement, arthrogryposis, and ophthalmoplegia in 3 patients, and femur fractures or hip dislocation at birth. Four patients had dominant RYR1 mutations, and 7 had recessive RYR1 mutations. One patient had a cleft palate, and another a congenital rigid spine phenotype—findings not previously described in the literature in patients with early-onset RYR1 mutations. Six patients who underwent muscle ultrasound showed relative sparing of the rectus femoris muscle. Histologically, all patients with dominant mutations had classic central cores on muscle biopsy. Patients with recessive mutations showed great histologic heterogeneity, including fibrosis, variation in fiber size, skewed fiber typing, very small fibers, and nuclear internalization with or without ill-defined cores. Conclusions: This series confirms and expands the clinical and histologic variability associated with severe congenital RYR1-associated myopathy. Both dominant and recessive mutations of the RYR1 gene can result in a severe neonatal-onset phenotype, but more clinical and histologic heterogeneity has been seen in those with recessive RYR1 gene mutations. Central cores are not obligatory histologic features in recessive RYR1 mutations. Sparing of the rectus femoris muscle on imaging should prompt evaluation for RYR1-associated

  3. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies.

    PubMed

    Mohassel, Payam; Mammen, Andrew L

    2013-10-01

    Statins are among the most commonly prescribed medications that significantly reduce cardiovascular risk in selected individuals. However, these drugs can also be associated with muscle symptoms ranging from mild myalgias to severe rhabdomyolysis. Although statin myotoxicity is usually self-limited, in some instances statin-exposed subjects can develop an autoimmune myopathy typically characterized by progressive weakness, muscle enzyme elevations, a necrotizing myopathy on muscle biopsy, and autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the pharmacologic target of statins. These antibodies are also found in some autoimmune myopathy patients without statin exposure. Importantly, anti-HMGCR antibodies are not found in the vast majority of statin-exposed subjects without autoimmune myopathy, including those with self-limited statin intolerance. Thus, testing for these antibodies may help differentiate those with self-limited statin myopathy who recover after statin discontinuation from those with a progressive statin-associated autoimmune myopathy who typically require immunosuppressive therapy.

  4. The Clinical and Histological Spectrum of Idiopathic Inflammatory Myopathies.

    PubMed

    Cavazzana, Ilaria; Fredi, Micaela; Selmi, Carlo; Tincani, Angela; Franceschini, Franco

    2017-02-01

    Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of myositis, characterised by chronic muscle weakness, cutaneous features, different extra-muscular manifestations and circulating autoantibodies. IIMs included classical polymyositis (PM), dermatomyositis (DM) and other different types of myositis with a wide range of muscle involvement. A complete autoantibody profile and a muscle biopsy are mandatory to correctly diagnose different clinical entities and to define their different prognosis. Bohan and Peter's criteria included five items to diagnose adult onset PM and DM. The sensitivity was 74-100 %, while the specificity is low, due to a poor ability to differentiate PM from neuromuscular diseases. Other criteria included a more accurate histological definition of PM, DM or amyopathic DM, obtaining a higher specificity. Autoantibodies' association, interstitial lung disease and clinical cardiac involvement represent the main items that could define the prognosis of these patients. On the other hand, inclusion body myositis is a different myopathy characterised by a peculiar muscle mass involvement, muscle atrophy and progressive loss of function, due to complete failure to all immunosuppressive drugs used. Treatment of IIMs is based on corticosteroids (CS), which show rapid clinical response and functional improvement. Different immunosuppressant drugs are given to obtain a better control of the disease during CS tapering dose. No controlled double blind trials demonstrated the superiority of one immunesuppressant on another. The occurrence of interstitial lung involvement requires the immediate introduction of immunosuppressants in addiction to CS. Severe dysphagia seems to improve with intravenous immunoglobulins (Ig). Physical therapy could be started after the acute phase of diseases and seems to have a beneficial role in muscle strength recovery.

  5. GNE Myopathy: Two Clusters with History and Several Founder Mutations

    PubMed Central

    Argov, Zohar; Mitrani Rosenbaum, Stella

    2015-01-01

    Abstract GNE myopathy (previous names: HIBM, DMRV, IBM2) is a unique distal myopathy with quadriceps sparing. This recessively inherited myopathy has been diagnosed in various regions of the world with more than 150 disease-causing mutations already identified. Several of those are proven or suspected to be founder mutations in certain regional clusters and are described in this review. The review also discusses some historical aspects that might be relevant to the mutational distribution. PMID:27858758

  6. Statin-induced myopathy in a patient with previous poliomyelitis.

    PubMed

    Martikainen, Mika H; Gardberg, Maria; Kohonen, Ia; Lähdesmäki, Janne

    2013-11-01

    This report describes a patient with a history of poliomyelitis who developed new, progressive symptoms of muscle fatigue and weakness, suggestive of postpoliomyelitis syndrome. However, comprehensive investigations led to the diagnosis of statin-induced myopathy as the cause of the patient's symptoms. This case highlights the possibility of statin-induced myopathy in patients with a history of poliomyelitis and the differential diagnosis between postpoliomyelitis syndrome and statin-induced myopathy in these patients. The possibility of statin-induced myopathy should be considered when patients with previous poliomyelitis who take statin medication develop symptoms suggestive of postpoliomyelitis syndrome.

  7. Glucocorticoid-induced apoptosis and cellular mechanisms of myopathy.

    PubMed

    Dirks-Naylor, Amie J; Griffiths, Carrie L

    2009-10-01

    Glucocorticoid-induced myopathy is a common side effect of chronic glucocorticoid therapy. Several mechanisms are currently being examined as ways in which glucocorticoid-induced myopathy occurs. These include apoptotic signaling through mitochondrial-mediated and Fas-mediated apoptosis, the role of the proteosome, the suppression of the IGF-1 signaling, and the role of ceramide in glucocorticoid-induced apoptosis and myopathy. It is difficult to differentiate which mechanism may be the initiating event responsible for the induction of apoptosis; however, all of the mechanisms play a vital role in glucocorticoid-induced myopathy.

  8. [Biologic therapy in idiopathic inflammatory myopathy].

    PubMed

    Selva-O'Callaghan, Albert; Ramos Casals, Manel; Grau Junyent, Josep M

    2014-09-15

    The aim of this article is to study the evidence-based knowledge related to the use of biological therapies in patients diagnosed with idiopathic inflammatory myopathy (dermatomyositis, polymyositis and inclusion body myositis). In this review the leading published studies related to the use of biological therapy in patients with myositis are analysed; mainly those with high methodological standards, that means randomized and controlled studies. Methodological drawbacks due to the rarity and heterogeneity of these complex diseases are also addressed. Up to now is not possible to ascertain the biologics as a recommended therapy in patients with myositis, at least based in the current evidence-based knowledge, although it can not be neglected as a therapeutic option in some clinical situations, taking into account the scarce of effective treatments in those patients, especially in refractory myositis. Future studies probably will help to better define the role of biological therapies in patients with idiopathic inflammatory myopathy.

  9. Presumed isotretinoin-induced extraocular myopathy

    PubMed Central

    Alam, Md. Shahid; Agarwal, Swati

    2016-01-01

    Isotretinoin a synthetic analogue of vitamin A is primarily used for cystic acne not responding to conventional treatment. Several ocular side effects including blurring of vision, decreased dark adaptation, corneal opacities and meibomian gland atrophy have been reported with prolonged use of isotretinoin. There have been reports of muscular damage caused by isotretinoin. Extra ocular myopathy as an adverse effect of long term used of isotretinoin has never been mentioned in literature. We report a case of a young male who presented to us with complaints of diplopia after using isotretinoin for a prolonged period. He was diagnosed as a case of presumed isotretinoin extraocular myopathy after imaging and other blood investigations. PMID:28163542

  10. Intranuclear rods myopathy with autonomic dysfunction.

    PubMed

    Chou, Po-Ching; Liang, Wen-Chen; Nonaka, Ikuya; Mitsuhashi, Satomi; Nishino, Ichizo; Jong, Yuh-Jyh

    2013-08-01

    Intranuclear rods myopathy (IRM), a variant of nemaline myopathy (NM), is characterized by rod structure in the myonuclei. Patients with IRM present with similar symptoms to those of severe infantile-type NM but have worse outcome. Several extramuscular manifestations have been reported in NM but no dysautonomia. We herein report a 2-year-old girl with IRM and a heterozygous mutation, c.430C>T (p.L144F) in ACTA1. During the infancy, the patient showed severe diaphoresis and facial flushing. Arrhythmia and hypertension with the precipitating factors of feeding, defecation, and urination were observed. Sympathetic antagonist was prescribed and showed some effectiveness. Our report may widen the clinical spectrum of IRM. It also reminds clinicians that autonomic dysfunction may occur in patients with IRM or other actinopathies and appropriate treatment may be necessary.

  11. Muscle biopsy findings in inflammatory myopathies.

    PubMed

    Dalakas, Marinos C

    2002-11-01

    The inflammatory myopathies encompass a heterogeneous group of acquired muscle diseases characterized clinically, by muscle weakness, and histologically, by inflammatory infiltrates within the skeletal muscles. The group of these myopathies comprise three major and discrete subsets: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). Each subset retains its characteristic clinical, immunopathologic, and morphologic features regardless of whether it occurs separately or in connection with other systemic diseases. Although the diagnosis of these disorders is based on the combination of clinical examination, electromyographic data, serum muscle enzyme levels, various autoantibodies, and the muscle biopsy findings, the muscle biopsy offers the most definitive diagnostic information in the majority of the cases. This article summarizes the main histologic features that characterize PM, DM, or IBM and emphasizes the main pitfalls associated with interpretation of the biopsies.

  12. [Statin myopathy--rarity or reality?].

    PubMed

    Pella, D

    2010-09-01

    Statins are the most effective drugs for reducing LDL-cholesterol and have strong evidence based medicine documented by significant reduction of cardiovascular events in wide variety of patients. Despite this fact, they are still underused in common clinical practice. Many physicians have expressed concern about potential adverse effects, particularly severe muscle toxicity, which is an impediment to appropriate statin use. The clinical symptoms of statin myopathy include myalgia or muscle weakness, tiredness, cramps and/or creatinkinase activity increases (CK). Because hypercholesterolaemia is usually asymptomatic, any unwanted effect of drug used for its management can undermine adherence. Therefore it is very important to evaluate myopathy magnitude, prompt and rational individual management, and if applicable, restart of lipid-lowering therapy as soon as possible with regard to its type, dose and concomitant treatment.

  13. Autoimmune Myopathies: Where Do We Stand?

    PubMed Central

    Simon, Jean-Philippe; Marie, Isabelle; Jouen, Fabienne; Boyer, Olivier; Martinet, Jérémie

    2016-01-01

    Autoimmune diseases (AIDs) as a whole represent a major health concern and remain a medical and scientific challenge. Some of them, such as multiple sclerosis or type 1 diabetes, have been actively investigated for many decades. Autoimmune myopathies (AIMs), also referred to as idiopathic inflammatory myopathies or myositis, represent a group of very severe AID for which we have a more limited pathophysiological knowledge. AIM encompass a group of, individually rare but collectively not so uncommon, diseases characterized by symmetrical proximal muscle weakness, increased serum muscle enzymes such as creatine kinase, myopathic changes on electromyography, and several typical histological patterns on muscle biopsy, including the presence of inflammatory cell infiltrates in muscle tissue. Importantly, some AIMs are strongly related to cancer. Here, we review the current knowledge on the most prevalent forms of AIM and, notably, the diagnostic contribution of autoantibodies. PMID:27379096

  14. MITOCHONDRIAL MYOPATHY: A NEW THERAPEUTIC APPROACH.

    PubMed

    Hagiu, B A; Mungiu, C

    2016-01-01

    Restoration of deoxyribonucleic acid in mitochondrial myopathies may occur after a mechanical or chemical injury of striated muscle or by endurance training. Therapies with enzymes, gene therapies, or treatments with substances that stimulate mitochondrial biogenesis are used at the moment. Genesis of mitochondria may also come from myonuclei by releasing the nuclear respiratory factor-1/2 during muscle contractions. Multiplying of myonuclei depends on muscle satellite cell activation. Since the electromyostimulation increase the number of circulating stem cells that may participate in the genesis of new muscle fibers (adding to the deposit of specific stem cells of the muscle), and intermittent hypoxia stimulates the proliferation of muscle satellite cells, we propose to combine the two processes for the treatment of mitochondrial myopathies. Respective combined therapy may be useful for restoring damaged mitochondria by drug side effects.

  15. Identifying statin-associated autoimmune necrotizing myopathy.

    PubMed

    Albayda, Jemima; Christopher-Stine, Lisa

    2014-12-01

    Statins up-regulate expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis and the major target of autoantibodies in statin-associated immune-mediated necrotizing myopathy. As muscle cells regenerate, they express high levels of HMGCR, which may sustain the immune response even after statin therapy is stopped. Awareness of this entity will help physicians who prescribe statins to take action to limit the associated morbidity.

  16. Statin-induced apoptosis and skeletal myopathy.

    PubMed

    Dirks, Amie J; Jones, Kimberly M

    2006-12-01

    Over 100 million prescriptions were filled for statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) in 2004. Statins were originally developed to lower plasma cholesterol in patients with hypercholesterolemia and are the most effective drugs on the market in doing so. Because of the discovered pleiotropic effects of statins, the use has expanded to the treatment of many other conditions, including ventricular arrythmias, idiopathic dilated cardiomyopathy, cancer, osteoporosis, and diabetes. The elderly population is growing. Therefore, it is estimated that the number of statin users will also increase. Fortunately, the use of statins is relatively safe with few side effects. Myopathy is the most common side effect with symptoms ranging from fatigue, weakness, and pain to symptoms associated with rhabdomyolysis which is a life-threatening condition. The development of statin-induced rhabdomyolysis is rare occurring in approximately 0.1% of patients; however, the occurrence of less severe symptoms is underreported and may be 1-5% or more. Physical exercise appears to increase the likelihood for the development of myopathy in patients taking statins. It is thought that as many as 25% of statin users who exercise may experience muscle fatigue, weakness, aches, and cramping due to statin therapy and potentially dismissed by the patient and physician. The mechanisms causing statin-induced myopathy have not been elucidated; however, research efforts suggest that apoptosis of myofibers may contribute. The mitochondrion is considered a regulatory center of apoptosis, and therefore its role in the induction of apoptosis will be discussed as well as the mechanism of statin-induced apoptosis and myopathy.

  17. Immune Mediated Necrotizing Myopathy: a Cause of Isolated Myopathy of Neck Extensor Muscle

    PubMed Central

    Sehgal, Rahul; Medina-Flores, Rafael; Yachoui, Ralph; Kenney, Charles V

    2016-01-01

    Immune mediated necrotizing myopathy (IMNM) is a unique form of myositis that is characterized by distinct muscle biopsy features including abundant myofiber necrosis, degeneration, and regeneration with only minimal, if any, inflammation on muscle biopsy. IMNM is clinically similar to idiopathic inflammatory myopathy (IIM); hence, muscle biopsy is essential to diagnose IMNM. Herein we describe a case of neck extensor weakness due to necrotizing myopathy. Isolated weakness of the neck extensor muscles is uncommon in IIM and IMNM. This case describes the diagnostic work-up, treatments utilized, and 2 year follow-up course without involvement of other muscle groups and without progression of neck extensor muscle weakness. Advanced imaging using magnetic resonance imaging (MRI) facilitated the diagnosis by identifying the affected muscles and site for muscle biopsy. PMID:27573534

  18. Muscle fibrillin deficiency in Marfan's syndrome myopathy

    PubMed Central

    Behan, W; Longman, C; Petty, R; Comeglio, P; Child, A; Boxer, M; Foskett, P; Harriman, D

    2003-01-01

    Objective: To report a family with Marfan's syndrome in whom a myopathy was associated with respiratory failure; muscle biopsies from affected individuals were examined to determine whether there were abnormalities in fibrillin. Methods: 21 family members underwent detailed clinical examination, including neurological and pulmonary assessment. Muscle biopsies in the most severely affected cases were immunostained using monoclonal antibodies to specific fibrillin components. Genomic DNA from all 21 members was analysed for mutations in the fibrillin gene, FBN1, on 15q21. Results: 13 individuals had a C4621T base change in exon 37 of the FBN1 gene, which in four cases segregated with muscle weakness or evidence of respiratory muscle dysfunction or both. Their muscle biopsies revealed an abnormality in fibrillin immunoreactivity. Conclusions: Abnormalities in fibrillin can be detected in muscle biopsies from patients with Marfan's syndrome who have myopathy. This pedigree, with a point mutation in FBN1, also draws attention to the potential for respiratory failure associated with myopathy. PMID:12700307

  19. The Spectrum of Renal Involvement in Patients With Inflammatory Myopathies

    PubMed Central

    Couvrat-Desvergnes, Grégoire; Masseau, Agathe; Benveniste, Olivier; Bruel, Alexandra; Hervier, Baptiste; Mussini, Jean-Marie; Buob, David; Hachulla, Eric; Rémy, Philippe; Azar, Raymond; Namara, Evelyne Mac; MacGregor, Brigitte; Daniel, Laurent; Lacraz, Adeline; Broucker, Thomas De; Rouvier, Philippe; Carli, Philippe; Laville, Maurice; Dantan, Etienne; Hamidou, Mohamed; Moreau, Anne

    2014-01-01

    Abstract Data regarding the incidence and outcome of renal involvement in patients with inflammatory myopathies (IM) remain scarce. We assessed the incidence and causes of acute kidney injury (AKI) and chronic kidney disease (CKD) in 150 patients with dermatomyositis, polymyositis, and antisynthetase syndrome followed in 3 French referral centers. Renal involvement occurred in 35 (23.3%) patients: AKI in 16 (10.7%), and CKD in 31 (20.7%) patients. The main cause of AKI was drug or myoglobinuria-induced acute tubular necrosis. Male sex, cardiovascular risk factors, cardiac involvement, and initial proteinuria >0.3 g/d were associated with the occurrence of AKI. The outcome of patients with AKI was poor: 13 (81%) progressed to CKD and 2 (12.5%) reached end-stage renal disease. In multivariate survival analysis, age at IM onset, male sex, a history of cardiovascular events, and a previous episode of AKI were associated with the risk of CKD. We also identified 14 IM patients who underwent a kidney biopsy in 10 nephrology centers. Renal pathology disclosed a wide range of renal disorders, mainly immune-complex glomerulonephritis. We identified in 5 patients a peculiar pattern of severe acute renal vascular damage consisting mainly of edematous thickening of the intima of arterioles. We found that AKI and CKD are frequent in patients with IM. Prevention of AKI is crucial in these patients, as AKI is a major contributor to their relatively high risk of CKD. A peculiar pattern of acute vascular damage is part of the spectrum of renal diseases associated with IM. PMID:24378741

  20. The spectrum of renal involvement in patients with inflammatory myopathies.

    PubMed

    Couvrat-Desvergnes, Grégoire; Masseau, Agathe; Benveniste, Olivier; Bruel, Alexandra; Hervier, Baptiste; Mussini, Jean-Marie; Buob, David; Hachulla, Eric; Rémy, Philippe; Azar, Raymond; Mac Namara, Evelyne; MacGregor, Brigitte; Daniel, Laurent; Lacraz, Adeline; De Broucker, Thomas; Rouvier, Philippe; Carli, Philippe; Laville, Maurice; Dantan, Etienne; Hamidou, Mohamed; Moreau, Anne; Fakhouri, Fadi

    2014-01-01

    Data regarding the incidence and outcome of renal involvement in patients with inflammatory myopathies (IM) remain scarce. We assessed the incidence and causes of acute kidney injury (AKI) and chronic kidney disease (CKD) in 150 patients with dermatomyositis, polymyositis, and antisynthetase syndrome followed in 3 French referral centers. Renal involvement occurred in 35 (23.3%) patients: AKI in 16 (10.7%), and CKD in 31 (20.7%) patients. The main cause of AKI was drug or myoglobinuria-induced acute tubular necrosis. Male sex, cardiovascular risk factors, cardiac involvement, and initial proteinuria >0.3 g/d were associated with the occurrence of AKI. The outcome of patients with AKI was poor: 13 (81%) progressed to CKD and 2 (12.5%) reached end-stage renal disease. In multivariate survival analysis, age at IM onset, male sex, a history of cardiovascular events, and a previous episode of AKI were associated with the risk of CKD. We also identified 14 IM patients who underwent a kidney biopsy in 10 nephrology centers. Renal pathology disclosed a wide range of renal disorders, mainly immune-complex glomerulonephritis. We identified in 5 patients a peculiar pattern of severe acute renal vascular damage consisting mainly of edematous thickening of the intima of arterioles. We found that AKI and CKD are frequent in patients with IM. Prevention of AKI is crucial in these patients, as AKI is a major contributor to their relatively high risk of CKD. A peculiar pattern of acute vascular damage is part of the spectrum of renal diseases associated with IM.

  1. The Impact of Exercise on Statin-Associated Skeletal Muscle Myopathy

    PubMed Central

    Chung, Hae R.; Vakil, Mayand; Munroe, Michael; Parikh, Alay; Meador, Benjamin M.; Wu, Pei T.; Jeong, Jin H.; Woods, Jeffrey A.; Wilund, Kenneth R.; Boppart, Marni D.

    2016-01-01

    HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p<0.05). Cholesterol, grip strength, and maximal isometric force were significantly lower in all groups following statin treatment (statin main effect, p<0.05). Mitochondrial content and myofiber size were increased and 4-HNE was decreased by exercise (statin x exercise interaction, p<0.05), and these beneficial effects were abrogated by statin treatment. Exercise (Acct and Nov) increased atrogin-1 mRNA in combination with statin treatment, yet enhanced fiber damage or atrophy was not observed. The results from this study suggest that exercise (Nov, Acct) does not exacerbate statin-induced myopathy in ApoE-/- mice, yet statin treatment reduces activity in a manner that prevents muscle from mounting a beneficial adaptive response to training. PMID:27936249

  2. Isolated inflammatory myopathy with rimmed vacuoles presenting with dropped head.

    PubMed

    Kataoka, Hiroshi; Sugie, Kazuma; Terashima, Mari; Koizumi, Munehisa; Horikawa, Hirosei; Nishino, Ichizo; Nonaka, Ikuya; Ueno, Satoshi

    2009-12-01

    We describe an unusual case of inflammatory myopathy with rimmed vacuoles associated with dropped head syndrome. Muscle biopsy in our patient revealed variations in fiber size with fiber necrosis and regeneration, accompanied by many rimmed vacuoles and areas of endomysial cell infiltration. Electron microscopy demonstrated autophagic vacuoles and tubulofilamentous inclusions. This myopathy can cause dropped head syndrome in a subgroup of patients.

  3. Myopathy with tubulin-reactive inclusions in two cats.

    PubMed

    Shelton, G Diane; Sturges, Beverly K; Lyons, Leslie A; Williams, D Colette; Aleman, Monica; Jiang, Yun; Mizisin, Andrew P

    2007-11-01

    Many types of inclusions have been described in human myopathies including but not limited to nemaline rod bodies, cylindrical spirals, tubular aggregates, cytoplasmic bodies, reducing bodies, and fingerprint bodies, and hyaline inclusions in myofibrillar myopathy and inclusion body myositis. There are very few reports describing inclusions in spontaneously occurring myopathies in cats, and these reports are limited to nemaline rod myopathy. A myopathy with tubulin-reactive crystalline inclusions has recently been reported in a human patient with a clinical presentation of myalgia and fatigue. Similarly, a myopathy with chronic, slowly progressive muscle weakness has been identified here in two unrelated cats. Inclusions were the only pathological change in skeletal muscle biopsies and, ultrastructurally, groups of crystalline structures were evident that had a subsarcolemmal or central location, rhomboid or rectangular shapes, lacked orientation, and were not membrane bound. The crystalline structures reacted positively with an antibody against tubulin. This feline myopathy may be the equivalent of the human myopathy with tubulin-positive crystalline inclusions.

  4. An Unusual Case of Statin-Induced Myopathy: Anti-HMGCoA Necrotizing Autoimmune Myopathy.

    PubMed

    Nichols, Laura; Pfeifer, Kurt; Mammen, Andrew L; Shahnoor, Nazima; Konersman, Chamindra G

    2015-12-01

    Statins are some of the most widely prescribed medications, and though generally well tolerated, can lead to a self-limited myopathy in a minority of patients. Recently, these medications have been associated with a necrotizing autoimmune myopathy (NAM). Statin-associated NAM is characterized by irritable myopathy on electromyography (EMG) and muscle necrosis with minimal inflammation on muscle biopsy. The case presented is a 63-year-old woman who has continued elevation of creatine kinase (CK) after discontinuation of statin therapy. She has irritable myopathy on EMG and NAM is confirmed by muscle biopsy. She subsequently tests positive for an experimental anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMGCoA) antibody that is found to be present in patients with statin-associated NAM. Though statin-associated NAM is a relatively rare entity, it is an important consideration for the general internist in patients who continue to have CK elevation and weakness after discontinuation of statin therapy. Continued research is necessary to better define statin-specific and dose-dependent risk, as well as optimal treatment for this condition.

  5. Exertional myopathy in whooping cranes (Grus americana) with prognostic guidelines.

    PubMed

    Hanley, Christopher S; Thomas, Nancy J; Paul-Murphy, Joanne; Hartup, Barry K

    2005-09-01

    Exertional myopathy developed in three whooping cranes (Grus americana) secondary to routine capture, handling, and trauma. Presumptive diagnosis of exertional myopathy was based on history of recent capture or trauma, clinical signs, and elevation of aspartate aminotransferase, alanine aminotransferase, creatine kinase, lactate dehydrogenase, and serum potassium. Treatments were attempted in each case, but ultimately were not successful. Gross and microscopic lesions at necropsy confirmed the diagnosis in each case, with the leg musculature most severely affected. Guidelines for determining prognosis of exertional myopathy in cranes have been included based on the analysis of these cases and others in the literature. As treatment is largely unrewarding, prevention remains the key in controlling exertional myopathy. Identification of predisposing factors and proper handling, immobilization, and transportation techniques can help prevent development of exertional myopathy in cranes.

  6. Exertional myopathy in whooping cranes (Grus americana) with prognostic guidlelines

    USGS Publications Warehouse

    Hanley, C.S.; Thomas, N.J.; Paul-Murphy, P.; Hartup, B.K.

    2005-01-01

    Exertional myopathy developed in three whooping cranes (Grus americana) secondary to routine capture, handling, and trauma. Presumptive diagnosis of exertional myopathy was based on history of recent capture or trauma, clinical signs, and elevation of aspartate aminotransferase, alanine aminotransferase, creatine kinase, lactate dehydrogenase, and serum potassium. Treatments were attempted in each case, but ultimately were not successful. Gross and microscopic lesions at necropsy confirmed the diagnosis in each case, with the leg musculature most severely affected. Guidelines for determining prognosis of exertional myopathy in cranes have been included based on the analysis of these cases and others in the literature. As treatment is largely unrewarding, prevention remains the key in controlling exertional myopathy. Identification of predisposing factors and proper handling, immobilization, and transportation techniques can help prevent development of exertional myopathy in cranes.

  7. Clinical approach to the diagnosis of congenital myopathies.

    PubMed

    North, Kathryn N

    2011-12-01

    In this issue of Seminars in Pediatric Neurology, each chapter will focus on the features and management of individual congenital myopathies. This introductory chapter will provide an overview of the clinical features that alert the clinician to the likely diagnosis of a congenital myopathy, and specific features on history and examination that are characteristic of a specific genetic subtype. Most congenital myopathies share a common pattern of clinical features, which makes it difficult to predict the genetic cause in a patient by clinical assessment alone. Although no single feature is specific for the congenital myopathies, the presence of this common pattern highlights patients in whom a muscle biopsy is likely to provide important diagnostic information. The diagnosis of a specific congenital myopathy should only be made when the defining morphologic feature is the predominant pathologic change, other possible causes have been excluded, and the clinical course is nonprogressive or only slowly progressive.

  8. Idiopathic inflammatory myopathy with diffuse alveolar damage.

    PubMed

    Lee, C-S; Chen, T-L; Tzen, C-Y; Lin, F-J; Peng, M-J; Wu, C-L; Chen, P-J

    2002-09-01

    Interstitial lung disease (ILD) in patients with myositis is defined by the presence of interstitial changes on radiographic examination. The reported prevalence of ILD varies from 0% to nearly 50%. However, only rarely has the pathological pattern of diffuse alveolar damage (DAD) associated with idiopathic inflammatory myopathy (IIM) been reported. We report five patients with IIM (one with dermatomyositis, one with polymyositis, and three with amyopathic dermatomyositis) and respiratory failure. Four underwent open lung biopsy with pathological proof of diffuse alveolar damage (DAD). Despite intensive immunosuppressive therapy, all of them died. In addition to the case reports, we discuss DAD in patients with IIM.

  9. [Sarcopenia or uremic myopathy in CKD patients].

    PubMed

    Chauveau, Philippe; Moreau, Karine; Lasseur, Catherine; Fouque, Denis; Combe, Christian; Aparicio, Michel

    2016-04-01

    Often underestimated or misunderstood in chronic renal failure (CRF), muscle wasting is nevertheless common and concerns about 50% of dialysis patients. The consequences of this myopathy on quality of life and outcomes of patients are unfavorable, identical to those observed in sarcopenia in elderly subjects with sarcopenia. The similarities between the two situations also concern the symptoms, the underlying muscle damages and the pathogenic mechanisms and may be partly explained by the frequently high age of ESRD patients. Skeletal muscle involvement should be systematically investigated in the IRC patient as in the elderly with sarcopenia to propose as early as possible a treatment of which physical activity and nutritional interventions are the mainstay.

  10. Bethlem myopathy is not allelic to limb-girdle muscular dystrophy type 1A

    SciTech Connect

    Speer, M.C.; Yamaoka, L.H.; Stajich, J.; Lewis, K.

    1995-08-28

    The Bethlem myopathy, an autosomal-dominant myopathy, shows a distribution of proximal muscle weakness similar to that observed in dominant limb-girdle muscular dystrophy (LGMD). Yet the Bethlem myopathy differs from most limb-girdle dystrophies in two important regards. First, the Bethlem myopathy presents with joint contractures most commonly observed at the elbows, ankles, and neck. Secondly, disease onset in the Bethlem myopathy is in early childhood, while most dominant LGMDs present with adult onset. 6 refs., 1 fig.

  11. Calcium Dyshomeostasis in Tubular Aggregate Myopathy

    PubMed Central

    Lee, Jong-Mok; Noguchi, Satoru

    2016-01-01

    Calcium is a crucial mediator of cell signaling in skeletal muscles for basic cellular functions and specific functions, including contraction, fiber-type differentiation and energy production. The sarcoplasmic reticulum (SR) is an organelle that provides a large supply of intracellular Ca2+ in myofibers. Upon excitation, it releases Ca2+ into the cytosol, inducing contraction of myofibrils. During relaxation, it takes up cytosolic Ca2+ to terminate the contraction. During exercise, Ca2+ is cycled between the cytosol and the SR through a system by which the Ca2+ pool in the SR is restored by uptake of extracellular Ca2+ via a specific channel on the plasma membrane. This channel is called the store-operated Ca2+ channel or the Ca2+ release-activated Ca2+ channel. It is activated by depletion of the Ca2+ store in the SR by coordination of two main molecules: stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (ORAI1). Recently, myopathies with a dominant mutation in these genes have been reported and the pathogenic mechanism of such diseases have been proposed. This review overviews the calcium signaling in skeletal muscles and role of store-operated Ca2+ entry in calcium homeostasis. Finally, we discuss the phenotypes and the pathomechanism of myopathies caused by mutations in the STIM1 and ORAI1 genes. PMID:27879676

  12. Mitochondrial function is altered in horse atypical myopathy.

    PubMed

    Lemieux, Hélène; Boemer, François; van Galen, Gaby; Serteyn, Didier; Amory, Hélène; Baise, Etienne; Cassart, Dominique; van Loon, Gunther; Marcillaud-Pitel, Christel; Votion, Dominique-M

    2016-09-01

    Equine atypical myopathy in Europe is a fatal rhabdomyolysis syndrome that results from the ingestion of hypoglycin A contained in seeds and seedlings of Acer pseudoplatanus (sycamore maple). Acylcarnitine concentrations in serum and muscle OXPHOS capacity were determined in 15 atypical myopathy cases. All but one acylcarnitine were out of reference range and mitochondrial respiratory capacity was severely decreased up to 49% as compared to 10 healthy controls. The hallmark of atypical myopathy thus consists of a severe alteration in the energy metabolism including a severe impairment in muscle mitochondrial respiration that could contribute to its high death rate.

  13. Statin-associated myopathy and its exacerbation with exercise.

    PubMed

    Meador, Benjamin M; Huey, Kimberly A

    2010-10-01

    3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are a common and effective treatment for hypercholesterolemia, with a low overall rate of side-effects. The most common complication is some degree of skeletal muscle myopathy, ranging from painless serum creatine kinase elevations to rhabdomyolysis. Unfortunately, the likelihood and/or severity of complications increases with the combination of statin treatment and physical activity. The specific pathways that mediate statin-associated myopathy are unclear, and research directly addressing the exacerbation with exercise is limited. Potential mechanisms include the induction of skeletal muscle fiber apoptosis, alterations in ubiquitin-proteasome pathway activity, mitochondrial dysfunction, and terpenoid depletion. In this review we provide an overview of research that specifically addresses the combination of statin-associated myopathy and physical activity and highlight some deficiencies in the available literature, as well as future directions for this important subset of statin-associated myopathy.

  14. Atypical presentation of GNE myopathy with asymmetric hand weakness.

    PubMed

    de Dios, John Karl L; Shrader, Joseph A; Joe, Galen O; McClean, Jeffrey C; Williams, Kayla; Evers, Robert; Malicdan, May Christine V; Ciccone, Carla; Mankodi, Ami; Huizing, Marjan; McKew, John C; Bluemke, David A; Gahl, William A; Carrillo-Carrasco, Nuria

    2014-12-01

    GNE myopathy is a rare autosomal recessive muscle disease caused by mutations in GNE, the gene encoding the rate-limiting enzyme in sialic acid biosynthesis. GNE myopathy usually manifests in early adulthood with distal myopathy that progresses slowly and symmetrically, first involving distal muscles of the lower extremities, followed by proximal muscles with relative sparing of the quadriceps. Upper extremities are typically affected later in the disease. We report a patient with GNE myopathy who presented with asymmetric hand weakness. He had considerably decreased left grip strength, atrophy of the left anterior forearm and fibro-fatty tissue replacement of left forearm flexor muscles on T1-weighted magnetic resonance imaging. The patient was an endoscopist and thus the asymmetric hand involvement may be associated with left hand overuse in daily repetitive pinching and gripping movements, highlighting the possible impact of environmental factors on the progression of genetic muscle conditions.

  15. Genetics Home Reference: collagen VI-related myopathy

    MedlinePlus

    ... hands and soles of the feet; and abnormal wound healing that creates shallow scars. The intermediate form of ... skin on the palms and soles; and abnormal wound healing. Individuals with collagen VI-related myopathy often have ...

  16. Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy.

    PubMed

    Scruggs, Erin R; Dirks Naylor, Amie J

    2008-01-01

    Zidovudine (3-azido-3'-deoxythymidine), also referred to as azidothymidine (AZT), has become an integral component in highly active antiretroviral therapy, and has also been used in the treatment of cancer. The clinical effectiveness of AZT is constrained due to its association with increased adverse effects, such as myopathy. There are numerous potential mechanisms that may contribute to AZT-induced myopathy. The first hypothesized mechanism to explain AZT-induced toxicity was mtDNA depletion due to inhibition of DNA polymerase gamma. Although mtDNA depletion is present in patients with myopathy, current data suggests that alternative mechanisms may play a more direct role in the myotoxicity. These mechanisms include AZT-induced oxidative stress, direct inhibition of mitochondrial bioenergetic machinery, and mitochondrial depletion of L-carnitine. Furthermore, we hypothesize that apoptosis may play a role in AZT-induced myopathy.

  17. Review of Critical Illness Myopathy and Neuropathy

    PubMed Central

    Shepherd, Starane; Batra, Ayush

    2016-01-01

    Critical illness myopathy (CIM) and neuropathy are underdiagnosed conditions within the intensive care setting and contribute to prolonged mechanical ventilation and ventilator wean failure and ultimately lead to significant morbidity and mortality. These conditions are often further subdivided into CIM, critical illness polyneuropathy (CIP), or the combination—critical illness polyneuromyopathy (CIPNM). In this review, we discuss the epidemiology and pathophysiology of CIM, CIP, and CIPNM, along with diagnostic considerations such as detailed clinical examination, electrophysiological studies, and histopathological review of muscle biopsy specimens. We also review current available treatments and prognosis. Increased awareness and early recognition of CIM, CIP, and CIPNM in the intensive care unit setting may lead to earlier treatments and rehabilitation, improving patient outcomes. PMID:28042370

  18. Excitation-Contraction Coupling Alterations in Myopathies

    PubMed Central

    Marty, Isabelle; Fauré, Julien

    2016-01-01

    During the complex series of events leading to muscle contraction, the initial electric signal coming from motor neurons is transformed into an increase in calcium concentration that triggers sliding of myofibrils. This process, referred to as excitation–contraction coupling, is reliant upon the calcium-release complex, which is restricted spatially to a sub-compartment of muscle cells (“the triad”) and regulated precisely. Any dysfunction in the calcium-release complex leads to muscle impairment and myopathy. Various causes can lead to alterations in excitation–contraction coupling and to muscle diseases. The latter are reviewed and classified into four categories: (i) mutation in a protein of the calcium-release complex; (ii) alteration in triad structure; (iii) modification of regulation of channels; (iv) modification in calcium stores within the muscle. Current knowledge of the pathophysiologic mechanisms in each category is described and discussed. PMID:27911331

  19. Mitochondrial myopathy presenting as fibromyalgia: a case report

    PubMed Central

    2012-01-01

    Introduction To the best of our knowledge, we describe for the first time the case of a woman who met the diagnostic criteria for fibromyalgia, did not respond to therapy for that disorder, and was subsequently diagnosed by biochemical and genetic studies with a mitochondrial myopathy. Treatment of the mitochondrial myopathy resulted in resolution of symptoms. This case demonstrates that mitochondrial myopathy may present in an adult with a symptom complex consistent with fibromyalgia. Case presentation Our patient was a 41-year-old Caucasian woman with symptoms of fatigue, exercise intolerance, headache, and multiple trigger points. Treatment for fibromyalgia with a wide spectrum of medications including non-steroidal anti-inflammatory drugs, antidepressants, gabapentin and pregabalin had no impact on her symptoms. A six-minute walk study demonstrated an elevated lactic acid level (5 mmol/L; normal < 2 mmol/L). Biochemical and genetic studies from a muscle biopsy revealed a mitochondrial myopathy. Our patient was started on a compound of coenzyme Q10 (ubiquinone) 200 mg, creatine 1000 mg, carnitine 200 mg and folic acid 1 mg to be taken four times a day. She gradually showed significant improvement in her symptoms over a course of several months. Conclusions This case demonstrates that adults diagnosed with fibromyalgia may have their symptom complex related to an adult onset mitochondrial myopathy. This is an important finding since treatment of mitochondrial myopathy resulted in resolution of symptoms. PMID:22325469

  20. Clinical characterization and molecular mechanisms of statin myopathy.

    PubMed

    Toth, Peter P; Harper, Charles R; Jacobson, Terry A

    2008-08-01

    Myopathy has been reported in a small percentage of statin-treated patients for the past 30 years, but the etiologic mechanisms for inducing muscle injury have not yet been fully characterized. Statin-induced myopathy is now understood to be a heterogeneous condition that may be due to: mechanisms of the drug itself; interactions with other drugs; or genetic, metabolic and immunological vulnerabilities in individual patients. In some cases, statins may unmask latent conditions (e.g., asymptomatic baseline myopathy) that predispose patients to muscle toxicity. The definitions, epidemiology, clinical features, risk factors and proposed mechanisms of statin-induced myopathy are reviewed. Muscle metabolism can be adversely impacted by statin therapy, including changes in fatty acid oxidation, possibly reduced coenzyme Q(10) biosynthesis, and increased myocyte protein degradation via the activity of atrogin-1 and the ubiquitin-proteasome pathway. Statin therapy may also activate a variety of autoimmune phenomena that potentiate myocellular injury. Improving our understanding of statin-induced myopathy is a high clinical priority given the large number of patients eligible for statin therapy and the fact that the development of myalgia and myopathy are leading reasons cited by patients for statin discontinuation.

  1. Hypertensive crises in quadriplegic patients. Changes in cardiac output, blood volume, serum dopamine-beta-hydroxylase activity, and arterial prostaglandin PGE2.

    PubMed

    Naftchi, N E; Demeny, M; Lowman, E W; Tuckman, J

    1978-02-01

    The syndrome of autonomic dysreflexia often occurs in quadriplegic subjects and is characterized by paroxysmal hypertension, headache, vasoconstriction below and flushing of the skin above the level of transection, and bradycardia. These attacks may cause hypertnesive encephalopathy, cerebral vascular accidents, and death. In five patients during crises, the mean arterial pressure changed from 95 to 154 mm Hg, heart rate 72 to 45 beats/min, cardiac output 4.76 to 4.70 L/min, and peripheral resistance 1650 to 2660 dynes.sec.cm-5. In eight subjects the control plasma, red cell, and total blood volumes were 19.1, 10.5, and 29.6 ml/cm body height, respectively, and when hypertensive, the plasma protein concentration increased by 9.9% and the hematocrit by 9.5%. Plasma volume was only reduced by an estimated 10-15%. At that time, arterial dopamine-beta-hydroxylase (DbetaH) activity increased 65% and prostaglandin E2 concentration by 68%. Thus, the augmented DbetaH activity presented primarily an elevated sympathetic tone and not hemoconcentration of that protein. The rise in prostaglandin may contribute to the severe headaches during hypertensive episodes.

  2. [The phrenic nerve stimulator, a valid ventilatory support in the management of quadriplegic patients receiving home health care services. A case report].

    PubMed

    Giglio, A M; Rovella, C; Botindari, E; Alba, M

    2002-06-01

    The authors describe the case of a quadriplegic child with post-traumatic respiratory insufficiency and total dependency on mechanical ventilation. The child was a long-term inpatient at the Pediatric Intensive Care Unit of Palermo. Considering the patient's long life expectancy, psychological distress and determination of the patient and family members to have the patient at home again, the plan for dehospitalization included the use of a phrenic stimulator as a supplement to conventional mechanical ventilation that would simplify home health care and improve the patient's quality of life. Electromyography, fluoroscopy and gas analysis were conducted to evaluate whether the patient was physically fit to receive a stimulator. The device was then implanted at the Spinal Cord Injury Treatment Unit in Sondalo. The stimulator is compact in design, operates silently, and affords more natural ventilation without interfering with breathing rhythm, and maintains muscle trophism. In combination with mechanical ventilation, the pacing device is an ideal system for home respiratory assistance. Additional benefits include increased patient mobility outside the home and improved quality of life. The system provides good respiration, as shown by EtCO2 and SpO2 measurements and long-term monitoring performed at our unit.

  3. Rapid diagnosis of hypoglycin A intoxication in atypical myopathy of horses.

    PubMed

    Sander, Johannes; Cavalleri, Jessika-M V; Terhardt, Michael; Bochnia, Mandy; Zeyner, Annette; Zuraw, Aleksandra; Sander, Stefanie; Peter, Michael; Janzen, Nils

    2016-03-01

    Hypoglycin A (2-amino-3-(2-methylidenecyclopropyl)propanoic acid) is the plant toxin shown to cause atypical myopathy in horses. It is converted in vivo to methylenecyclopropyl acetic acid, which is transformed to a coenzyme A ester that subsequently blocks beta oxidation of fatty acids. Methylenecyclopropyl acetic acid is also conjugated with carnitine and glycine. Acute atypical myopathy may be diagnosed by quantifying the conjugates of methylenecyclopropyl acetic acid plus a selection of acyl conjugates in urine and serum. We describe a new mass spectrometric method for sample volumes of <0.5 mL. Samples were extracted with methanol containing 5 different internal standards. Extracts were analyzed by ultra-high-performance liquid chromatography-tandem mass spectrometry focusing on 11 metabolites. The total preparation time for a series of 20 samples was 100 min. Instrument run time was 14 min per sample. For the quantification of carnitine and glycine conjugates of methylenecyclopropyl acetic acid in urine, the coefficients of variation for intraday quantification were 2.9% and 3.0%, respectively. The respective values for interday were 9.3% and 8.0%. Methylenecyclopropyl acetyl carnitine was detected as high as 1.18 µmol/L in serum (median: 0.46 µmol/L) and 1.98 mmol/mol creatinine in urine (median: 0.79 mmol/mol creatinine) of diseased horses, while the glycine derivative accumulated up to 1.97 mmol/mol creatinine in urine but was undetectable in most serum samples. In serum samples from horses with atypical myopathy, the intraday coefficients of variation for C4-C8 carnitines and glycines were ≤4.5%. Measured concentrations exceeded those in healthy horses by ~10 to 1,400 times.

  4. Genetics Home Reference: myopathy with deficiency of iron-sulfur cluster assembly enzyme

    MedlinePlus

    ... myopathy with deficiency of iron-sulfur cluster assembly enzyme Enable Javascript to view the expand/collapse boxes. ... Myopathy with deficiency of iron-sulfur cluster assembly enzyme is an inherited disorder that primarily affects muscles ...

  5. Hypothyroid acute renal failure.

    PubMed

    Birewar, Sonali; Oppenheimer, Mark; Zawada, Edward T

    2004-03-01

    Muscular disorders and even hypothyroid myopathy with elevated muscle enzymes are commonly seen in hypothyroidism. In this paper, we report a case of acute renal failure in a 35-year old male patient with myalgia. His serum creatinine reached a level of 2.4 mg/dl. Later, his myalgia was found to be due to hypothyroidism with TSH of over 500 uiv/ml. With thyroid replacement therapy, myalgia and his serum creatinine stabilized and subsequently improved. Hypothyroidism, although rare, has been reported as a definite and authentic cause of rhabdomyolysis. As a result, hypothyroidism must be considered in patients presenting with acute renal failure and elevated muscle enzymes.

  6. Epigenetic changes as a common trigger of muscle weakness in congenital myopathies.

    PubMed

    Rokach, Ori; Sekulic-Jablanovic, Marijana; Voermans, Nicol; Wilmshurst, Jo; Pillay, Komala; Heytens, Luc; Zhou, Haiyan; Muntoni, Francesco; Gautel, Mathias; Nevo, Yoram; Mitrani-Rosenbaum, Stella; Attali, Ruben; Finotti, Alessia; Gambari, Roberto; Mosca, Barbara; Jungbluth, Heinz; Zorzato, Francesco; Treves, Susan

    2015-08-15

    Congenital myopathies are genetically and clinically heterogeneous conditions causing severe muscle weakness, and mutations in the ryanodine receptor gene (RYR1) represent the most frequent cause of these conditions. A common feature of diseases caused by recessive RYR1 mutations is a decrease of ryanodine receptor 1 protein content in muscle. The aim of the present investigation was to gain mechanistic insight into the causes of this reduced ryanodine receptor 1. We found that muscle biopsies of patients with recessive RYR1 mutations exhibit decreased expression of muscle-specific microRNAs, increased DNA methylation and increased expression of class II histone deacetylases. Transgenic mouse muscle fibres over-expressing HDAC-4/HDAC-5 exhibited decreased expression of RYR1 and of muscle-specific miRNAs, whereas acute knock-down of RYR1 in mouse muscle fibres by siRNA caused up-regulation of HDAC-4/HDAC-5. Intriguingly, increased class II HDAC expression and decreased ryanodine receptor protein and miRNAs expression were also observed in muscles of patients with nemaline myopathy, another congenital neuromuscular disorder. Our results indicate that a common pathophysiological pathway caused by epigenetic changes is activated in some forms of congenital neuromuscular disorders.

  7. Proximal weakness of the extremities as main feature of amyloid myopathy.

    PubMed Central

    Jennekens, F G; Wokke, J H

    1987-01-01

    Two patients with muscle weakness caused by amyloid myopathy are described. Characteristic features such as pseudohypertrophy and abnormal firmness, and tumours of muscles were absent. It is suggested that muscle weakness in amyloid myopathy is caused by layers of amyloid covering muscle fibres. In middle aged or elderly patients with proximal muscle weakness the diagnosis of amyloid myopathy should be considered. Images PMID:3681315

  8. Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies

    PubMed Central

    Lehtokari, Vilma-Lotta; Kiiski, Kirsi; Sandaradura, Sarah A.; Laporte, Jocelyn; Repo, Pauliina; Frey, Jennifer A.; Donner, Kati; Marttila, Minttu; Saunders, Carol; Barth, Peter G.; den Dunnen, Johan T.; Beggs, Alan H.; Clarke, Nigel F.; North, Kathryn N.; Laing, Nigel G.; Romero, Norma B.; Winder, Thomas L.; Pelin, Katarina; Wallgren-Pettersson, Carina

    2015-01-01

    A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (~7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype–phenotype correlations in NEB-associated disease. PMID:25205138

  9. Consensus Statement on Standard of Care for Congenital Myopathies

    PubMed Central

    Wang, Ching H.; Dowling, James J.; North, Kathryn; Schroth, Mary K.; Sejersen, Thomas; Shapiro, Frederic; Bellini, Jonathan; Weiss, Hali; Guillet, Marc; Amburgey, Kimberly; Apkon, Susan; Bertini, Enrico; Bonnemann, Carsten; Clarke, Nigel; Connolly, Anne M.; Estournet-Mathiaud, Brigitte; Fitzgerald, Dominic; Florence, Julaine M.; Gee, Richard; Gurgel-Giannetti, Juliana; Glanzman, Allan M.; Hofmeister, Brittany; Jungbluth, Heinz; Koumbourlis, Anastassios C.; Laing, Nigel G.; Main, Marion; Morrison, Leslie A.; Munns, Craig; Rose, Kristy; Schuler, Pamela M.; Sewry, Caroline; Storhaug, Kari; Vainzof, Mariz; Yuan, Nanci

    2016-01-01

    Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee’s recommendations for symptom assessments and therapeutic interventions. It is the committee’s goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome. PMID:22431881

  10. Myopathy in patients with Hashimoto's disease.

    PubMed

    Villar, Jaqueline; Finol, Héctor J; Torres, Sonia H; Roschman-González, Antonio

    2015-03-01

    Hashimoto thyroiditis (HT) is an autoimmune disease of the thyroid gland. Patients may present or not a hypothyroid state, and frequently have manifestations of myopathy. The present work was aimed to assess the clinical symptoms and signs of skeletal muscle alterations in HT, describe the muscular pathological changes and relate them to the functional thyroid status and to the autoimmune condition of the patient. Clinical and laboratory studies were performed in ten HT patients and three control subjects (hormonal levels and electromyography). Biopsies from their vastus lateralis of quadriceps femoris muscle were analyzed under light (histochemistry and immunofluorescense) and electron microscopy. All patients showed muscle focal alterations, ranging from moderate to severe atrophy, necrosis, activation of satellite cells, presence of autophagosomes, capillary alterations and macrophage and mast cell infiltration, common to autoimmune diseases. The intensity of clinical signs and symptoms was not related to the morphological muscle findings, the electromyography results, or to the state of the thyroid function. Reactions for immunoglobulin in muscle fibers were positive in 80% of the patients. Fiber type II proportion was increased in all patients, with the exception of those treated with L-thyroxine. In conclusion, autoimmune processes in several of the patients may be associated to the skeletal muscle alterations, independently of the functional state of the thyroid gland; however, fiber II type proportion could have been normalized by L-thyroxine treatment.

  11. Mendelian bases of myopathies, cardiomyopathies, and neuromyopathies

    PubMed Central

    Piluso, G; Aurino, S; Cacciottolo, M; Del Vecchio Blanco, F; Lancioni, A; Rotundo, IL; Torella, A; Nigro, V

    2010-01-01

    Summary A second genetic revolution is approaching thanks to next-generation DNA sequencing technologies. In the next few years, the 1,000$-genome sequencing promises to reveal every individual variation of DNA. There is, however, a major problem: the identification of thousands of nucleotide changes per individual with uncertain pathological meaning. This is also an ethical issue. In the middle, there is today the possibility to address the sequencing analysis of genetically heterogeneous disorders to selected groups of genes with defined mutation types. This will be cost-effective and safer. We assembled an easy-to manage overview of most Mendelian genes involved in myopathies, cardiomyopathies, and neuromyopathies. This was entirely put together using a number of open access web resources that are listed below. During this effort we realized that there are unexpected countless sources of data, but the confusion is huge. In some cases, we got lost in the validation of disease genes and in the difficulty to discriminate between polymorphisms and disease-causing alleles. In the table are the annotated genes, their associated disorders, genomic, mRNA and coding sizes. We also counted the number of pathological alleles so far reported and the percentage of single nucleotide mutations. PMID:22029103

  12. Zellweger syndrome and secondary mitochondrial myopathy.

    PubMed

    Salpietro, Vincenzo; Phadke, Rahul; Saggar, Anand; Hargreaves, Iain P; Yates, Robert; Fokoloros, Christos; Mankad, Kshitij; Hertecant, Jozef; Ruggieri, Martino; McCormick, David; Kinali, Maria

    2015-04-01

    Defects in peroxisomes such as those associated with Zellweger syndrome (ZS) can influence diverse intracellular metabolic pathways, including mitochondrial functioning. We report on an 8-month-old female infant and a 6-month-old female infant with typical clinical, radiological and laboratory features of Zellweger syndrome; light microscopic and ultrastructural evidence of mitochondrial pathology in their muscle biopsies; and homozygous pathogenic mutations of the PEX16 gene (c.460 + 5G > A) and the PEX 12 gene (c.888_889 del p.Leu297Thrfs*12), respectively. Additionally, mitochondrial respiratory chain enzymology analysis in the first girl showed a mildly low activity in complexes II-III and IV. We also review five children previously reported in the literature with a presumptive diagnosis of ZS and additional mitochondrial findings in their muscle biopsies. In conclusion, this is the first study of patients with a molecularly confirmed peroxisomal disorder with features of a concomitant mitochondrial myopathy and underscores the role of secondary mitochondrial dysfunction in Zellweger syndrome, potentially contributing to the clinical phenotype.

  13. An unusual case of glipizide-induced proximal myopathy

    PubMed Central

    Das, Saibal; Ramasamy, Anand; De, Soumyadip; Mondal, Somnath

    2016-01-01

    This case report outlines a very rare case of glipizide-induced severe proximal myopathy in a 61-year-old diabetic man. After taking 10 mg glipizide for 5 months, diabetes was well controlled but the patient presented with progressive proximal muscle weakness in all the four limbs. Clinical examination and relevant investigations suggested it to be a case of proximal myopathy and might be drug induced. De-challenge was done and was treated resulting in reversal of the diseased state. After 3 more months, controlled re-challenge was done and there was recurrence of proximal muscle weakness. There were no evidences of any other possible metabolic, infective, organic or other pathologic causes giving rise to that condition and Naranjo adverse drug reaction probability scale suggested that it was “probable” that glipizide was responsible for the development of myopathy in this patient. PMID:27440956

  14. Myosin storage (hyaline body) myopathy: a case report.

    PubMed

    Shingde, Meena V; Spring, Penelope J; Maxwell, Adam; Wills, Edward J; Harper, Clive G; Dye, Danielle E; Laing, Nigel G; North, Kathryn N

    2006-12-01

    Myosin storage myopathy/hyaline body myopathy is a rare congenital myopathy, with less than 30 cases reported in the literature. It is characterised by the presence of subsarcolemmal hyaline bodies in type 1 muscle fibres and predominantly proximal muscle weakness. Recently, a single mutation (Arg1845Trp) in the slow/beta-cardiac myosin heavy chain gene (MYH7) was identified in four unrelated probands from Sweden and Belgium. The clinical severity and age of onset was variable, despite the same disease-causing mutation and similar histological findings. Here, we report the clinical and morphological findings of two brothers of English/Scottish background with the Arg1845Trp mutation in MYH7. This case report adds to the clinical description of this rare disorder and confirms that Arg1845Trp is a common mutation associated with this phenotype, at least in the White European population.

  15. Amyloid myopathy: characteristic features of a still underdiagnosed disease.

    PubMed

    Chapin, John E; Kornfeld, Mario; Harris, Alexis

    2005-02-01

    A 62-year-old man with progressive proximal weakness underwent extensive evaluation including muscle biopsy without a clear diagnosis being established. A repeat muscle biopsy including Congo red-stained sections revealed infiltration of blood-vessel walls and endomysium with amyloid protein, as well as an unusual pattern of pathologic changes to muscle fibers. From a review of 79 cases of amyloid myopathy reported in the English-language literature, the characteristic features of this disorder are described. Congo red-stained sections of muscle biopsy viewed under fluorescent or polarized optics, and serum or urine protein immunoelectrophoresis, play an important role in the evaluation of myopathy. Amyloid myopathy should be a consideration in adults with progressive neuromuscular weakness of uncertain cause.

  16. Whole Exome Sequencing Identifies Atypical Welander Distal Myopathy in Patient

    PubMed Central

    Blackburn, Patrick; Jackson, Jessica; Harris, Kimberly; Selcen, Duygu; Dimberg, Elliot; Atwal, Paldeep

    2017-01-01

    Abstract Welander distal myopathy is a rare autosomal dominant disorder characterized by muscle weakness in the hands and feet. Exome sequencing of affected families discovered a segregating p.Glu384Lys pathogenic variant in TIA-1 as the main genetic cause of Welander distal myopathy. TIA-1 encodes an RNA-binding protein which serves as a key component of stress granules. This protein also regulates splicing and translation of mRNA. Our patient developed progressive weakness in his hands and feet during his late 40s that was misdiagnosed as a neuropathy that caused muscle atrophy. Follow-up genetic testing revealed a p.Glu384Lys pathogenic variant in TIA-1, and he was then diagnosed with Welander distal myopathy. Our case report underlines the importance of electrodiagnostic and genetic testing of patients. PMID:28221306

  17. Immune-mediated necrotizing myopathy associated with statins.

    PubMed

    Grable-Esposito, Phyllis; Katzberg, Hans D; Greenberg, Steven A; Srinivasan, Jayashri; Katz, Jonathan; Amato, Anthony A

    2010-02-01

    We report patients from two neuromuscular centers who were evaluated between the years 2000 and 2008 and met the following criteria: (1) proximal muscle weakness occurring during or after treatment with statins; (2) elevated serum creatine kinase (CK); (3) persistence of weakness and elevated CK despite discontinuation of the statin; (4) improvement with immunosuppressive agents; and (5) muscle biopsy showing necrotizing myopathy without significant inflammation. Twenty-five patients fulfilled our inclusion criteria. Twenty-four patients required multiple immunosuppressive agents. Fifteen patients relapsed after being tapered off immunosuppressive therapy. Exposure to statins prior to onset was significantly higher in patients with necrotizing myopathy (82%) as compared to those with dermatomyositis (18%), polymyositis (24%), and inclusion-body myositis (38%) seen in the same time period. The lack of improvement following discontinuation of statins, the need for immunosuppressive therapy, and frequent relapse when treatment was tapered suggest an immune-mediated etiology for this rare, statin-associated necrotizing myopathy.

  18. Inspiratory Muscle Training in a Child with Nemaline Myopathy and Organ Transplantation

    PubMed Central

    Smith, Barbara K.; Bleiweis, Mark S.; Zauhar, Joni; Martin, A. Daniel

    2013-01-01

    Objective To report the use of inspiratory muscle strength training (IMST) to treat repeated ventilatory insufficiency in a child with nemaline myopathy (NM) who underwent cardiac and renal transplantation. Design Case report. Setting Pediatric intensive care unit of a tertiary care university teaching hospital. Intervention IMST was provided five days weekly for two weeks, accompanied by progressive weaning from non-invasive ventilation. Measurements and Main Results Maximal inspiratory pressure (MIP) increased from −36.7 cm H2O to −77.8 cm H2O, accompanied by improved inspiratory flow, volume, pressure activation and power. During the training period, the patient weaned from continuous non-invasive ventilatory assist to her pre-operative level of ventilatory function. Conclusions Inspiratory muscle training may be a beneficial component of care for children with NM who experience acute ventilatory insufficiency. PMID:20407395

  19. Guillain–Barré syndrome mimics primary biliary cirrhosis-related myopathy

    PubMed Central

    Munday, William R.; DiCapua, Daniel; Vortmeyer, Alexander; Gomez, Jose Luis

    2015-01-01

    Guillain–Barré syndrome (GBS) is an immune-mediated disorder characterized by acute polyneuropathy, ascending paralysis and post infectious polyneuritis. Two-thirds of patients present with a history of recent upper respiratory tract or gastrointestinal infection. The clinical history, neurologic examination and laboratory assessment allow for a straightforward diagnosis in the majority of cases. However, primary biliary cirrhosis (PBC) is known to cause clinically detectable muscular weakness. It is therefore critical to differentiate between PBC-associated muscular weakness and GBS-induced paralysis. Here, we report a patient with a longstanding history of PBC who developed progressive weakness and respiratory failure due to GBS, which clinically mimicked PBC myopathy. This is the first reported association between GBS and PBC. PMID:26634144

  20. [Two cases with dropped head syndrome caused by hypokalemic myopathy].

    PubMed

    Taniguchi, Koichiro; Okino, Iwao; Yamamoto, Nobuaki; Matsumoto, Shinichi; Tachibana, Naoko; Hamano, Toshiaki

    2011-02-01

    We reported two women (78 and 85 years of age) with dropped head syndrome caused by hypokalemic myopathy restricted to the posterior cervical muscles. Both presented with relatively rapid onset of severe neck extensor weakness. Needle EMG demonstrated myogenic changes in the cervical paraspinal muscles and there were high intensity signals in the posterior cervical muscles on the neck MRI. Dropped head syndrome resolved in both patients as potassium normalized. One of the patients relapsed 11 months later with recurrent hypokalemia, but recovered rapidly with supplementation of potassium. Focal myopathy localized in the posterior cervical muscles due to hypokalemia should be considered as one of the possible causes of dropped head syndrome.

  1. Genetic and immunologic susceptibility to statin-related myopathy.

    PubMed

    Patel, Jaideep; Superko, H Robert; Martin, Seth S; Blumenthal, Roger S; Christopher-Stine, Lisa

    2015-05-01

    Statin-related myopathy (SRM) undermines drug adherence that is critical for achieving the benefits of lipid-lowering therapy. While the exact mechanism of SRM remains largely unknown, recent evidence supports specific genetic and immunologic influence on the development of intolerance. Genes of interest include those involved in the pharmacokinetics of statin response (i.e. drug metabolism, uptake transporters, and efflux transporters), pharmacodynamics (i.e. drug toxicity and immune-mediated myopathy), and gene expression. We examine the influence of genetic and immunologic variation on the pharmacokinetics, pharmacodynamics, and gene expression of SRM.

  2. Acute Onset Significant Muscle Weakness in a Patient Awaiting Liver Transplantation: Look for Statins.

    PubMed

    Choudhary, Narendra S; Saigal, Sanjiv; Saraf, Neeraj; Soin, Arvinder S

    2017-03-01

    Statins are commonly used drugs in patients with liver and cardiac disease. Statin-induced severe myopathy is a very uncommon presentation and rhabdomyolysis may occur in extreme cases which leads to renal failure. Patients with comorbidities like diabetes, hypothyroidism, and liver disease have higher chances of development of statin-induced myopathy. We describe a case of Child's C cirrhosis wherein the patient had acute onset significant muscle weakness and improved on statin discontinuation.

  3. Statin induced myopathy does not show up in MIBI scintigraphy.

    PubMed

    Lupattelli, G; Palumbo, B; Sinzinger, H

    2001-05-01

    Statin induced myopathy is the most commonly seen side effect in users of this family of drugs. Their different forms present with either creatine phosphokinase (CK) elevation or not, signs of in vivo oxidation injury or not or a combination of both. The pathogenetic background, however, still remains obscure. As MIBI, beside myocardial and tumour scintigraphy, is useful in detecting muscle metabolic abnormalities, an increased uptake of MIBI in the diseased muscular segments could be expected. We investigated seven patients (five males, two females; aged 36-56 years) with statin induced myopathy with either elevated CK, isoprostanes or muscle pains at varying combinations. MIBI whole-body imaging was done immediately, the patients still being on the respective statin. Sixteen patients (six males, 10 females) suffering from lung or breast cancer and being on statins served as controls. No uptake abnormalities in any muscular segment either in the patients or the control group were seen. Thus, MIBI scintigraphy is not useful, apparently, in diagnosing and eventually localizing statin induced myopathy. These findings indicate that MIBI scintigraphy is of no help for diagnosis and gaining further insight into statin induced myopathy.

  4. Current and future therapeutic approaches to the congenital myopathies.

    PubMed

    Jungbluth, Heinz; Ochala, Julien; Treves, Susan; Gautel, Mathias

    2016-08-08

    The congenital myopathies - including Central Core Disease (CCD), Multi-minicore Disease (MmD), Centronuclear Myopathy (CNM), Nemaline Myopathy (NM) and Congenital Fibre Type Disproportion (CFTD) - are a genetically heterogeneous group of early-onset neuromuscular conditions characterized by distinct histopathological features, and associated with a substantial individual and societal disease burden. Appropriate supportive management has substantially improved patient morbidity and mortality but there is currently no cure. Recent years have seen an exponential increase in the genetic and molecular understanding of these conditions, leading to the identification of underlying defects in proteins involved in calcium homeostasis and excitation-contraction coupling, thick/thin filament assembly and function, redox regulation, membrane trafficking and/or autophagic pathways. Based on these findings, specific therapies are currently being developed, or are already approaching the clinical trial stage. Despite undeniable progress, therapy development faces considerable challenges, considering the rarity and diversity of specific conditions, and the size and complexity of some of the genes and proteins involved. The present review will summarize the key genetic, histopathological and clinical features of specific congenital myopathies, and outline therapies already available or currently being developed in the context of known pathogenic mechanisms. The relevance of newly discovered molecular mechanisms and novel gene editing strategies for future therapy development will be discussed.

  5. Anesthesia for sickle cell disease and congenital myopathy in combination.

    PubMed

    Fanning, Rebecca; O'Donnell, Brian; Lynch, Brian; Stephens, Michael; O'Donovan, Frances

    2006-08-01

    We report on the perioperative management of anesthesia and analgesia in a child with sickle cell disease and a congenital myopathy, presenting for corrective orthopedic surgery. The case illustrates two valuable points of interest: the many benefits of regional anesthesia in complex medical cases and the successful use of tourniquets in children with sickle cell disease.

  6. Congenital myopathy is caused by mutation of HACD1

    PubMed Central

    Muhammad, Emad; Reish, Orit; Ohno, Yusuke; Scheetz, Todd; DeLuca, Adam; Searby, Charles; Regev, Miriam; Benyamini, Lilach; Fellig, Yakov; Kihara, Akio; Sheffield, Val C.; Parvari, Ruti

    2013-01-01

    Congenital myopathies are heterogeneous inherited diseases of muscle characterized by a range of distinctive histologic abnormalities. We have studied a consanguineous family with congenital myopathy. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous non-sense mutation in 3-hydroxyacyl-CoA dehydratase 1 (HACD1) in affected individuals. The mutation results in non-sense mediated decay of the HACD1 mRNA to 31% of control levels in patient muscle and completely abrogates the enzymatic activity of dehydration of 3-hydroxyacyl-CoA, the third step in the elongation of very long-chain fatty acids (VLCFAs). We describe clinical findings correlated with a deleterious mutation in a gene not previously known to be associated with congenital myopathy in humans. We suggest that the mutation in the HACD1 gene causes a reduction in the synthesis of VLCFAs, which are components of membrane lipids and participants in physiological processes, leading to congenital myopathy. These data indicate that HACD1 is necessary for muscle function. PMID:23933735

  7. Genetics Home Reference: X-linked myotubular myopathy

    MedlinePlus

    ... myotubular myopathy is inherited in an X-linked recessive pattern . The gene associated with this condition is located on the ... females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic ...

  8. Exertional myopathy in pileated woodpeckers (Dryocopus pileatus) subsequent to capture.

    PubMed

    Ruder, Mark G; Noel, Brandon L; Bednarz, James C; Keel, M Kevin

    2012-04-01

    Out of 33 Pileated Woodpeckers (Dryocopus pileatus) captured and fitted with radio-transmitters, 12 were later found dead. Three carcasses were recovered and submitted for necropsy. One bird had large pale foci in multiple muscles. Microscopically, skeletal muscle in all three had evidence of severe coagulative necrosis, consistent with capture myopathy.

  9. Pulmonary arterial hypertension in idiopathic inflammatory myopathies

    PubMed Central

    Sanges, Sébastien; Yelnik, Cécile M.; Sitbon, Olivier; Benveniste, Olivier; Mariampillai, Kuberaka; Phillips-Houlbracq, Mathilde; Pison, Christophe; Deligny, Christophe; Inamo, Jocelyn; Cottin, Vincent; Mouthon, Luc; Launay, David; Lambert, Marc; Hatron, Pierre-Yves; Rottat, Laurence; Humbert, Marc; Hachulla, Eric

    2016-01-01

    Abstract Occurrence of pulmonary arterial hypertension (PAH) in idiopathic inflammatory myopathies (IIMs) without extensive interstitial lung disease (ILD) has rarely been described in the medical literature. This study aimed to report all cases with association of PAH and IIM in the French Pulmonary Hypertension (PH) Registry, to identify IIM features associated with the presence of PAH, and to describe treatment modalities of these patients. All cases of IIM-PAH were retrieved from the French PH Registry, which gathers PH patients prospectively enrolled by 27 referral hospital centers across France. Patients were excluded if they had an extensive ILD or overlap syndrome. Characteristics of IIM-PAH patients were compared with a control group of IIM patients without PH. Among the 5223 PH patients in the Registry, 34 had a diagnosis of IIM. Among them, 3 IIM-PAH patients (2 females and 1 male) had no evidence of extensive ILD or overlap syndrome, and were included in this study. In these 3 patients, dermatomyositis (DM) was the only identified IIM. One patient had autoantibodies classically associated with IIM (anti-Ku). PAH had always developed after IIM onset, was severe in all cases, and led to a marked functional impairment. By pooling our cases with 6 patients previously reported in the literature, and comparing them with a control cohort of 35 IIM patients without PH, we identify several IIM characteristics possibly associated with PAH occurrence, including DM subtype (78% vs 46%; P = 0.02), skin involvement (P = 0.04), anti-SSA antibodies (P = 0.05), and peripheral microangiopathy (P = 0.06). Overall, IIM-PAH patients were managed by corticosteroids and/or immunosuppressants, either alone or combined with PAH therapy. Patients did not seem to respond to IIM treatment alone. Our study reports for the first time the rare but possible association of PAH and IIM in a large prospective PH Registry. In that setting, PAH seems associated with DM, skin involvement

  10. Managing the underestimated risk of statin-associated myopathy.

    PubMed

    Rallidis, Loukianos S; Fountoulaki, Katerina; Anastasiou-Nana, Maria

    2012-09-06

    In clinical practice 5-10% of patients receiving statins develop myopathy, a side effect that had been systematically underestimated in the randomized controlled trials with statins. The most common manifestation of myopathy is muscle pain (usually symmetrical, involving proximal muscles) without creatinine kinase (CK) elevation or less frequently with mild CK elevation. Clinically significant rhabdomyolysis (muscle symptoms with CK elevation >10 times the upper limit of normal and with creatinine elevation) is extremely rare. Myopathy complicates the use of all statins (class effect) and is dose-dependent. The pathophysiologic mechanism of statin-associated myopathy is unknown and probably multifactorial. The risk of statin-associated myopathy can be minimized by identifying vulnerable patients (i.e. patients with impaired renal or liver function, advanced age, hypothyroidism, etc.) and/or by eliminating-avoiding statin interactions with specific drugs (cytochrome P-450 3A4 inhibitors, gemfibrozil, etc.). In symptomatic patients, the severity of symptoms, the magnitude of CK elevation and the risk/benefit ratio of statin continuation should be considered before statin treatment is discontinued. Potential strategies are the use of the same statin at a lower dose and if symptoms recur the initiation of fluvastatin XL 80 mg daily or rosuvastatin intermittently in low dose (5-10mg), combined usually with ezetimibe 10mg daily. Failure of these approaches necessitates the use of non-statin lipid lowering drugs (ezetimibe, colesevelam). In order to provide evidence based recommendations for the appropriate management of statin-intolerant patients we need randomized clinical trials directly comparing the myopathic potential of different lipid-lowering medications at comparable doses.

  11. Congenital myopathy caused by a novel missense mutation in the CFL2 gene

    PubMed Central

    Ockeloen, C.W.; Gilhuis, H.J.; Pfundt, R.; Kamsteeg, E.J.; Agrawal, P.B.; Beggs, A.H.; Hama-Amin, A. Dara; Diekstra, A.; Knoers, N.V.A.M.; Lammens, M.; van Alfen, N.

    2012-01-01

    Nemaline myopathy and myofibrillar myopathy are heterogeneous myopathies that both comprise early-onset forms. We present two sisters from a consanguineous Iraqi Kurdish family with predominant axial and limb girdle weakness. Muscle biopsies showed features of both nemaline myopathy and myofibrillar myopathy. We performed homozygosity mapping in both siblings using an Affymetrix 250K Nspl SNP array. One of the overlapping homozygous regions harbored the gene CFL2. Because a mutation in CFL2 was identified in a family with nemaline myopathy, we performed sequence analysis of the gene and a novel homozygous missense mutation in exon 2 (c.19G>A, p.Val7Met) of CFL2 was identified in both siblings. CFL2 encodes the protein cofilin-2, which plays an important role in regulation of sarcomeric actin filaments. To our knowledge, this is the second family in which a mutation in CFL2 causes an autosomal recessive form of congenital myopathy with features of both nemaline and myofibrillar myopathy. Given the clinical variability and the multitude of histological features of congenital myopathies, CFL2 sequence analysis should be considered in patients presenting with an autosomal recessive form of congenital myopathy. PMID:22560515

  12. Anasarca and myopathy in ostrich chicks.

    PubMed

    Philbey, A W; Button, C; Gestier, A W; Munro, B E; Glastonbury, J R; Hindmarsh, M; Love, S C

    1991-07-01

    Twenty ostrich chicks that died at, or within, 1 week after hatching were examined from 7 farms with poor (43 to 75%) hatchability. All chicks had anasarca and 15 had mild, generalised, acute degenerative changes in the complexus and pelvic limb muscles. One had fibrinoid degeneration of arterioles. Biochemical examinations produced no evidence of deficiencies of selenium, vitamin A or vitamin E. The syndrome was related to high relative humidity during incubation. Malpositioning also was a cause of embryo mortality.

  13. Statin-induced necrotizing myositis - a discrete autoimmune entity within the "statin-induced myopathy spectrum".

    PubMed

    Hamann, Philip D H; Cooper, Robert G; McHugh, Neil J; Chinoy, Hector

    2013-10-01

    Statin-induced necrotizing myositis is increasingly being recognised as part of the "statin-induced myopathy spectrum". As in other immune-mediated necrotizing myopathies, statin-induced myositis is characterised by proximal muscle weakness with marked serum creatinine kinase elevations and histological evidence of myonecrosis, with little or no inflammatory cell infiltration. Unlike other necrotizing myopathies, statin-induced myopathy is associated with the presence of autoantibodies directed against 3-hydroxy-3-methylglutaryl- coenzyme A reductase (the enzyme target of statin therapies), and with Human Leukocyte Antigen-DRB1*11. This article summarises the clinical presentation, investigations and management of this rare, but serious complication of statin therapy.

  14. Coenzyme Q10 and statin-related myopathy.

    PubMed

    2015-05-01

    Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is involved in the production of mevalonic acid in the cholesterol biosynthesis pathway. This pathway also results in the production of other bioactive molecules including coenzyme Q10 (also known as ubiquinone or ubidecarenone). Coenzyme Q10 is a naturally-occurring coenzyme with antioxidant effects that is involved in electron transport in mitochondria and is thought to play a role in energy transfer in skeletal muscle. Muscle-related problems are a frequently reported adverse effect of statins, and it has been hypothesised that a reduced endogenous coenzyme Q10 concentration is a cause of statin-induced myopathy. Coenzyme Q10 supplementation has therefore been proposed to reduce the adverse muscular effects sometimes seen with statins. Here, we consider whether coenzyme Q10 has a place in the management of statin-induced myopathy.

  15. Chronic primary intestinal pseudo-obstruction from visceral myopathy.

    PubMed

    Muñoz-Yagüe, M T; Marín, J C; Colina, F; Ibarrola, C; López-Alonso, G; Martín, M A; Solís-Herruzo, J A

    2006-04-01

    Chronic intestinal pseudo-obstruction is an uncommon syndrome characterized by relapsing episodes suggesting intestinal obstruction during which no mechanical causes are identified to account for symptoms. Etiologic factors may be manifold. Among them a number of neurologic conditions, gastrointestinal smooth muscle myopathies, endocrino-metabolic and autoimmune diseases, and the use of selected drugs stand out. We report a case of chronic intestinal pseudo-obstruction originating in a sporadic, primary intestinal myopathy that corresponds to no type thus far described. A histological study of the intestinal wall showed disrupted muscle bundles and the presence of interstitial edema. Myocytes had severe degenerative changes, and no alterations were seen in submucosal and myenteric plexus neurons. The activity of enzyme complexes in the mitochondrial respiratory chain, and of thymidine phosphorylase was normal. No mitochondrial DNA changes were seen.

  16. Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.

    PubMed

    Horvath, Rita; Kemp, John P; Tuppen, Helen A L; Hudson, Gavin; Oldfors, Anders; Marie, Suely K N; Moslemi, Ali-Reza; Servidei, Serenella; Holme, Elisabeth; Shanske, Sara; Kollberg, Gittan; Jayakar, Parul; Pyle, Angela; Marks, Harold M; Holinski-Feder, Elke; Scavina, Mena; Walter, Maggie C; Coku, Jorida; Günther-Scholz, Andrea; Smith, Paul M; McFarland, Robert; Chrzanowska-Lightowlers, Zofia M A; Lightowlers, Robert N; Hirano, Michio; Lochmüller, Hanns; Taylor, Robert W; Chinnery, Patrick F; Tulinius, Mar; DiMauro, Salvatore

    2009-11-01

    Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.

  17. Andersen-Tawil syndrome with early fixed myopathy.

    PubMed

    Lefter, Stela; Hardiman, Orla; Costigan, Donal; Lynch, Bryan; McConville, John; Hand, Collette K; Ryan, Aisling M

    2014-12-01

    Andersen-Tawil syndrome (ATS) is a rare autosomal dominant potassium channelopathy characterized by a triad of periodic paralysis, ventricular arrhythmias, and distinctive dysmorphic abnormalities. We present a 19-year-old man with characteristic skeletal dysmorphic features of ATS, early nonfluctuating proximal lower limb weakness from childhood, and neonatal focal seizures. He later developed fluctuating weakness in addition to a fixed proximal myopathy. A 12-lead electrocardiogram showed prominent "U" waves, and McManis protocol prolonged exercise test showed an unusually early decline in the compound motor action potential amplitude by 51%. Genetic testing revealed a de novo heterozygous mutation (R218W) in KCNJ2 associated with ATS. This is the first reported case of ATS in an Irish population with an unusual fixed myopathy from early childhood.

  18. Chronic myopathy due to immunoglobulin light chain amyloidosis

    PubMed Central

    Manoli, Irini; Kwan, Justin Y.; Wang, Qian; Rushing, Elisabeth J.; Tsokos, Maria; Arai, Andrew E.; Burch, Warner M.; Dispenzieri, Angela; McPherron, Alexandra C.; Gahl, William A.

    2013-01-01

    Amyloid myopathy associated with a plasma cell dyscrasia is a rare cause of muscle hypertrophy. It can be a challenging diagnosis, since pathological findings are often elusive. In addition, the mechanism by which immunoglobulin light-chain deposition stimulates muscle overgrowth remains poorly understood. We present a 53–year old female with a 10-year history of progressive generalized muscle overgrowth. Congo-red staining and immunohistochemistry revealed perivascular lambda light chain amyloid deposits, apparent only in a second muscle biopsy. The numbers of central nuclei and satellite cells were increased, suggesting enhanced muscle progenitor cell formation. Despite the chronicity of the light chain disease, the patient showed complete resolution of hematologic findings and significant improvement of her muscle symptoms following autologous bone marrow transplantation. This case highlights the importance of early diagnosis and therapy for this treatable cause of a chronic myopathy with muscle hypertrophy. PMID:23465863

  19. Nemaline myopathy in a newborn infant: a rare muscle disorder.

    PubMed

    Olukman, O; Calkavur, S; Diniz, G; Unalp, A; Atlihan, F

    2013-01-01

    Nemaline myopathy (NM) is a genetically and clinically heterogeneous muscle disorder, defined by the presence of characteristic nemaline bodies on muscle biopsy. The disease has a wide spectrum of phenotypes, ranging from forms with neonatal onset and fatal outcome to asymptomatic forms. The neonatal form is severe and usually fatal. The clinical variability, with differing age of onset and severity of symptoms makes the diagnosis difficult during infancy. There is no curative treatment. L-tyrosine may prevent aspiration by reducing pharyngeal secretions and drooling. Most of the patients die from respiratory and cardiac failure. This article discusses a newborn infant who presented with generalized weakness and respiratory failure. Partial response to L-tyrosine treatment was noted. The case is worth presenting to remind clinicians of congenital myopathies in the differential diagnosis of floppy infant during neonatal period and to emphasize the importance of muscle biopsy in diagnosis.

  20. Exercise training in mitochondrial myopathy: a randomized controlled trial.

    PubMed

    Cejudo, Pilar; Bautista, Juan; Montemayor, Teodoro; Villagómez, Rafael; Jiménez, Luis; Ortega, Francisco; Campos, Yolanda; Sánchez, Hildegard; Arenas, Joaquín

    2005-09-01

    Patients with mitochondrial myopathies (MM) usually suffer from exercise intolerance due to their impaired oxidative capacity and physical deconditioning. We evaluated the effects of a 12-week supervised randomized rehabilitation program involving endurance training in patients with MM. Twenty MM patients were assigned to a training or control group. For three nonconsecutive days each week, patients combined cycle exercise at 70% of their peak work rate with three upper-body weight-lifting exercises performed at 50% of maximum capacity. Training increased maximal oxygen uptake (28.5%), work output (15.5%), and minute ventilation (40%), endurance performance (62%), walking distance in shuttle walking test (+95 m), and peripheral muscle strength (32%-62%), and improved Nottingham Health Profile scores (21.47%) and clinical symptoms. Control MM patients did not change from baseline. Results show that our exercise program is an adequate training strategy for patients with mitochondrial myopathy.

  1. An unusual myopathy: speckled muscle fibers due to enlarged mitochondria.

    PubMed

    Jeffree, Rosalind L; Wills, Edward J; Harper, Clive

    2007-07-01

    We report a 52-year-old woman who presented with a 6-month history of proximal muscle weakness, elevated serum creatine kinase, and myopathic pattern on electromyography (EMG). Histology of the muscle shows a speckled pattern due to clustering of enlarged mitochondria. The pathology resembles that of selenium deficiency. The patient was found to have borderline low serum selenium and also low vitamin D and thyroid-stimulating hormone. The cause of this unusual myopathy is probably multifactorial. This case is important because the unusual pathological picture represents a potentially treatable myopathy. In addition, we hope that publication of the complex clinical and biochemical abnormalities of this case, in conjunction with other case reports, may facilitate future elucidation of muscle mitochondrial function and dysfunction.

  2. Analysis of lipid profile in lipid storage myopathy.

    PubMed

    Aguennouz, M'hammed; Beccaria, Marco; Purcaro, Giorgia; Oteri, Marianna; Micalizzi, Giuseppe; Musumesci, Olimpia; Ciranni, Annmaria; Di Giorgio, Rosa Maria; Toscano, Antonio; Dugo, Paola; Mondello, Luigi

    2016-09-01

    Lipid dysmetabolism disease is a condition in which lipids are stored abnormally in organs and tissues throughout the body, causing muscle weakness (myopathy). Usually, the diagnosis of this disease and its characterization goes through dosage of Acyl CoA in plasma accompanied with evidence of droplets of intra-fibrils lipids in the patient muscle biopsy. However, to understand the pathophysiological mechanisms of lipid storage diseases, it is useful to identify the nature of lipids deposited in muscle fiber. In this work fatty acids and triglycerides profile of lipid accumulated in the muscle of people suffering from myopathies syndromes was characterized. In particular, the analyses were carried out on the muscle biopsy of people afflicted by lipid storage myopathy, such as multiple acyl-coenzyme A dehydrogenase deficiency, and neutral lipid storage disease with myopathy, and by the intramitochondrial lipid storage dysfunctions, such as deficiencies of carnitine palmitoyltransferase II enzyme. A single step extraction and derivatization procedure was applied to analyze fatty acids from muscle tissues by gas chromatography with a flame ionization detector and with an electronic impact mass spectrometer. Triglycerides, extracted by using n-hexane, were analyzed by high performance liquid chromatography coupled to mass spectrometer equipped with an atmospheric pressure chemical ionization interface. The most representative fatty acids in all samples were: C16:0 in the 13-24% range, C18:1n9 in the 20-52% range, and C18:2n6 in the 10-25% range. These fatty acids were part of the most representative triglycerides in all samples. The data obtained was statistically elaborated performing a principal component analysis. A satisfactory discrimination was obtained among the different diseases. Using component 1 vs component 3 a 43.3% of total variance was explained. Such results suggest the important role that lipid profile characterization can have in supporting a correct

  3. Filamin C-related myopathies: pathology and mechanisms

    PubMed Central

    Goldfarb, Lev G.; Kley, Rudolf A.; Vorgerd, Matthias; Olivé, Montse; van der Ven, Peter F. M.

    2016-01-01

    The term filaminopathy was introduced after a truncating mutation in the dimerization domain of filamin C (FLNc) was shown to be responsible for a devastating muscle disease. Subsequently, the same mutation was found in patients from diverse ethnical origins, indicating that this specific alteration is a mutational hot spot. Patients initially present with proximal muscle weakness, while distal and respiratory muscles become affected with disease progression. Muscle biopsies of these patients show typical signs of myofibrillar myopathy, including disintegration of myofibrils and aggregation of several proteins into distinct intracellular deposits. Highly similar phenotypes were observed in patients with other mutations in Ig-like domains of FLNc that result in expression of a noxious protein. Biochemical and biophysical studies showed that the mutated domains acquire an abnormal structure causing decreased stability and eventually becoming a seed for abnormal aggregation with other proteins. The disease usually presents only after the fourth decade of life possibly as a result of ageing-related impairments in the machinery that is responsible for disposal of damaged proteins. This is confirmed by mutations in components of this machinery that cause a highly similar phenotype. Transfection studies of cultured muscle cells reflect the events observed in patient muscles and, therefore, may provide a helpful model for testing future dedicated therapeutic strategies. More recently, FLNC mutations were also found in families with a distal myopathy phenotype, caused either by mutations in the actin-binding domain of FLNc that result in increased actin-binding and non-specific myopathic abnormalities without myofibrillar myopathy pathology, or a nonsense mutation in the rod domain that leads to RNA instability, haploinsufficiency with decreased expression levels of FLNc in the muscle fibers and myofibrillar abnormalities, but not to the formation of desmin-positive protein

  4. Idiopathic inflammatory myopathies: definition and management of refractory disease.

    PubMed

    Brandão, Mariana; Marinho, António

    2011-09-01

    Adult idiopathic inflammatory myopathies, commonly referred to as myositis, are a heterogeneous group of diseases with an autoimmune etiology. In this review, the authors are going to focus on myositis excluding inclusion body myositis. They will review the prognostic factors (for mortality and response to steroids), define refractory disease, introduce a new concept (presumed refractory disease), analyze definitions of active disease, damage and improvement criteria, and summarize therapeutic alternatives for refractory patients, based on different disease phenotypes.

  5. Statin myopathy: a common dilemma not reflected in clinical trials.

    PubMed

    Fernandez, Genaro; Spatz, Erica S; Jablecki, Charles; Phillips, Paul S

    2011-06-01

    Although statins are remarkably effective, they are still underprescribed because of concerns about muscle toxicity. We review the aspects of statin myopathy that are important to the primary care physician and provide a guide for evaluating patients on statins who present with muscle complaints. We outline the differential diagnosis, the risks and benefits of statin therapy in patients with possible toxicity, and the subsequent treatment options.

  6. Insights into muscle degeneration from heritable inclusion body myopathies.

    PubMed

    Krause, Sabine

    2015-01-01

    Muscle mass and function are gradually lost in age-related, degenerative neuromuscular disorders, which also reflect the clinical hallmarks of sarcopenia. The consensus definition of sarcopenia includes a condition of age-related loss of muscle mass, quality, and strength. The most common acquired muscle disease affecting adults aged over 50 years is sporadic inclusion body myositis (sIBM). Besides inflammatory effects and immune-mediated muscle injury, degenerative myofiber changes are characteristic features of the disease. Although the earliest triggering events in sIBM remain elusive, a plethora of downstream mechanisms are implicated in the pathophysiology of muscle wasting. Although it remains controversial whether hereditary forms of inclusion body myopathy (IBM) may be considered as degenerative sIBM disease models, partial pathophysiological aspects can mimic the much more frequent sporadic condition, in particular the occurrence of inclusion bodies in skeletal muscle. Various clinical aspects in genetically determined skeletal muscle disorders reflect age-related alterations observed in sarcopenia. Several intriguing clues from monogenic defects in heritable IBMs contributing to the molecular basis of muscle loss will be discussed with special emphasis on inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and GNE myopathy. Finally, also the recently identified dominant multisystem proteinopathy will be considered, which may rarely present as IBM.

  7. Dermatomyositis, polymyositis and immune-mediated necrotising myopathies.

    PubMed

    Luo, Yue-Bei; Mastaglia, Frank L

    2015-04-01

    Dermatomyositis, polymyositis and immune-mediated necrotising myopathy are major forms of idiopathic inflammatory myopathy. We review here recent developments in understanding the pathology and pathogenesis of these diseases, and characterisation of autoantibody biomarkers. Dermatomyositis is traditionally considered to be due to a complement-mediated microangiopathy but the factors responsible for complement activation remain uncertain. Recent studies have emphasised the importance of the type I interferon pathway in the pathogenesis of the disease and have identified autoantibodies with specificities for different clinical subgroups of patients. Polymyositis is characterised by a cytotoxic T cell response targeting as yet unidentified muscle antigens presented by MHC Class I molecules, and can occur in isolation but is more often part of a multi-systemic overlap syndrome. The immune-mediated necrotising myopathies are heterogeneous and are distinguished from polymyositis by the sparseness of inflammatory infiltrates and recognition of an association with specific autoantibodies such as anti-SRP and anti-HMGCR in many cases. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

  8. The genetic basis of undiagnosed muscular dystrophies and myopathies

    PubMed Central

    Savarese, Marco; Di Fruscio, Giuseppina; Torella, Annalaura; Fiorillo, Chiara; Magri, Francesca; Fanin, Marina; Ruggiero, Lucia; Ricci, Giulia; Astrea, Guja; Passamano, Luigia; Ruggieri, Alessandra; Ronchi, Dario; Tasca, Giorgio; D'Amico, Adele; Janssens, Sandra; Farina, Olimpia; Mutarelli, Margherita; Marwah, Veer Singh; Garofalo, Arcomaria; Giugliano, Teresa; Sanpaolo, Simone; Del Vecchio Blanco, Francesca; Esposito, Gaia; Piluso, Giulio; D'Ambrosio, Paola; Petillo, Roberta; Musumeci, Olimpia; Rodolico, Carmelo; Messina, Sonia; Evilä, Anni; Hackman, Peter; Filosto, Massimiliano; Di Iorio, Giuseppe; Siciliano, Gabriele; Mora, Marina; Maggi, Lorenzo; Minetti, Carlo; Sacconi, Sabrina; Santoro, Lucio; Claes, Kathleen; Vercelli, Liliana; Mongini, Tiziana; Ricci, Enzo; Gualandi, Francesca; Tupler, Rossella; De Bleecker, Jan; Udd, Bjarne; Toscano, Antonio; Moggio, Maurizio; Pegoraro, Elena; Bertini, Enrico; Mercuri, Eugenio; Angelini, Corrado; Santorelli, Filippo Maria; Politano, Luisa; Bruno, Claudio; Comi, Giacomo Pietro

    2016-01-01

    Objective: To apply next-generation sequencing (NGS) for the investigation of the genetic basis of undiagnosed muscular dystrophies and myopathies in a very large cohort of patients. Methods: We applied an NGS-based platform named MotorPlex to our diagnostic workflow to test muscle disease genes with a high sensitivity and specificity for small DNA variants. We analyzed 504 undiagnosed patients mostly referred as being affected by limb-girdle muscular dystrophy or congenital myopathy. Results: MotorPlex provided a complete molecular diagnosis in 218 cases (43.3%). A further 160 patients (31.7%) showed as yet unproven candidate variants. Pathogenic variants were found in 47 of 93 genes, and in more than 30% of cases, the phenotype was nonconventional, broadening the spectrum of disease presentation in at least 10 genes. Conclusions: Our large DNA study of patients with undiagnosed myopathy is an example of the ongoing revolution in molecular diagnostics, highlighting the advantages in using NGS as a first-tier approach for heterogeneous genetic conditions. PMID:27281536

  9. Capture myopathy in an endangered sandhill crane (Grus canadensis pulla)

    USGS Publications Warehouse

    Carpenter, J.W.; Thomas, N.J.; Reeves, S.

    1991-01-01

    Despite precautions to protect cranes, a 3-year-old endangered Mississippi sandhill crane (Grus canadensis pulla) was found caught in a leghold trap in Gautier, Mississippi, on 11 November 1987. The bird could have been in the trap for up to 16 hr and was standing and struggling to escape when it was discovered. Serum chemistries of the crane on 12 November revealed elevated lactic dehydrogenase (2,880 IU/L), alanine aminotransferase (ALT) (152 IU/L), and aspartate aminotransferase (AST) (>1,000 IU/L) values. Following surgical amputation of a fractured toe, the bird never attempted to stand and was unable to stand even when manually supported. Radiographic and physical examination of both legs did not reveal any anatomical abnormalities. Despite medical care, including supportive therapy, no improvement was observed in the bird's ability to stand and to support itself, and the bird died on 19 November. Serum chemistries and the postmortem and histopathologic findings were compatible with capture myopathy described in other species. Because of the possible susceptibility of long-legged birds such as the Mississippi sandhill crane to capture myopathy, special care must be taken when trapping, handling, chemically immobilizing, and transporting these species. In addition, precautions must be taken when conducting a predator-control program to ensure that nontarget wildlife are unlikely to encounter traps. Capture myopathy has only rarely been observed in wild birds, and this case represents the first report in a Mississippi sandhill crane.

  10. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy

    PubMed Central

    Ceyhan-Birsoy, Ozge; Agrawal, Pankaj B.; Hidalgo, Carlos; Schmitz-Abe, Klaus; DeChene, Elizabeth T.; Swanson, Lindsay C.; Soemedi, Rachel; Vasli, Nasim; Iannaccone, Susan T.; Shieh, Perry B.; Shur, Natasha; Dennison, Jane M.; Lawlor, Michael W.; Laporte, Jocelyn; Markianos, Kyriacos; Fairbrother, William G.; Granzier, Henk

    2013-01-01

    Objective: To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and hypotonia, using next-generation sequencing of whole exomes and genomes. Methods: Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest. Results: Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations. Conclusions: Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes. PMID:23975875

  11. Polymyositis without Beneficial Response to Steroid Therapy: Should Miyoshi Myopathy be a Differential Diagnosis?

    PubMed Central

    Scalco, Renata Siciliani; Lorenzoni, Paulo José; Lynch, David S.; Martins, William Alves; Jungbluth, Heinz; Quinlivan, Ros; Becker, Jefferson; Houlden, Henry

    2017-01-01

    Patient: Male, 16 Final Diagnosis: Miyoshi myopathy Symptoms: HyperCKemia • myalgia • weakness Medication: — Clinical Procedure: — Specialty: Neurology Objective: Rare disease Background: Miyoshi myopathy (MM) is an autosomal-recessive muscle disorder caused by mutations in the DYSF gene. Clinical features and histopathological changes in dysferlinopathies may mimic inflammatory myopathies and a high degree of clinical suspicion is required to guide the genetic investigation. Case Report: We report the case of a 16-year-old male who presented with severe bilateral calf pain and elevated CK levels (15 000 IU/l) who was on prolonged steroid therapy prompted by the clinical suspicion of inflammatory myopathy. Three years into his illness, he was referred for neuromuscular evaluation presenting with untreatable muscle pain and progressive weakness. The diagnosis of “refractory polymyositis” was revisited. Targeted exome sequencing revealed homozygous pathogenic mutations in the DYSF gene, confirming a diagnosis of Miyoshi myopathy. Conclusions: Our case illustrates that severe muscle pain may be the initial feature of Miyoshi myopathy and should be considered in the differential diagnosis of inflammatory myopathies. Although the described patient reported partial clinical improvement in muscle pain, steroid treatment is not an effective therapy for dysferlinopathy patients and it did not prevent disease progression. In addition, we confirm the utility of next-generation sequencing approaches to myopathies, particularly in complex or unusual cases when muscle biopsy is not available. PMID:28053302

  12. Myopathy induced by statin-ezetimibe combination: Evaluation of potential risk factors.

    PubMed

    Brahmachari, Ballari; Chatterjee, Suparna

    2015-01-01

    Although both atorvastatin and ezetimibe may cause myopathy, statin-induced myopathy is less likely at low doses, and ezetimibe is only rarely reported to induce myopathy. Also, ezetimibe is not usually known to potentiate statin-induced myopathy. We report a case of myalgia with elevated serum creatinine phosphokinase in a patient after 2 months of therapy with fixed dose combination of atorvastatin and ezetimibe (10 mg each). At the time of the event, patient was undertaking moderate physical exertion in the form of brisk walking for 30-40 min a day and was detected to have low serum Vitamin D levels. The adverse event resolved after stopping atorvastatin-ezetimibe combination therapy. Potential risk factors, such as physical exertion and Vitamin D deficiency, co-existent in dyslipidemic patients, may exacerbate myopathy potential of these drugs, and precipitate muscular symptoms even at a low-dose.

  13. Steroid myopathy in a child with juvenile rheumatoid arthritis. Case report.

    PubMed

    Genel, F; Arslanoglu, S; Hizarcioglu, M; Durmaz, B; Uran, N; Aktaş, S

    2003-03-01

    An 8-year-old boy who had been diagnosed as systemic-onset juvenile rheumatoid arthritis were on treatment for 8 months with methotrexate and additional steroids during activation. At the end of the 8th month when the corticosteroid dose was 12.5 mg/day, he began to suffer from numbness and weakness in his hands. Physical examination, laboratory findings and electromyography results demonstrated myopathy. Steroid myopathy was considered. Corticosteroids were tapered and stopped. At follow-up clinical findings remitted and electromyography became normal at the 4th month. We present here this case to direct attention to drug-induced myopathy besides myopathy due to primary disease in connective tissue disorders whenever myopathy exists.

  14. Obstructive sleep apnea in patients with inflammatory myopathies.

    PubMed

    Selva-O'Callaghan, Albert; Sampol, Gabriel; Romero, Odile; Lloberes, Patricia; Trallero-Araguás, Ernesto; Vilardell-Tarrés, Miquel

    2009-02-01

    The purpose of this study was to determine the frequency of obstructive sleep apnea in patients with inflammatory myopathy. An observational and prospective study was performed on a cohort of adult patients with inflammatory myopathy followed at a specialized outpatient clinic. Sixteen consecutive adult patients were evaluated by the Epworth Sleepiness Scale (ESS) and by complete polysomnography study. Disease activity and severity were assessed using the Myositis Disease Activity Assessment Tool (MDAAT) and Myositis Damage Index (MDI), respectively. Associations between sleep parameters and other factors were calculated using the chi-square test, Fisher's exact test, Mann-Whitney U-test, and Wilcoxon's test. A serum autoantibody profile was determined for all patients. The mean apnea-hypopnea index was 28.7 (23.8), and 14 patients (87%) had an apnea-hypopnea index >5. The mean frequency of respiratory arousals was 20.1 (12.5). Eleven (68%) patients reported frequently-always snoring, and 3 (19%) had excessive daytime sleepiness (ESS >10). Seven patients were offered continuous positive airway pressure (CPAP) therapy; 4 tolerated the procedure well and reported a clear improvement in daytime sleepiness and/or sleep quality. No significant association was observed between the apnea-hypopnea index and clinical or immunological groups. Dysphagia, disease activity, and disease severity were not significantly associated with any sleep parameters. The frequency of obstructive sleep apnea in adult patients with inflammatory myopathy is high. The possibility that these alterations play a role in persistent fatigue in these patients cannot be ruled out.

  15. Ketogenic diet slows down mitochondrial myopathy progression in mice.

    PubMed

    Ahola-Erkkilä, Sofia; Carroll, Christopher J; Peltola-Mjösund, Katja; Tulkki, Valtteri; Mattila, Ismo; Seppänen-Laakso, Tuulikki; Oresic, Matej; Tyynismaa, Henna; Suomalainen, Anu

    2010-05-15

    Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre-symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in mitochondrial RC deficiencies, and prevented completely the formation of the mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced mitochondrial biogenesis and restored liver lipid levels. Our results show that mitochondrial myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for mitochondrial late-onset myopathies.

  16. [Myopathy and rhabdomyolysis after treatment with simvastatin, amlodipine, and roxithromycin].

    PubMed

    Skovbølling, Sara Lyngby; Lindelof, Mette

    2014-10-06

    This is a case report of a 71-year-old male with known diabetes, hypertension and diabetic nephropaty who over the course of one year developed an unrecognized myopathy due to concomitant treatment with high-dose simvastatin and amlodipin. Due to rhabdomyolysis he was after seven days of treatment with roxithromycin admitted to hospital with loss of the ability to walk. We wish to raise awareness of the potentially severe side effects of simvastatin and to emphasize that these can be limited by increased attention to patients with risk factors and to interactions with other drugs.

  17. Histopathologic and MRI findings in hypokalemic myopathy induced by glycyrrhizin.

    PubMed

    Hayashi, K; Hayashi, R; Maruyama, K; Yanagisawa, N

    1995-08-01

    Histopathologic studies and magnetic resonance images of the leg muscles were conducted in two patients with glycyrrhizin-induced hypokalemic myopathy (GHM). Muscle biopsy showed myopathic changes and vacuolated fibers with light microscopy, and dilatation of the sarcoplasmic reticulum, various types of vacuoles and myofibrillar degeneration with electron microscopy. High signal intensities in T2-weighted images obtained during severe muscle weakness were widely distributed in the leg muscles, especially the pretibial and soleus muscles. These high signal intensities disappeared after full recovery of muscle weakness. We suggest that high signal intensity in T2-weighted images can be seen and correspond to histopathologic changes in the muscles of GHM patients.

  18. Polymyositis without Beneficial Response to Steroid Therapy: Should Miyoshi Myopathy be a Differential Diagnosis?

    PubMed

    Scalco, Renata Siciliani; Lorenzoni, Paulo José; Lynch, David S; Martins, William Alves; Jungbluth, Heinz; Quinlivan, Ros; Becker, Jefferson; Houlden, Henry

    2017-01-05

    BACKGROUND Miyoshi myopathy (MM) is an autosomal-recessive muscle disorder caused by mutations in the DYSF gene. Clinical features and histopathological changes in dysferlinopathies may mimic inflammatory myopathies and a high degree of clinical suspicion is required to guide the genetic investigation. CASE REPORT We report the case of a 16-year-old male who presented with severe bilateral calf pain and elevated CK levels (15 000 IU/l) who was on prolonged steroid therapy prompted by the clinical suspicion of inflammatory myopathy. Three years into his illness, he was referred for neuromuscular evaluation presenting with untreatable muscle pain and progressive weakness. The diagnosis of "refractory polymyositis" was revisited. Targeted exome sequencing revealed homozygous pathogenic mutations in the DYSF gene, confirming a diagnosis of Miyoshi myopathy. CONCLUSIONS Our case illustrates that severe muscle pain may be the initial feature of Miyoshi myopathy and should be considered in the differential diagnosis of inflammatory myopathies. Although the described patient reported partial clinical improvement in muscle pain, steroid treatment is not an effective therapy for dysferlinopathy patients and it did not prevent disease progression. In addition, we confirm the utility of next-generation sequencing approaches to myopathies, particularly in complex or unusual cases when muscle biopsy is not available.

  19. Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy.

    PubMed

    Dowling, James J; Arbogast, Sandrine; Hur, Junguk; Nelson, Darcee D; McEvoy, Anna; Waugh, Trent; Marty, Isabelle; Lunardi, Joel; Brooks, Susan V; Kuwada, John Y; Ferreiro, Ana

    2012-04-01

    The skeletal muscle ryanodine receptor is an essential component of the excitation-contraction coupling apparatus. Mutations in RYR1 are associated with several congenital myopathies (termed RYR1-related myopathies) that are the most common non-dystrophic muscle diseases of childhood. Currently, no treatments exist for these disorders. Although the primary pathogenic abnormality involves defective excitation-contraction coupling, other abnormalities likely play a role in disease pathogenesis. In an effort to discover novel pathogenic mechanisms, we analysed two complementary models of RYR1-related myopathies, the relatively relaxed zebrafish and cultured myotubes from patients with RYR1-related myopathies. Expression array analysis in the zebrafish disclosed significant abnormalities in pathways associated with cellular stress. Subsequent studies focused on oxidative stress in relatively relaxed zebrafish and RYR1-related myopathy myotubes and demonstrated increased oxidant activity, the presence of oxidative stress markers, excessive production of oxidants by mitochondria and diminished survival under oxidant conditions. Exposure to the antioxidant N-acetylcysteine reduced oxidative stress and improved survival in the RYR1-related myopathies human myotubes ex vivo and led to significant restoration of aspects of muscle function in the relatively relaxed zebrafish, thereby confirming its efficacy in vivo. We conclude that oxidative stress is an important pathophysiological mechanism in RYR1-related myopathies and that N-acetylcysteine is a successful treatment modality ex vivo and in a vertebrate disease model. We propose that N-acetylcysteine represents the first potential therapeutic strategy for these debilitating muscle diseases.

  20. Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy

    PubMed Central

    Kadoya, Masato; Hida, Ayumi; Hashimoto Maeda, Meiko; Taira, Kenichiro; Ikenaga, Chiseko; Uchio, Naohiro; Kubota, Akatsuki; Kaida, Kenichi; Miwa, Yusuke; Kurasawa, Kazuhiro; Shimada, Hiroyuki; Sonoo, Masahiro; Chiba, Atsuro; Shiio, Yasushi; Uesaka, Yoshikazu; Sakurai, Yasuhisa; Izumi, Toru; Inoue, Manami; Kwak, Shin; Tsuji, Shoji

    2016-01-01

    Objective: To show cancer association is a risk factor other than statin exposure for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody-positive (anti-HMGCR Ab+) myopathy. Methods: We analyzed the clinical features and courses of 33 patients (23 female and 10 male) with anti-HMGCR Ab+ myopathy among 621 consecutive patients with idiopathic inflammatory myopathies. Results: Among the 33 patients, 7 (21%) were statin-exposed and 26 were statin-naive. In relation with cancer, there were 12 patients (statin-exposed, n = 4) with cancers detected within 3 years of myopathy diagnosis (cancer association), 3 patients (all statin-naive) with cancers detected more than 3 years before myopathy diagnosis (cancer history), 10 cancer-free patients followed up for more than 3 years (all statin-naive), and 8 patients without cancer detection but followed up for less than 3 years (statin-exposed, n = 3). Therefore, 12 patients with cancer association (36%) formed a larger group than that of 7 statin-exposed patients (21%). Among 12 patients with cancer association, 92% had cancer detection within 1 year of myopathy diagnosis (after 1.3 years in the remaining patient), 83% had advanced cancers, and 75% died of cancers within 2.7 years. Of interest, 1 patient with cancer history had sustained increase in creatine kinase level over 12 years from cancer removal to the development of weakness. Conclusions: Patients with cancer association formed a large group with poor prognosis in our series of patients with anti-HMGCR Ab+ myopathy. The close synchronous occurrence of cancers and myopathies suggested that cancer association is one of the risk factors for developing anti-HMGCR Ab+ myopathy. PMID:27761483

  1. Respiratory Motor Function in Individuals with Centronuclear Myopathies

    PubMed Central

    Smith, Barbara K.; Renno, Markus S.; Green, Meghan M.; Sexton, Terry M.; Lawson, Lee Ann; Martin, Anatole D.; Corti, Manuela; Byrne, Barry J.

    2015-01-01

    Introduction Individuals with X-linked myotubular myopathy (XLMTM) and other centronuclear myopathies (CNMs) frequently have profound respiratory insufficiency that requires support early in life. Still, few quantitative data exist to characterize respiratory motor function in CNM. Methods We evaluated the reliance upon mechanical ventilation (MV), ventilatory kinematics, unassisted tidal volumes, and maximal respiratory pressures in 14 individuals with CNMs, including 10 boys with XLMTM. Results Thirteen participants required full-time, invasive MV. Maximal inspiratory pressures were higher in subjects who breathed unsupported at least 1 hour per day than 24-hour MV users [33.7 (11.9–42.3) vs 8.4 (6.0–10.9) cm H2O, P<0.05]. Years of MV dependence significantly correlated with MEP (r=−0.715, P<0.01). Discussion Respiratory function in CNMs may be related to deconditioning from prolonged MV and/or differences in residual respiratory muscle strength. Results from this study may assist in evaluating severe respiratory insufficiency in neuromuscular clinical care and research. PMID:26351754

  2. [Current views on lipid metabolism: statin-induced myopathy].

    PubMed

    Teichmann, L L; Fleck, M

    2010-10-01

    Cardiovascular diseases are the most common causes of death in Germany and the prevalence is increased in patients with inflammatory rheumatic diseases. Statins are often employed for primary and secondary prophylaxis of cardiovascular events but can potentially induce myopathy as a side-effect. In addition to an asymptomatic elevation of muscle enzymes, myalgia and myositis as well as rhabdomyolysis, the most severe side-effect, have been observed, which are mostly manifested within 6 months after initiation of therapy. Statin-induced myopathy is rare but if risk factors are present, the individual risk can be much higher. Such factors are in particular interaction with other medications, statin dosage, the characteristics of the statin preparation used, comorbidities, age and sex of the patient. Regular testing of muscle enzymes after induction of statin therapy is not generally recommended for asymptomatic patients, but is indispensable when muscle symptoms appear. Statin therapy must be immediately terminated and a diagnostic evaluation must be carried out at the latest when creatine kinase values show a more than 10-fold increase.

  3. Mitochondrial Bioenergetics in the Metabolic Myopathy Accompanying Peripheral Artery Disease

    PubMed Central

    Rontoyanni, Victoria G.; Nunez Lopez, Omar; Fankhauser, Grant T.; Cheema, Zulfiqar F.; Rasmussen, Blake B.; Porter, Craig

    2017-01-01

    Peripheral artery disease (PAD) is a serious but relatively underdiagnosed and undertreated clinical condition associated with a marked reduction in functional capacity and a heightened risk of morbidity and mortality. The pathophysiology of lower extremity PAD is complex, and extends beyond the atherosclerotic arterial occlusion and subsequent mismatch between oxygen demand and delivery to skeletal muscle mitochondria. In this review, we evaluate and summarize the available evidence implicating mitochondria in the metabolic myopathy that accompanies PAD. Following a short discussion of the available in vivo and in vitro methodologies to quantitate indices of muscle mitochondrial function, we review the current evidence implicating skeletal muscle mitochondrial dysfunction in the pathophysiology of PAD myopathy, while attempting to highlight questions that remain unanswered. Given the rising prevalence of PAD, the detriment in quality of life for patients, and the associated significant healthcare resource utilization, new alternate therapies that ameliorate lower limb symptoms and the functional impairment associated with PAD are needed. A clear understanding of the role of mitochondria in the pathophysiology of PAD may contribute to the development of novel therapeutic interventions. PMID:28348531

  4. Statin-associated myopathy: from genetic predisposition to clinical management.

    PubMed

    Vrablik, M; Zlatohlavek, L; Stulc, T; Adamkova, V; Prusikova, M; Schwarzova, L; Hubacek, J A; Ceska, R

    2014-01-01

    Statin-associated myopathy (SAM) represents a broad spectrum of disorders from insignificant myalgia to fatal rhabdomyolysis. Its frequency ranges from 1-5 % in clinical trials to 15-20 % in everyday clinical practice. To a large extent, these variations can be explained by the definition used. Thus, we propose a scoring system to classify statin-induced myopathy according to clinical and biochemical criteria as 1) possible, 2) probable or 3) definite. The etiology of this disorder remains poorly understood. Most probably, an underlying genetic cause is necessary for overt SAM to develop. Variants in a few gene groups that encode proteins involved in: i) statin metabolism and distribution (e.g. membrane transporters and enzymes; OATP1B1, ABCA1, MRP, CYP3A4), ii) coenzyme Q10 production (e.g. COQ10A and B), iii) energy metabolism of muscle tissue (e.g. PYGM, GAA, CPT2) and several others have been proposed as candidates which can predispose to SAM. Pharmacological properties of individual statin molecules (e.g. lipophilicity, excretion pathways) and patients´ characteristics influence the likelihood of SAM development. This review summarizes current data as well as our own results.

  5. Idiopathic Inflammatory Myopathies and Malignancy: a Comprehensive Review.

    PubMed

    Tiniakou, Eleni; Mammen, Andrew L

    2017-02-01

    The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases (collectively known as myositis) affecting the skeletal muscles as well as other organ systems such as skin, lungs, and joints. The primary forms of myositis include polymyositis (PM), dermatomyositis (PM), and immune-mediated necrotizing myopathy (IMNM). Patients with these diseases experience progressive proximal muscle weakness, have characteristic muscle biopsy findings, and produce autoantibodies that are associated with unique clinical features. One distinguishing feature of these patients is that they are also known to have an increased risk of cancer. Since the first description of the association in 1916, it has been extensively reported in the medical literature. However, there have been significant variations between the different studies with regard to the degree of cancer risk in patients with IIM. These discrepancies can, in part, be attributed to differences in the definition of malignancy-associated myositis used in different studies. In recent years, significant advances have been made in defining specific features of IIM that are associated with the development of malignancy. One of these has been myositis-specific antibodies (MSAs), which are linked to distinct clinical phenotypes and categorize patients into groups with more homogeneous features. Indeed, patients with certain MSAs seem to be at particularly increased risk of malignancy. This review attempts a systematic evaluation of research regarding the association between malignancy and myositis.

  6. Mitochondrial myopathy induces a starvation-like response.

    PubMed

    Tyynismaa, Henna; Carroll, Christopher J; Raimundo, Nuno; Ahola-Erkkilä, Sofia; Wenz, Tina; Ruhanen, Heini; Guse, Kilian; Hemminki, Akseli; Peltola-Mjøsund, Katja E; Tulkki, Valtteri; Oresic, Matej; Moraes, Carlos T; Pietiläinen, Kirsi; Hovatta, Iiris; Suomalainen, Anu

    2010-10-15

    Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.

  7. Human congenital myopathy actin mutants cause myopathy and alter Z-disc structure in Drosophila flight muscle.

    PubMed

    Sevdali, Maria; Kumar, Vikash; Peckham, Michelle; Sparrow, John

    2013-03-01

    Over 190 mutations in the human skeletal muscle α-actin gene, ACTA1 cause congenital actin myopathies. We transgenically expressed six different mutant actins, G15R, I136M, D154N, V163L, V163M and D292V in Drosophila indirect flight muscles and investigated their effects in flies that express one wild type and one mutant actin copy. All the flies were flightless, and the IFMs showed incomplete Z-discs, disorganised actin filaments and 'zebra bodies'. No differences in levels of sarcomeric protein expression were observed, but tropomodulin staining was somewhat disrupted in D164N, V163L, G15R and V163M heterozygotes. A single copy of D292V mutant actin rescued the hypercontractile phenotypes caused by TnI and TnT mutants, suggesting that the D292V mutation interferes with thin filament regulation. Our results show that expression of actin mutations homologous to those in humans in the indirect flight muscles of Drosophila disrupt sarcomere organisation, with somewhat similar phenotypes to those observed in humans. Using Drosophila to study actin mutations may help aid our understanding of congential myopathies caused by actin mutations.

  8. The Myositis Autoantibody Phenotypes of the Juvenile Idiopathic Inflammatory Myopathies

    PubMed Central

    Shah, Mona; Mamyrova, Gulnara; Huber, Adam M.; Rice, Madeline Murguia; Targoff, Ira N.; Miller, Frederick W.

    2013-01-01

    Abstract The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. In follow-up to our study defining the major clinical subgroup phenotypes of JIIM, we compared demographics, clinical features, laboratory measures, and outcomes among myositis-specific autoantibody (MSA) subgroups, as well as with published data on adult idiopathic inflammatory myopathy patients enrolled in a separate natural history study. In the present study, of 430 patients enrolled in a nationwide registry study who had serum tested for myositis autoantibodies, 374 had either a single specific MSA (n = 253) or no identified MSA (n = 121) and were the subject of the present report. Following univariate analysis, we used random forest classification and exact logistic regression modeling to compare autoantibody subgroups. Anti-p155/140 autoantibodies were the most frequent subgroup, present in 32% of patients with juvenile dermatomyositis (JDM) or overlap myositis with JDM, followed by anti-MJ autoantibodies, which were seen in 20% of JIIM patients, primarily in JDM. Other MSAs, including anti-synthetase, anti-signal recognition particle (SRP), and anti-Mi-2, were present in only 10% of JIIM patients. Features that characterized the anti-p155/140 autoantibody subgroup included Gottron papules, malar rash, “shawl-sign” rash, photosensitivity, cuticular overgrowth, lowest creatine kinase (CK) levels, and a predominantly chronic illness course. The features that differed for patients with anti-MJ antibodies included muscle cramps, dysphonia, intermediate CK levels, a high frequency of hospitalization, and a monocyclic disease course. Patients with anti-synthetase antibodies had higher frequencies of interstitial lung disease, arthralgia, and “mechanic’s hands,” and had an older age at diagnosis. The anti-SRP group, which had exclusively juvenile polymyositis, was

  9. The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies.

    PubMed

    Rider, Lisa G; Shah, Mona; Mamyrova, Gulnara; Huber, Adam M; Rice, Madeline Murguia; Targoff, Ira N; Miller, Frederick W

    2013-07-01

    The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. In follow-up to our study defining the major clinical subgroup phenotypes of JIIM, we compared demographics, clinical features, laboratory measures, and outcomes among myositis-specific autoantibody (MSA) subgroups, as well as with published data on adult idiopathic inflammatory myopathy patients enrolled in a separate natural history study. In the present study, of 430 patients enrolled in a nationwide registry study who had serum tested for myositis autoantibodies, 374 had either a single specific MSA (n = 253) or no identified MSA (n = 121) and were the subject of the present report. Following univariate analysis, we used random forest classification and exact logistic regression modeling to compare autoantibody subgroups. Anti-p155/140 autoantibodies were the most frequent subgroup, present in 32% of patients with juvenile dermatomyositis (JDM) or overlap myositis with JDM, followed by anti-MJ autoantibodies, which were seen in 20% of JIIM patients, primarily in JDM. Other MSAs, including anti-synthetase, anti-signal recognition particle (SRP), and anti-Mi-2, were present in only 10% of JIIM patients. Features that characterized the anti-p155/140 autoantibody subgroup included Gottron papules, malar rash, "shawl-sign" rash, photosensitivity, cuticular overgrowth, lowest creatine kinase (CK) levels, and a predominantly chronic illness course. The features that differed for patients with anti-MJ antibodies included muscle cramps, dysphonia, intermediate CK levels, a high frequency of hospitalization, and a monocyclic disease course. Patients with anti-synthetase antibodies had higher frequencies of interstitial lung disease, arthralgia, and "mechanic's hands," and had an older age at diagnosis. The anti-SRP group, which had exclusively juvenile polymyositis, was characterized by high

  10. Myopathy caused by polymyxin E: functional disorder of the cell membrane

    PubMed Central

    Vanhaeverbeek, M.; Ectors, M.; Vanhaelst, L.; Franken, L.

    1974-01-01

    A myopathy caused by the activity of polymyxin E on the cell membrane was accompained by immunological manifestations. There were also disturbances of the central nervous system, contrasting with the absence of serious renal lesion. PMID:4615135

  11. Toxic myopathy induced by industrial minerals oils: clinical and histopathological features.

    PubMed

    Rossi, B; Siciliano, G; Giraldi, C; Angelini, C; Marchetti, A; Paggiaro, P L

    1986-12-01

    We report a case of subacute myopathy in a 47 years old man engaged on boiler maintenance at an oil-fired thermoelectric power station. The occupational history highlighted heavy exposure to inhalation of ash derived from mineral oil combustion and containing several elements, metals and metalloids, including vanadium and nickel. The presenting symptoms, clinical course and muscle histopathology suggest that exposure to toxic agents probably played an important part in the causation of the myopathy.

  12. Prominent subcutaneous oedema as a masquerading symptom of an underlying inflammatory myopathy.

    PubMed

    Anantharajah, Anthea; Vucic, Steve; Tarafdar, Surjit; Vongsuvanh, Roslyn; Wilcken, Nicholas; Swaminathan, Sanjay

    2017-02-01

    The inflammatory myopathies are a group of immune-mediated inflammatory muscle disorders that typically present with marked proximal muscle weakness. We report four cases of inflammatory myopathies with marked subcutaneous oedema as their main complaint. Three of the four patients had normal or low levels of creatine kinase, an enzyme often markedly elevated in these disorders. Magnetic resonance imaging of the muscles, followed by a muscle biopsy were used to make a definitive diagnosis.

  13. Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.

    PubMed

    Haubenberger, D; Bittner, R E; Rauch-Shorny, S; Zimprich, F; Mannhalter, C; Wagner, L; Mineva, I; Vass, K; Auff, E; Zimprich, A

    2005-10-25

    Mutations in the valosin-containing protein (VCP) on chromosome 9p13-p12 were recently found to be associated with hereditary inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD). We identified a novel missense mutation in the VCP gene (R159H; 688G>A) segregating with this disease in an Austrian family of four affected siblings, who exhibited progressive proximal myopathy and Paget disease of the bone but without clinical signs of dementia.

  14. Mitochondrial depletion causes neonatal-onset leigh syndrome, myopathy, and renal tubulopathy.

    PubMed

    Lee, Inn-Chi; Lee, Ni-Chung; Lu, Jang-Jih; Su, Pen-Hua

    2013-03-01

    The authors describe a newborn with postnatal myopathy who subsequently developed feeding difficulties, ophthalmoplegia, ptosis, encephalopathy, and seizures. She became ventilator dependent after sudden apnea. The myopathy was without ragged red fibers in the muscle biopsy. An electron transport chain study showed a markedly generalized low level of enzyme activity, particularly in complexes I, I + III, and IV. An initial electroencephalogram finding was normal; subsequent electroencephalograms showed suppression bursts. The mitochondrial copy number in skeletal muscle was 2% of normal.

  15. Sequential muscle biopsy changes in a case of congenital myopathy.

    SciTech Connect

    Danon, M. J.; Giometti, C. S.; Manaligod, J. R.; Swisher, C.; Center for Mechanistic Biology and Biotechnology; New York Medical Coll.; Univ. of Illinois at Chicago; Children's Memorial Hospital

    1997-05-01

    Muscle biopsies at age 7 months in a set of dizygotic male twins born floppy showed typical features of congenital fiber-type disproportion (CFTD). One of the twins died at age 1 year due to respiratory complications. The second one subsequently developed facial diplegia and external ophthalmoplegia. He never walked, remained wheelchair bound, and required continuous ventilatory support. He underwent repeat biopsies at ages 2 and 4, which showed many atrophic type 1 muscle fibers containing central nuclei and severe type 2 fiber deficiency compatible with centronuclear myopathy (CNM). Two-dimensional gel electrophoresis of muscle showed decreases of type II myosin light chains 2 and 3, suggestive of histochemical type I fiber deficiency. The progressive nature of morphological changes in one of our patients cannot be explained by maturational arrest. Repeat biopsies in cases of CFTD with rapid clinical deterioration may very well show CNM.

  16. The Spectrum of Mitochondrial Ultrastructural Defects in Mitochondrial Myopathy

    PubMed Central

    Vincent, Amy E.; Ng, Yi Shiau; White, Kathryn; Davey, Tracey; Mannella, Carmen; Falkous, Gavin; Feeney, Catherine; Schaefer, Andrew M.; McFarland, Robert; Gorman, Grainne S.; Taylor, Robert W.; Turnbull, Doug M.; Picard, Martin

    2016-01-01

    Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease. PMID:27506553

  17. Inborn Errors of Energy Metabolism Associated with Myopathies

    PubMed Central

    Das, Anibh M.; Steuerwald, Ulrike; Illsinger, Sabine

    2010-01-01

    Inherited neuromuscular disorders affect approximately one in 3,500 children. Structural muscular defects are most common; however functional impairment of skeletal and cardiac muscle in both children and adults may be caused by inborn errors of energy metabolism as well. Patients suffering from metabolic myopathies due to compromised energy metabolism may present with exercise intolerance, muscle pain, reversible or progressive muscle weakness, and myoglobinuria. In this review, the physiology of energy metabolism in muscle is described, followed by the presentation of distinct disorders affecting skeletal and cardiac muscle: glycogen storage diseases types III, V, VII, fatty acid oxidation defects, and respiratory chain defects (i.e., mitochondriopathies). The diagnostic work-up and therapeutic options in these disorders are discussed. PMID:20589068

  18. Hypokalemic myopathy in primary aldosteronism: A case report

    PubMed Central

    Wu, Chuifen; Xin, Jun; Xin, Minghua; Zou, Hai; Jing, Lie; Zhu, Caoyong; Lei, Wenhui

    2016-01-01

    Primary aldosteronism (PA) is a rare disorder. The majority of patients with PA present with typical features and are easily diagnosed. This disorder is usually diagnosed with hypokalemia, hypertension or an adrenal mass. However, patients with atypical symptoms may present a challenge for diagnosis and treatment. In the present study, a case of PA is described that presented with hypokalemic myopathy simulating polymyositis. The patient was a 44-year-old woman who presented with weakness and difficulty walking. The patient was initially suspected to have PM and was treated with methylprednisolone. The patient was found to have hypokalemia which persisted despite high-dose supplementation of potassium. Adrenal computed tomography revealed a right adrenal mass. Surgical adrenalectomy was conducted. The final pathological diagnosis was benign adrenocortical adenoma. The serum tests remained normal and the patient's symptoms were resolved during the 8-month follow-up. PMID:28101185

  19. Rituximab in the treatment of inflammatory myopathies: a review.

    PubMed

    Fasano, Serena; Gordon, Patrick; Hajji, Raouf; Loyo, Esthela; Isenberg, David A

    2017-01-01

    Several uncontrolled studies have encouraged the use of rituximab (RTX) in patients with myositis. Unfortunately, the first placebo-phase trial to assess the efficacy of RTX in refractory myositis did not show a significant difference between the two treatment groups, and doubts have been expressed about its study design. In this review we present an up-to-date overview of the reported experiences of RTX therapy in myositis. A PubMed search was performed to find all the available cases of refractory myositis patients treated with RTX up to July 2015. The following terms were assessed: inflammatory myopathies OR anti-synthetase syndrome OR polymyositis OR dermatomyositis AND RTX. A total of 48 studies were included. We identified 458 patients with myositis treated with RTX. We found a rate of response to RTX of 78.3%. RTX can play a role in the management of patients with myositis, at least in those with positive myositis-specific autoantibodies.

  20. Multiple mitochondrial alterations in a case of myopathy.

    PubMed

    Fujioka, H; Tandler, B; Cohen, M; Koontz, D; Hoppel, C L

    2014-05-01

    Mitochondrial alterations are the most common feature of human myopathies. A biopsy of quadriceps muscle from a 50-year-old woman exhibiting myopathic symptoms was examined by transmission electron microscopy. Biopsied fibers from quadriceps muscle displayed numerous subsarcolemmal mitochondria that contained crystalloids. Numbering 1-6 per organelle, these consisted of rows of punctuate densities measuring ∼0.34 nm; the parallel rows of these dots had a periodicity of ∼0.8 nm. The crystalloids were ensconced within cristae or in the outer compartment. Some mitochondria without crystalloids had circumferential cristae, leaving a membrane-free center that was filled with a farinaceous material. Other scattered fibrocyte defects included disruption of the contractile apparatus or its sporadic replacement by a finely punctuate material in some myofibers. Intramitochondrial crystalloids, although morphologically striking, do not impair organelle physiology to a significant degree, so the muscle weakness of the patient must originate elsewhere.

  1. Comparison of blood aminotransferase methods for assessment of myopathy and hepatopathy in Florida manatees (Trichechus manatus latirostris).

    PubMed

    Harr, Kendal E; Allison, Kathryn; Bonde, Robert K; Murphy, David; Harvey, John W

    2008-06-01

    Muscle injury is common in Florida manatees (Trichechus manatus latirostris). Plasma aspartate aminotransferase (AST) is frequently used to assess muscular damage in capture myopathy and traumatic injury. Therefore, accurate measurement of AST and alanine aminotransferase (ALT) is important in managed, free-ranging animals, as well as in those rehabilitating from injury. Activities of these enzymes, however, are usually not increased in manatees with either acute or chronic muscle damage, despite marked increases in plasma creatine kinase activity. It is hypothesized that this absence of response is due to apoenzymes in the blood not detected by commonly used veterinary assays. Addition of coenzyme pyridoxal-5-phosphate (P5P or vitamin B6) should, therefore, result in higher measured enzyme activities. The objective of this study was to determine the most accurate, precise, and diagnostically useful method for aminotransferase measurement in manatees that can be used in veterinary practices and diagnostic laboratories. Additionally, appropriate collection and storage techniques were assessed. The use of an optimized commercial wet chemical assay with 100 micromol P5P resulted in a positive bias of measured enzyme activities in a healthy population of animals. However, AST and ALT were still much lower than that typically observed in domestic animals and should not be used alone in the assessment of capture myopathy and muscular trauma. Additionally, the dry chemistry analyzer, typically used in clinics, reported significantly higher and less precise AST and ALT activities with poor correlation to those measured with wet chemical methods found in diagnostic laboratories. Therefore, these results cannot be clinically compared. Overall, the optimized wet chemical method was the most precise and diagnostically useful measurement of aminotransferase in samples. Additionally, there was a statistically significant difference between paired serum and plasma measurement

  2. KLHL40-related nemaline myopathy with a sustained, positive response to treatment with acetylcholinesterase inhibitors.

    PubMed

    Natera-de Benito, D; Nascimento, A; Abicht, A; Ortez, C; Jou, C; Müller, J S; Evangelista, T; Töpf, A; Thompson, R; Jimenez-Mallebrera, C; Colomer, J; Lochmüller, H

    2016-03-01

    Congenital myopathies are a group of inherited muscle disorders characterized by hypotonia, weakness and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. Neuromuscular transmission defects have recently been reported in several patients with congenital myopathies (CM). Mutations in KLHL40 are among the most common causes of severe forms of nemaline myopathy. Clinical features of affected individuals include fetal akinesia or hypokinesia, respiratory failure, and swallowing difficulties at birth. Muscle weakness is usually severe and nearly half of the individuals have no spontaneous antigravity movement. The average age of death has been reported to be 5 months in a recent case series. Herein we present a case of a patient with a nemaline myopathy due to KLHL40 mutations (c.604delG, p.Ala202Argfs*56 and c.1513G>C, p.Ala505Pro) with an impressive and prolonged beneficial response to treatment with high-dose pyridostigmine. Myasthenic features or response to ACEI have not previously been reported as a characteristic of nemaline myopathy or KLHL40-related myopathy.

  3. Modern Therapies for Idiopathic Inflammatory Myopathies (IIMs): Role of Biologics

    PubMed Central

    Moghadam-Kia, Siamak; Oddis, Chester V.

    2016-01-01

    Despite the lack of placebo-controlled trials, glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myopathy (IIMs) and myositis-associated ILD (MA-ILD). Glucocorticoid-sparing agents are often given concomitantly with other immunosuppressive agents, particularly in patients with moderate or severe disease. As treatment of refractory cases of idiopathic inflammatory myopathies has been challenging, there is growing interest in evaluating newer therapies including biologics that target various pathways involved in the pathogenesis of IIMs. In a large clinical trial of rituximab in adult and juvenile myositis, the primary outcome was not met, but the definition of improvement was met by most of this refractory group of myositis patients. Rituximab use was also associated with a significant glucocorticoid-sparing effect. Intravenous immune globulin (IVIg) can be used for refractory IIMs or those with severe dysphagia or concomitant infections. Anti-tumor necrosis factor (anti-TNF) utility in IIMs is generally limited by previous negative studies along with recent reports suggesting their potential for inducing myositis. Further research is required to assess the role of new therapies such as tocilizumab (anti-IL6), ACTH gel, sifalimumab (anti-IFNα), and abatacept (inhibition of T cell co-stimulation) given their biological plausibility and encouraging small case series results. Other potential novel therapies include alemtuzumab (a humanized monoclonal antibody which binds CD52 on B and T lymphocytes), fingolimod (a sphingosine 1-phosphate receptor modulator that traps T lymphocytes in the lymphoid organs), eculizumab, and basiliximab. The future investigations in IIMs will depend on well-designed controlled clinical trials using validated consensus core set measures and improvements in myositis classification schemes based on serologic and histopathologic features. PMID:26767526

  4. Modern Therapies for Idiopathic Inflammatory Myopathies (IIMs): Role of Biologics.

    PubMed

    Moghadam-Kia, Siamak; Oddis, Chester V; Aggarwal, Rohit

    2017-02-01

    Despite the lack of placebo-controlled trials, glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myopathy (IIMs) and myositis-associated ILD (MA-ILD). Glucocorticoid-sparing agents are often given concomitantly with other immunosuppressive agents, particularly in patients with moderate or severe disease. As treatment of refractory cases of idiopathic inflammatory myopathies has been challenging, there is growing interest in evaluating newer therapies including biologics that target various pathways involved in the pathogenesis of IIMs. In a large clinical trial of rituximab in adult and juvenile myositis, the primary outcome was not met, but the definition of improvement was met by most of this refractory group of myositis patients. Rituximab use was also associated with a significant glucocorticoid-sparing effect. Intravenous immune globulin (IVIg) can be used for refractory IIMs or those with severe dysphagia or concomitant infections. Anti-tumor necrosis factor (anti-TNF) utility in IIMs is generally limited by previous negative studies along with recent reports suggesting their potential for inducing myositis. Further research is required to assess the role of new therapies such as tocilizumab (anti-IL6), ACTH gel, sifalimumab (anti-IFNα), and abatacept (inhibition of T cell co-stimulation) given their biological plausibility and encouraging small case series results. Other potential novel therapies include alemtuzumab (a humanized monoclonal antibody which binds CD52 on B and T lymphocytes), fingolimod (a sphingosine 1-phosphate receptor modulator that traps T lymphocytes in the lymphoid organs), eculizumab, and basiliximab. The future investigations in IIMs will depend on well-designed controlled clinical trials using validated consensus core set measures and improvements in myositis classification schemes based on serologic and histopathologic features.

  5. Motor unit reorganization in progressive muscular dystrophies and congenital myopathies.

    PubMed

    Szmidt-Sałkowska, Elżbieta; Gaweł, Małgorzata; Lipowska, Marta

    2015-01-01

    The aim of this study was to analyze motor unit reorganization in different types of progressive muscular dystrophies and congenital myopathies. The study population consisted of patients with genetically verified progressive muscular dystrophies: Duchenne (DMD) (n=54), Becker (BMD) (n=30), facio-scapulo-humeral (FSHD) (n=37), and Emery-Dreifuss (E-DD) (n=26). Patients with probable limb-girdle dystrophy (L-GD) (n=58) and congenital myopathies (n=35) were also included in the study. Quantitative EMG recordings were obtained from 469 muscles. Muscle activity at rest and during slight voluntary and maximal muscle contraction was analyzed. The motor unit activity potential (MUAP) duration, amplitude, area, size index (SI), polyphasicity, and the presence of "outliers" were evaluated. Diminished values of MUAP parameters and decreased maximal amplitude of maximal muscle contraction were recorded most frequently in DMD and mainly in the biceps brachii muscles. SI was the most frequently changed EMG parameter. "Outliers" with amplitude below the normal range were recorded more frequently then a decreased mean MUAP amplitude (what could indicate a very high sensitivity of this EMG parameter). Pathological interference pattern was recorded in 34.7% of biceps brachii and in 21.2% of rectus femoris muscles. In FSHD, decreased MUAP duration and SI and pathological interference pattern with low amplitude were recorded most frequently in the tibial anterior and deltoid muscles. The presence of potentials with reduced parameters is a result of decreasing motor unit area (reduced number and size of muscle fibers), while high amplitude potentials recorded in BMD and E-DD could indicate a slow and mild course of disease and muscle regeneration.

  6. Correlation of Clinicoserologic and Pathologic Classifications of Inflammatory Myopathies

    PubMed Central

    Fernandez, Carla; Bardin, Nathalie; De Paula, André Maues; Salort-Campana, Emmanuelle; Benyamine, Audrey; Franques, Jérôme; Schleinitz, Nicolas; Weiller, Pierre-Jean; Pouget, Jean; Pellissier, Jean-François; Figarella-Branger, Dominique

    2013-01-01

    Abstract The idiopathic inflammatory myopathies (IIM) are acquired muscle diseases characterized by muscle weakness and inflammation on muscle biopsy. Clinicoserologic classifications do not take muscle histology into account to distinguish the subsets of IIM. Our objective was to determine the pathologic features of each serologic subset of IIM and to correlate muscle biopsy results with the clinicoserologic classification defined by Troyanov et al, and with the final diagnoses. We retrospectively studied a cohort of 178 patients with clinicopathologic features suggestive of IIM with the exclusion of inclusion body myositis. At the end of follow-up, 156 of 178 cases were still categorized as IIM: pure dermatomyositis, n = 44; pure polymyositis, n = 14; overlap myositis, n = 68; necrotizing autoimmune myopathy, n = 8; cancer-associated myositis, n = 18; and unclassified IIM, n = 4. The diagnosis of IIM was ruled out in the 22 remaining cases. Pathologic dermatomyositis was the most frequent histologic picture in all serologic subsets of IIM, with the exception of patients with anti-Ku or anti-SRP autoantibodies, suggesting that it supports the histologic diagnosis of pure dermatomyositis, but also myositis of connective tissue diseases and cancer-associated myositis. Unspecified myositis was the second most frequent histologic pattern. It frequently correlated with overlap myositis, especially with anti-Ku or anti-PM-Scl autoantibodies. Pathologic polymyositis was rare and more frequently correlated with myositis mimickers than true polymyositis. The current study shows that clinicoserologic and pathologic data are complementary and must be taken into account when classifying patients with IIM patients. We propose guidelines for diagnosis according to both clinicoserologic and pathologic classifications, to be used in clinical practice. PMID:23269233

  7. Natural history of pulmonary function in collagen VI-related myopathies

    PubMed Central

    Foley, A. Reghan; Quijano-Roy, Susana; Collins, James; Straub, Volker; McCallum, Michelle; Deconinck, Nicolas; Mercuri, Eugenio; Pane, Marika; D’Amico, Adele; Bertini, Enrico; North, Kathryn; Ryan, Monique M.; Richard, Pascale; Allamand, Valérie; Hicks, Debbie; Lamandé, Shireen; Hu, Ying; Gualandi, Francesca; Auh, Sungyoung; Muntoni, Francesco

    2013-01-01

    The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed ‘collagen VI-related myopathies’ and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with

  8. [Acute quadriplegia after diabetic ketoacidosis].

    PubMed

    Mihalik, Zoltán; Arányi, Zsuzsanna; Siska, Eva; Nyulasi, Tibor; Pénzes, István

    2003-11-02

    A 36-year-old female was admitted to the intensive care unit after resuscitation diagnosed with diabetic ketoacidotic coma, which was the first manifestation of her diabetes mellitus. It may have been provoked by pulmonary or gastrointestinal coinfection. Five days following admission the patient regained consciousness and homeostasis returned to normal. One week after the stabilization of her cardiopulmonary state, weaning from the respirator turned out to be unsuccessful: flaccid tetraparesis developed with rapid muscle atrophy and absence of deep tendon reflexes. The sensory system and cranial nerves remained intact. Electrophysiological studies and muscle biopsy showed serious acute illness myopathy with mild demyelination owing probably to the latent diabetes. The course of acute quadriplegia was fluctuating and correlated mainly with the activity of the systemic inflammatory response syndrome mechanisms. Myopathy might have been aggravated by using high-dose glucocorticoid therapy. The patient's general condition improved quickly as a result of full recovery from sepsis, discontinuation of glucocorticoids and normoglicaemia maintained by subcutan insulin substitution. Eight months after admission almost full neuromuscular restitution was achieved showing the reversibility of this grave illness.

  9. The clinical phenotypes of the juvenile idiopathic inflammatory myopathies.

    PubMed

    Shah, Mona; Mamyrova, Gulnara; Targoff, Ira N; Huber, Adam M; Malley, James D; Rice, Madeline Murguia; Miller, Frederick W; Rider, Lisa G

    2013-01-01

    The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. Although juvenile dermatomyositis (JDM), the most common form of JIIM, has been well studied, the other major clinical subgroups of JIIM, including juvenile polymyositis (JPM) and juvenile myositis overlapping with another autoimmune or connective tissue disease (JCTM), have not been well characterized, and their similarity to the adult clinical subgroups is unknown. We enrolled 436 patients with JIIM, including 354 classified as JDM, 33 as JPM, and 49 as JCTM, in a nationwide registry study. The aim of the study was to compare demographics; clinical features; laboratory measures, including myositis autoantibodies; and outcomes among these clinical subgroups, as well as with published data on adult patients with idiopathic inflammatory myopathies (IIM) enrolled in a separate natural history study. We used random forest classification and logistic regression modeling to compare clinical subgroups, following univariate analysis. JDM was characterized by typical rashes, including Gottron papules, heliotrope rash, malar rash, periungual capillary changes, and other photosensitive and vasculopathic skin rashes. JPM was characterized by more severe weakness, higher creatine kinase levels, falling episodes, and more frequent cardiac disease. JCTM had more frequent interstitial lung disease, Raynaud phenomenon, arthralgia, and malar rash. Differences in autoantibody frequency were also evident, with anti-p155/140, anti-MJ, and anti-Mi-2 seen more frequently in patients with JDM, anti-signal recognition particle and anti-Jo-1 in JPM, and anti-U1-RNP, PM-Scl, and other myositis-associated autoantibodies more commonly present in JCTM. Mortality was highest in patients with JCTM, whereas hospitalizations and wheelchair use were highest in JPM patients. Several demographic and clinical features

  10. Histopathological findings in systemic sclerosis-related myopathy: fibrosis and microangiopathy with lack of cellular inflammation

    PubMed Central

    Corallo, Claudio; Cutolo, Maurizio; Volpi, Nila; Franci, Daniela; Aglianò, Margherita; Montella, Antonio; Chirico, Chiara; Gonnelli, Stefano; Nuti, Ranuccio; Giordano, Nicola

    2016-01-01

    Objectives: The objective of this study was to identify specific histopathological features of skeletal muscle involvement in systemic sclerosis (SSc) patients. Methods: A total of 35 out of 112 SSc-patients (32%, including 81% female and 68% diffuse scleroderma) presenting clinical, biological and electromyographic (EMG) features of muscle weakness, were included. Patients underwent vastus lateralis biopsy, assessed for individual pathologic features including fibrosis [type I collagen (Coll-I), transforming growth factor β (TGF-β)], microangiopathy [cluster of differentiation 31 (CD31), pro-angiogenic vascular endothelial growth factor A (VEGF-A), anti-angiogenic VEGF-A165b], immune/ inflammatory response [CD4, CD8, CD20, human leucocyte antigens ABC (HLA-ABC)], and membranolytic attack complex (MAC). SSc biopsies were compared with biopsies of (n = 35) idiopathic inflammatory myopathies (IIMs) and to (n = 35) noninflammatory myopathies (NIMs). Ultrastructural abnormalities of SSc myopathy were also analyzed by transmission electron microscopy (TEM). Results: Fibrosis in SSc myopathy (81%) is higher compared with IIM (32%, p < 0.05) and with NIM (18%, p < 0.05). Vascular involvement is dominant in SSc muscle (92%), and in IIM (78%) compared with NIM (21%, p < 0.05). In particular, CD31 shows loss of endomysial vessels in SSc myopathy compared with IIM (p < 0.05) and with NIM (p < 0.01). VEGF-A is downregulated in SSc myopathy compared with IIM (p < 0.05) and NIM (p < 0.05). Conversely, VEGF-A165b is upregulated in SSc myopathy. The SSc immune/inflammatory response suggested humoral process with majority (85%) HLA-ABC fibral neoexpression and complement deposits on endomysial capillaries MAC, compared with IIM (p < 0.05), characterized by CD4+/CD8+/B-cell infiltrate, and NIM (p < 0.05). TEM analysis showed SSc vascular alterations consisting of thickening and lamination of basement membrane and endothelial cell ‘swelling’ coupled to endomysial

  11. Clinical Studies in Familial VCP Myopathy Associated With Paget Disease of Bone and Frontotemporal Dementia

    PubMed Central

    Kimonis, Virginia. E.; Mehta, Sarju G.; Fulchiero, Erin C.; Thomasova, Dana; Pasquali, Marzia; Boycott, Kym; Neilan, Edward G.; Kartashov, Alex; Forman, Mark S.; Tucker, Stuart; Kimonis, Katerina; Mumm, Steven; Whyte, Michael P.; Smith, Charles D.; Watts, Giles D. J.

    2008-01-01

    Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9–60.2 years); however, several individuals had been diagnosed with Alzheimer disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy. PMID:18260132

  12. Statin myopathy: significant problem with minimal awareness by clinicians and no emphasis by clinical investigators.

    PubMed

    Whayne, Thomas F

    2011-07-01

    High cardiovascular risk patients need reduction of low-density-lipoprotein cholesterol (LDL-C) to <70 mg/dL (1.8 mmol/L). Statins are optimal treatment but myopathy can be a limitation to their use. The incidence of statin-related myopathy is difficult to determine but up to 10.5% appears an appropriate estimate. Short-term trials report lower incidence than long-term trials. Statin-related myopathy may be influenced by genetics and tends to be dose-dependent. Ezetimibe can contribute to LDL-C reduction allowing a lower dose of statin to be used. Another approach is to administer rosuvastatin twice weekly. Statins have been shown to interfere with the cellular role of coenzyme Q10. Coenzyme Q10 supplementation may decrease or prevent statin myopathy, but this has not been proven. The occurrence of the most serious complication of myopathy-rhabdomyolysis-is very rare, but awareness of the problem, risks, and prevention are essential.

  13. SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles

    PubMed Central

    Bucelli, Robert C.; Arhzaouy, Khalid; Pestronk, Alan; Pittman, Sara K.; Rojas, Luisa; Sue, Carolyn M.; Evilä, Anni; Hackman, Peter; Udd, Bjarne; Harms, Matthew B.

    2015-01-01

    Objective: To identify the genetic etiology and characterize the clinicopathologic features of a novel distal myopathy. Methods: We performed whole-exome sequencing on a family with an autosomal dominant distal myopathy and targeted exome sequencing in 1 patient with sporadic distal myopathy, both with rimmed vacuolar pathology. We also evaluated the pathogenicity of identified mutations using immunohistochemistry, Western blot analysis, and expression studies. Results: Sequencing identified a likely pathogenic c.1165+1 G>A splice donor variant in SQSTM1 in the affected members of 1 family and in an unrelated patient with sporadic distal myopathy. Affected patients had late-onset distal lower extremity weakness, myopathic features on EMG, and muscle pathology demonstrating rimmed vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions. The c.1165+1 G>A SQSTM1 variant results in the expression of 2 alternatively spliced SQSTM1 proteins: 1 lacking the C-terminal PEST2 domain and another lacking the C-terminal ubiquitin-associated (UBA) domain, both of which have distinct patterns of cellular and skeletal muscle localization. Conclusions: SQSTM1 is an autophagic adaptor that shuttles aggregated and ubiquitinated proteins to the autophagosome for degradation via its C-terminal UBA domain. Similar to mutations in VCP, dominantly inherited mutations in SQSTM1 are now associated with rimmed vacuolar myopathy, Paget disease of bone, amyotrophic lateral sclerosis, and frontotemporal dementia. Our data further suggest a pathogenic connection between the disparate phenotypes. PMID:26208961

  14. Myopathy mutations in alpha-skeletal-muscle actin cause a range of molecular defects.

    PubMed

    Costa, Céline F; Rommelaere, Heidi; Waterschoot, Davy; Sethi, Kamaljit K; Nowak, Kristen J; Laing, Nigel G; Ampe, Christophe; Machesky, Laura M

    2004-07-01

    Mutations in the gene encoding alpha-skeletal-muscle actin, ACTA1, cause congenital myopathies of various phenotypes that have been studied since their discovery in 1999. Although much is now known about the clinical aspects of myopathies resulting from over 60 different ACTA1 mutations, we have very little evidence for how mutations alter the behavior of the actin protein and thus lead to disease. We used a combination of biochemical and cell biological analysis to classify 19 myopathy mutants and found a range of defects in the actin. Using in vitro expression systems, we probed actin folding and actin's capacity to interact with actin-binding proteins and polymerization. Only two mutants failed to fold; these represent recessive alleles, causing severe myopathy, indicating that patients produce nonfunctional actin. Four other mutants bound tightly to cyclase-associated protein, indicating a possible instability in the nucleotide-binding pocket, and formed rods and aggregates in cells. Eleven mutants showed defects in the ability to co-polymerize with wild-type actin. Some of these could incorporate into normal actin structures in NIH 3T3 fibroblasts, but two of the three tested also formed aggregates. Four mutants showed no defect in vitro but two of these formed aggregates in cells, indicating functional defects that we have not yet tested for. Overall, we found a range of defects and behaviors of the mutants in vitro and in cultured cells, paralleling the complexity of actin-based muscle myopathy phenotypes.

  15. Myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy

    PubMed Central

    Sobreira*, C; Marques, W; Barreira, A

    2003-01-01

    Objective: To report the occurrence of myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy. Methods: The clinical cases of three patients with fibre type disproportion myopathy and one with multicore disease are described. Skeletal muscle biopsies were processed for routine histological and histochemical studies. Results: The clinical picture was unusual in that the symptoms were of late onset and the predominant complaint was muscle pain exacerbated by exercise. Muscle weakness was found in only a single patient, the mother of a patient with fibre type disproportion myopathy. Physical examination was unremarkable in the other patients. Muscle biopsies from patients 1 and 2 contained type I fibres that were considerably smaller than the type II fibres, supporting the diagnosis of fibre type disproportion myopathy. Skeletal muscle of patient 4 showed multiple areas, predominantly but not exclusively in the type I fibres, from which oxidative enzyme activities were absent, as seen in multicore disease. Conclusions: Muscle pain was the main clinical manifestation in our patients. Recognition of the broader clinical expression of these myopathies is important for prognostic reasons and for genetic counselling of the family members. PMID:12933945

  16. Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy.

    PubMed

    Spiegel, Ronen; Saada, Ann; Halvardson, Jonatan; Soiferman, Devorah; Shaag, Avraham; Edvardson, Simon; Horovitz, Yoseph; Khayat, Morad; Shalev, Stavit A; Feuk, Lars; Elpeleg, Orly

    2014-07-01

    Isolated metabolic myopathies encompass a heterogeneous group of disorders, with mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness. In this study, we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy. Analysis of enzyme activities of the five respiratory chain complexes in our patients' skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase. We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A>T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein. The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria. Fdx2 is the second component of the Fe-S cluster biogenesis machinery, the first being IscU that is associated with isolated mitochondrial myopathy. We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III.

  17. Potassium dependent rescue of a myopathy with core-like structures in mouse.

    PubMed

    Hanson, M Gartz; Wilde, Jonathan J; Moreno, Rosa L; Minic, Angela D; Niswander, Lee

    2015-01-07

    Myopathies decrease muscle functionality. Mutations in ryanodine receptor 1 (RyR1) are often associated with myopathies with microscopic core-like structures in the muscle fiber. In this study, we identify a mouse RyR1 model in which heterozygous animals display clinical and pathological hallmarks of myopathy with core-like structures. The RyR1 mutation decreases sensitivity to activated calcium release and myoplasmic calcium levels, subsequently affecting mitochondrial calcium and ATP production. Mutant muscle shows a persistent potassium leak and disrupted expression of regulators of potassium homeostasis. Inhibition of KATP channels or increasing interstitial potassium by diet or FDA-approved drugs can reverse the muscle weakness, fatigue-like physiology and pathology. We identify regulators of potassium homeostasis as biomarkers of disease that may reveal therapeutic targets in human patients with myopathy of central core disease (CCD). Altogether, our results suggest that amelioration of potassium leaks through potassium homeostasis mechanisms may minimize muscle damage of myopathies due to certain RyR1 mutations.

  18. Cardiac involvement in adult and juvenile idiopathic inflammatory myopathies

    PubMed Central

    Schwartz, Thomas; Diederichsen, Louise Pyndt; Lundberg, Ingrid E; Sanner, Helga

    2016-01-01

    Idiopathic inflammatory myopathies (IIM) include the main subgroups polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and juvenile DM (JDM). The mentioned subgroups are characterised by inflammation of skeletal muscles leading to muscle weakness and other organs can also be affected as well. Even though clinically significant heart involvement is uncommon, heart disease is one of the major causes of death in IIM. Recent studies show an increased prevalence of traditional cardiovascular risk factors in JDM and DM/PM, which need attention. The risk of developing atherosclerotic coronary artery disease is increased twofold to fourfold in DM/PM. New and improved diagnostic methods have in recent studies in PM/DM and JDM demonstrated a high prevalence of subclinical cardiac involvement, especially diastolic dysfunction. Interactions between proinflammatory cytokines and traditional risk factors might contribute to the pathogenesis of cardiac dysfunction. Heart involvement could also be related to myocarditis and/or myocardial fibrosis, leading to arrhythmias and congestive heart failure, demonstrated both in adult and juvenile IIM. Also, reduced heart rate variability (a known risk factor for cardiac morbidity and mortality) has been shown in long-standing JDM. Until more information is available, patients with IIM should follow the same recommendations for cardiovascular risk stratification and prevention as for the corresponding general population, but be aware that statins might worsen muscle symptoms mimicking myositis relapse. On the basis of recent studies, we recommend a low threshold for cardiac workup and follow-up in patients with IIM. PMID:27752355

  19. Mechanical Signaling in the Pathophysiology of Critical Illness Myopathy

    PubMed Central

    Kalamgi, Rebeca C.; Larsson, Lars

    2016-01-01

    The complete loss of mechanical stimuli of skeletal muscles, i.e., the loss of external strain, related to weight bearing, and internal strain, related to the contraction of muscle cells, is uniquely observed in pharmacologically paralyzed or deeply sedated mechanically ventilated intensive care unit (ICU) patients. The preferential loss of myosin and myosin associated proteins in limb and trunk muscles is a significant characteristic of critical illness myopathy (CIM) which separates CIM from other types of acquired muscle weaknesses in ICU patients. Mechanical silencing is an important factor triggering CIM. Microgravity or ground based microgravity models form the basis of research on the effect of muscle unloading-reloading, but the mechanisms and effects may differ from the ICU conditions. In order to understand how mechanical tension regulates muscle mass, it is critical to know how muscles sense mechanical information and convert stimulus to intracellular biochemical actions and changes in gene expression, a process called cellular mechanotransduction. In adult skeletal muscles and muscle fibers, this process may differ, the same stimulus can cause divergent response and the same fiber type may undergo opposite changes in different muscles. Skeletal muscle contains multiple types of mechano-sensors and numerous structures that can be affected differently and hence respond differently in distinct muscles. PMID:26869939

  20. Canine inflammatory myopathy associated with Leishmania Infantum infection.

    PubMed

    Paciello, Orlando; Oliva, Gaetano; Gradoni, Luigi; Manna, Laura; Foglia Manzillo, Valentina; Wojcik, Slawomir; Trapani, Francesca; Papparella, Serenella

    2009-02-01

    Inflammatory myopathy associated with several infectious diseases occurs in dogs including those caused by Toxoplasma gondii, Neospora caninum, Ehrlichia canis and Hepatozoon canis. However, muscle disease due to Leishmania infection has been poorly documented. The aim of this study was to examine the distribution and types of cellular infiltrates and expression of MHC class I and II in muscle biopsies obtained from 15 male beagle dogs from a breeder group with an established diagnosis of leishmaniasis. Myopathic features were characterized by necrosis, regeneration, fibrosis and infiltration of mononuclear inflammatory cells consisting of lymphocytes, plasma cells and histiocytes. The predominant leukocyte populations were CD3+, CD8+ and CD45RA+ with lesser numbers of CD4+ cells. Many muscle fibers had MHC class I and II positivity on the sarcolemma. There was a direct correlation between the severity of pathological changes, clinical signs, and the numbers of Leishmania amastigotes. Our studies provided evidence that: 1) Leishmania should be considered as a cause of IM in dogs; 2) Leishmania is not present within muscle fibers but in macrophages, and that 3) the muscle damage might be related to immunological alterations associated with Leishmania infection. Leishmania spp. should also be considered as a possible cause in the pathogenesis of human myositis.

  1. Repository Corticotropin Injection for Treatment of Idiopathic Inflammatory Myopathies

    PubMed Central

    Seely, Georgia; Aggarwal, Rohit

    2016-01-01

    Idiopathic inflammatory myopathies are a group of systemic autoimmune diseases that involve inflammation of skeletal muscle. The two most common forms are dermatomyositis and polymyositis, the former of which entails a skin component. There are few approved therapeutics available for treatment of this group of diseases and the first-line therapy is usually corticosteroid treatment. Considering that a large proportion of patients do not respond to or cannot tolerate corticosteroids, additional treatments are required. There are second-line therapies available, but many patients are also refractory to those options. H.P. Acthar® Gel (repository corticotropin injection [RCI]) is a melanocortin peptide that can induce steroid-dependent effects and steroid-independent effects. Herein, we present a series of cases that involved the use of RCI in the management of dermatomyositis and polymyositis. RCI treatments resulted in improvement in three of four patients, despite failure with previous therapies. The use of RCI did not exacerbate any comorbidity and no significant changes in blood pressure, weight, or glycemic control were observed. Overall, these results are encouraging and suggest that randomized, controlled clinical trials applying RCI to dermatomyositis and polymyositis are warranted. PMID:27642533

  2. Cardiac involvement in hereditary myopathy with early respiratory failure

    PubMed Central

    Steele, Hannah E.; Harris, Elizabeth; Barresi, Rita; Marsh, Julie; Beattie, Anna; Bourke, John P.; Straub, Volker

    2016-01-01

    Objective: To assess whether hereditary myopathy with early respiratory failure (HMERF) due to the c.951434T>C; (p.Cys31712Arg) TTN missense mutation also includes a cardiac phenotype. Method: Clinical cohort study of our HMERF cohort using ECG, 2D echocardiogram, and cross-sectional cardiac imaging with MRI or CT. Results: We studied 22 participants with the c.951434T>C; (p.Cys31712Arg) TTN missense mutation. Three were deceased. Cardiac conduction abnormalities were identified in 7/22 (32%): sustained atrioventricular tachycardia (n = 2), atrial fibrillation (n = 2), nonsustained atrial tachycardia (n = 1), premature supraventricular complexes (n = 1), and unexplained sinus bradycardia (n = 1). In addition, 4/22 (18%) had imaging evidence of otherwise unexplained cardiomyopathy. These findings are supported by histopathologic correlation suggestive of myocardial cytoskeletal remodeling. Conclusions: Coexisting cardiac and skeletal muscle involvement is not uncommon in patients with HMERF arising due to the c.951434T>C; (p.Cys31712Arg) TTN mutation. All patients with pathogenic or putative pathogenic TTN mutations should be offered periodic cardiac surveillance. PMID:27511179

  3. Hypermethylation: Causes and Consequences in Skeletal Muscle Myopathy.

    PubMed

    Majumder, Avisek; JyotirmayaBehera; Jeremic, Navena; Tyagi, Suresh C

    2016-12-16

    A detrimental consequence of hypermethylation is hyperhomocysteinemia (HHcy), that causes oxidative stress, inflammation and matrix degradation, which leads to multi-pathology in different organs. Although, it is well known that hypermethylation leads to overall gene silencing and hypomethylation leads to overall gene activation, the role of such process in skeletal muscle dysfunction during HHcy condition is unclear. In this study, we emphasized the multiple mechanisms including epigenetic alteration by which HHcy causes skeletal muscle myopathy. This review also highlights possible role of methylation, histone modification and RNA interference in skeletal muscle dysfunction during HHcy condition and potential therapeutic molecules, putative challenges, and methodologies to deal with HHcy mediated skeletal muscle dysfunction. We also highlighted that B vitamins (mainly B12 and B6) with folic acid supplementation, could be useful as an adjuvant therapy to reverse these consequences associated with this HHcy conditions in skeletal muscle. However, we would recommend to further study involving long-term trials could help to assess efficacy of the use of these therapeutic agents. This article is protected by copyright. All rights reserved.

  4. "Hiker's feet": a novel cutaneous finding in the inflammatory myopathies.

    PubMed

    Cox, Jacob T; Gullotti, David M; Mecoli, Christopher A; Lahouti, Arash H; Albayda, Jemima; Paik, Julie; Johnson, Cheilonda; Danoff, Sonye K; Mammen, Andrew L; Christopher-Stine, Lisa

    2017-04-07

    Mechanic's hands is a well-characterized manifestation of select idiopathic inflammatory myopathy (IIM) syndromes. Less well characterized is the hyperkeratosis of the toes and plantar surface of the feet that can also accompany these disorders. We aim to describe common pedal signs in the context of IIM, and suggest that it may be another key feature in the presentation of these syndromes. A cohort of 2145 myositis patient charts gathered since 2003 were retrospectively reviewed using the key search terms "mechanic's feet" and/or "mechanic's foot." Charts that included either phrase were further reviewed for clinical characteristics. Nine patients were identified with documentation describing "mechanic's feet" or "mechanic's foot." All nine affected individuals carried a diagnosis of DM, seven of whom also met criteria for antisynthetase syndrome. In eight patients (89%), it presented in conjunction with mechanic's hands. Six (67%) presented with anti-Jo-1 antibodies, and three (33%) were seronegative. Although the term "mechanic's feet" has been used to describe this clinical finding in patients in our myositis cohort, we propose the term "hiker's feet," given that the presentation resembles a callousing pattern more typical of avid hikers or long-distance walkers. Prevalence data are not yet known but should be considered for further study. If the presenting signs of IIM are expanded to include hiker's feet, it could aid in not only diagnosis and management but also provide insights into the pathophysiology of these diseases.

  5. Molecular and cellular insights into a distinct myopathy of Great Dane dogs.

    PubMed

    Chang, Kin-Chow; McCulloch, Maj-Lis C; Anderson, Thomas James

    2010-03-01

    A myopathy in the Great Dane dog with characteristic pathological and molecular features is reported. Young adults present with progressive weakness and generalised muscle atrophy. To better define this condition, an investigation using histopathology, confocal microscopy, biochemistry and microarray analysis was undertaken. The skeletal muscles of affected dogs exhibited increased oxidative fibre phenotype and core fibre lesions characterised by the disruption of the sarcomeric architecture and the accumulation of mitochondrial organelles. Affected muscles displayed co-ordinated expression of genes consistent with a slow-oxidative phenotype, which was possibly a compensatory response to chronic muscle damage. There was disruption of Z-lines in affected muscles which, at the molecular level, manifested as transcriptional dysregulation of several Z-line associated genes, including alpha-actinin, myotilin, desmin, vimentin and telethonin. The pathology of this canine myopathy is distinct from that of human central core myopathies that are characterised by cores devoid of mitochondria and by the presence of myofibrillar breakdown products.

  6. Individualized risk for statin-induced myopathy: current knowledge, emerging challenges and potential solutions.

    PubMed

    Feng, QiPing; Wilke, Russell A; Baye, Tesfaye M

    2012-04-01

    Skeletal muscle toxicity is the primary adverse effect of statins. In this review, we summarize current knowledge regarding the genetic and nongenetic determinants of risk for statin induced myopathy. Many genetic factors were initially identified through candidate gene association studies limited to pharmacokinetic (PK) targets. Through genome-wide association studies, it has become clear that SLCO1B1 is among the strongest PK predictors of myopathy risk. Genome-wide association studies have also expanded our understanding of pharmacodynamic candidate genes, including RYR2. It is anticipated that deep resequencing efforts will define new loci with rare variants that also contribute, and sophisticated computational approaches will be needed to characterize gene-gene and gene-environment interactions. Beyond environment, race is a critical covariate, and its influence is only partly explained by geographic differences in the frequency of known pharmacodynamic and PK variants. As such, admixture analyses will be essential for a full understanding of statin-induced myopathy.

  7. Camptocormia in a patient with Parkinson disease and a myopathy with nemaline rods.

    PubMed

    Ozer, Feriha; Ozturk, Oya; Meral, Hasan; Serdaroglu, Piraye; Yayla, Vildan

    2007-01-01

    Camptocormia, also referred to as bent spine, is a gait disorder characterized by hyperflexion of the thoracolumbar spine that develops in recumbent position while walking and that disappears in supine position. Myopathy is one of the frequent causes of camptocormia. A 77-yr-old male patient who was followed up with the diagnosis of rheumatoid arthritis for 2 yrs was admitted with progressive gait deterioration. Hyperflexion of trunk, disappearing in supine position, was detected and diagnosed as camptocormia. He also exhibited the signs of parkinsonism. A paraspinal muscle biopsy showed myopathy with rods in many muscle fibers. Camptocormia in this patient may be attributable to the myopathic weakness of thoracolumbar paraspinal muscles. The normal biceps brachii muscle biopsy refers to the isolated affection of paraspinal muscles in this patient. A camptocormia (bent spine) case of myopathy with nemaline rods associated with Parkinson disease is presented.

  8. Ultrastructural changes in muscle cells of patients with collagen VI-related myopathies

    PubMed Central

    Tagliavini, Francesca; Sardone, Francesca; Squarzoni, Stefano; Maraldi, Nadir Mario; Merlini, Luciano; Faldini, Cesare; Sabatelli, Patrizia

    2013-01-01

    Summary Collagen VI is an extracellular matrix protein expressed in several tissues including skeletal muscle. Mutations in COL6A genes cause Bethlem Myopathy (BM), Ullrich Congenital Muscular Dystrophy (UCMD) and Myosclerosis Myopathy (MM). Collagen VI deficiency causes increased opening of the mitochondrial permeability transition pore (mPTP), leading to ultrastructural and functional alterations of mitochondria, amplified by impairment of autophagy. Here we report for the first time ultrastructural studies on muscle biopsies from BM and UCMD patients, showing swollen mitochondria with hypodense matrix, disorganized cristae and paracrystalline inclusions, associated with dilated sarcoplasmic reticulum and apoptotic changes. These data were supported by scanning electron microscopy analysis on BM and UCMD cultured cells, showing alterations of the mitochondrial network. Morphometric analysis also revealed a reduced short axis and depicted swelling in about 3% of mitochondria. These data demonstrate that mitochondrial defects underlie the pathogenetic mechanism in muscle tissue of patients affected by collagen VI myopathies. PMID:24596691

  9. Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition.

    PubMed

    Schirris, Tom J J; Renkema, G Herma; Ritschel, Tina; Voermans, Nicol C; Bilos, Albert; van Engelen, Baziel G M; Brandt, Ulrich; Koopman, Werner J H; Beyrath, Julien D; Rodenburg, Richard J; Willems, Peter H G M; Smeitink, Jan A M; Russel, Frans G M

    2015-09-01

    Cholesterol-lowering statins effectively reduce the risk of major cardiovascular events. Myopathy is the most important adverse effect, but its underlying mechanism remains enigmatic. In C2C12 myoblasts, several statin lactones reduced respiratory capacity and appeared to be strong inhibitors of mitochondrial complex III (CIII) activity, up to 84% inhibition. The lactones were in general three times more potent inducers of cytotoxicity than their corresponding acid forms. The Qo binding site of CIII was identified as off-target of the statin lactones. These findings could be confirmed in muscle tissue of patients suffering from statin-induced myopathies, in which CIII enzyme activity was reduced by 18%. Respiratory inhibition in C2C12 myoblasts could be attenuated by convergent electron flow into CIII, restoring respiration up to 89% of control. In conclusion, CIII inhibition was identified as a potential off-target mechanism associated with statin-induced myopathies.

  10. Pathophysiological concepts in the congenital myopathies: blurring the boundaries, sharpening the focus

    PubMed Central

    Ravenscroft, Gianina; Laing, Nigel G.

    2015-01-01

    The congenital myopathies are a diverse group of genetic skeletal muscle diseases, which typically present at birth or in early infancy. There are multiple modes of inheritance and degrees of severity (ranging from foetal akinesia, through lethality in the newborn period to milder early and later onset cases). Classically, the congenital myopathies are defined by skeletal muscle dysfunction and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. However, mutations in multiple different genes can cause the same pathology and mutations in the same gene can cause multiple different pathologies. This is becoming ever more apparent now that, with the increasing use of next generation sequencing, a genetic diagnosis is achieved for a greater number of patients. Thus, considerable genetic and pathological overlap is emerging, blurring the classically established boundaries. At the same time, some of the pathophysiological concepts underlying the congenital myopathies are moving into sharper focus. Here we explore whether our emerging understanding of disease pathogenesis and underlying pathophysiological mechanisms, rather than a strictly gene-centric approach, will provide grounds for a different and perhaps complementary grouping of the congenital myopathies, that at the same time could help instil the development of shared potential therapeutic approaches. Stemming from recent advances in the congenital myopathy field, five key pathophysiology themes have emerged: defects in (i) sarcolemmal and intracellular membrane remodelling and excitation-contraction coupling; (ii) mitochondrial distribution and function; (iii) myofibrillar force generation; (iv) atrophy; and (v) autophagy. Based on numerous emerging lines of evidence from recent studies in cell lines and patient tissues, mouse models and zebrafish highlighting these unifying pathophysiological themes, here we review the congenital myopathies in relation to these

  11. Statin-induced Myopathy and Ubiquinone Levels in Serum - Results from a Prospective, Observational Study.

    PubMed

    Skilving, Ilona; Acimovic, Jure; Rane, Anders; Ovesjö, Marie-Louise; Björkhem-Bergman, Linda

    2015-08-01

    It has been suggested that an impaired ubiquinone (Q10) synthesis may be responsible for muscular side effects caused by statins. The primary aim of this study was to investigate whether low Q10 levels in serum could be used as a marker to predict the risk of developing statin-induced myopathy. The secondary aim was to compare the change in Q10 levels during statin treatment and differences between men and women. Serum samples from a prospective, observational study in statin-treated patients who were thoroughly followed regarding muscular symptoms were used. In this cohort, 16 developed myopathy and 126 had no muscular symptoms related to statin treatment. Q10 levels were measured with a novel LC-MS method at baseline and after 2 months of statin treatment. Q10 levels showed no correlation with the risk of developing statin-induced myopathy. Individuals with low levels, Q10 < 200 ng/ml, at baseline had no increased risk of developing myopathy. In consistence with earlier reports, we showed that Q10 levels were reduced by 30% during statin treatment. There was no significant difference in the reduction between patients with or without myopathy. Women had approximately 30% lower Q10 levels compared to men both before and after treatment. In this study, there was no association between Q10 levels at baseline and statin-induced muscular side effects during a 2-month follow-up period, and our results indicate that Q10 levels in serum is not a useful marker to predict statin-induced myopathy.

  12. Familial visceral myopathy diagnosed by exome sequencing of a patient with chronic intestinal pseudo-obstruction.

    PubMed

    Holla, Oystein L; Bock, Gunter; Busk, Oyvind L; Isfoss, Björn Logi

    2014-06-01

    A 55-year-old woman with a history of bowel dysmotility presented with abdominal distension and peritonitis. Family history included premature deaths with intestinal symptomatology, suggesting autosomal dominant inheritance. Computed tomography showed a distended small bowel. Symptoms were alleviated by enterocutaneous stomas. Initial ileal biopsy suggested neuropathy; however, exome sequencing revealed an Arg148Ser mutation in the enteric smooth muscle actin gamma 2 (ACTG2) gene. Histological reassessment showed abnormal muscularis propria and smooth muscle actin, with the same findings in sibling, confirming familial visceral myopathy. Thus, noninvasive genomic analysis can provide early and specific diagnosis of familial visceral myopathy, which may help to avoid inappropriate surgery.

  13. Unfolded protein response and aggresome formation in hereditary reducing-body myopathy.

    PubMed

    Liewluck, Teerin; Hayashi, Yukiko K; Ohsawa, Maki; Kurokawa, Rumi; Fujita, Masako; Noguchi, Satoru; Nonaka, Ikuya; Nishino, Ichizo

    2007-03-01

    Reducing-body myopathy (RBM) is a rare myopathy characterized by the presence of unique sarcoplasmic inclusions called reducing bodies (RBs). We characterized the aggresomal features of RBs that contained gamma-tubulin, ubiquitin, and endoplasmic reticulum (ER) chaperones, together with a set of membrane proteins, in a family with hereditary RBM. Increased messenger ribonucleic acid and protein levels of a molecular chaperone, glucose-related protein 78, were also observed. These results suggest that the unfolded protein response caused by the accumulation of misfolded proteins in the endoplasmic reticulum plays an important role in the formation of RBs.

  14. A case of isolated neck extensor myopathy responding favorably to immunotherapy.

    PubMed

    Larsen, Håvard; Bogaard, Pauline W; Oppel, Lorenz

    2013-12-01

    We report on a case of a 79-year-old man with dropped head syndrome, where diagnostic tests, ruling out other differential diagnoses, confirmed the relatively rarely occurring condition known as isolated neck extensor myopathy. Biopsy of the neck extensor musculature was with classical pronounced fibrosis, without signs of myositis. The patient was treated with 3 cycles of corticosteroids with pronounced clinical improvement of his symptoms. This emphasizes the importance of considering isolated neck extensor myopathy as a differential diagnosis when encountered with a patient with dropped head syndrome and the importance of trying therapy with corticosteroids even when myositis is absent.

  15. Capture myopathy in a free-flying greater sandhill crane (Grus canadensis tabida) from Wisconsin

    USGS Publications Warehouse

    Windingstad, R.M.; Hurley, S.S.; Sileo, L.

    1983-01-01

    Capture myopathy has been reported Frequently in wild mammals (Bartsch et al., 1977, Vet. Pathol. 14: 314-324). There are, however, fewer reports of this disease in wild birds (Young, 1967, mt. Zoo Yearb. 7: 226-227; Bartsch et al., 1977, op. cit. ; Henschel and Low, 1978, S. Afr. J. Sci. 74: 305-306; Wobeser, 1981, Diseases of Wild Waterfowl, Plenum Press, New York, 300 pp.). We are reporting a case of skeletal muscle necrosis in a greater sandhill crane found dead 5 days after its capture, radio-tagging, and release. We believe this is the first case of capture myopathy to be reported for this species.

  16. [Myopathy due to potassium deficiency in eight cats and a dog].

    PubMed

    Grevel, V; Opitz, M; Steeb, C; Skrodzki, M

    1993-01-01

    Eight cats and one dog with signs of cervical ventroflexion, reluctance to walk, a stiff and stilted gait and muscle weakness are introduced. Though blood potassium concentration was very low (< 3.0 mval/l) in one cat and the dog only, a potassium depletion myopathy was assumed as the cause of these symptoms. Two of three cats had elevated values of the urinary fractional potassium excretion compared to ten healthy cats. Blood creatinine values were within normal ranges. Five of seven cats had elevated creatine kinase values. All animals improved after potassium substitution. Causes of potassium depletion are discussed and differential diagnoses of myopathies are briefly mentioned.

  17. Autophagy, inflammation and innate immunity in inflammatory myopathies.

    PubMed

    Cappelletti, Cristina; Galbardi, Barbara; Kapetis, Dimos; Vattemi, Gaetano; Guglielmi, Valeria; Tonin, Paola; Salerno, Franco; Morandi, Lucia; Tomelleri, Giuliano; Mantegazza, Renato; Bernasconi, Pia

    2014-01-01

    Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs). In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM), polymyositis (PM), dermatomyositis (DM) and juvenile dermatomyositis (JDM). We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1). These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous 'danger signal'. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types.

  18. Immune-mediated myopathy related to anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies as an emerging cause of necrotizing myopathy induced by statins.

    PubMed

    Lahaye, Clément; Beaufrére, Anne Marie; Boyer, Olivier; Drouot, Laurent; Soubrier, Martin; Tournadre, Anne

    2014-01-01

    Immune-mediated necrotizing myopathy (IMNM) associated with statin use and anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody is a new and emerging entity that supports a link between statin use and IMNM and raises the questions of distinct clinical phenotypes and treatment strategy. We describe the clinical and histopathological characteristics of a patient and discuss the spectrum of IMNM and statin-induced myopathies. A 65-year-old man was suffering from proximal muscle weakness and elevated CK levels, following exposure to statin therapy. The symptoms worsened despite discontinuation of the drug. At that point, no myositis-specific or -associated antibodies were detected. Malignancy screening did not reveal abnormalities. Muscle biopsy demonstrated a predominantly necrotizing myopathy with minimal lymphocytic infiltrates, MHC class I expression in necrotic muscle fibers, and complement deposition on scattered non-necrotic muscle fibers. Muscle protein analysis by western blot was normal. The patient did not improve with steroid and methotrexate and required monthly intravenous immunoglobulin (IVIG) therapy. Muscle strength gradually improved, CK levels normalized and IVIG were stopped 1 year later. Screening for anti-HMGCR antibodies, not available at the time of presentation, was highly positive. Identification of anti-HMGCR antibodies in statin-exposed patients with myopathy appears to be helpful both for differential diagnosis and for treatment strategy. In patients who did not improve after discontinuation of the statin treatment, a muscle biopsy should be performed as well as screening for anti-HMGCR antibodies. Patients with this disorder require aggressive immunosuppressive treatment.

  19. Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin.

    PubMed

    Brunham, L R; Lansberg, P J; Zhang, L; Miao, F; Carter, C; Hovingh, G K; Visscher, H; Jukema, J W; Stalenhoef, A F; Ross, C J D; Carleton, B C; Kastelein, J J P; Hayden, M R

    2012-06-01

    Statins reduce cardiovascular morbidity and mortality in appropriately selected patients. However, statin-associated myopathy is a significant risk associated with these agents. Recently, variation in the SLCO1B1 gene was reported to predict simvastatin-associated myopathy. The aim of this study was to replicate association of the rs4149056 variant in SLCO1B1 with severe statin-associated myopathy in a cohort of patients using a variety of statin medications and to investigate the association with specific statin types. We identified 25 cases of severe statin-associated myopathy and 84 controls matched for age, gender, statin type and dose. The rs4149056 variant in SLCO1B1 was not significantly associated with myopathy in this group as a whole. However, when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin.

  20. Comparison of blood aminotransferase methods for assessment of myopathy and hepatopathy in Florida manatees (Trichechus manatus latirostris)

    USGS Publications Warehouse

    Harr, K.E.; Allison, K.; Bonde, R.K.; Murphy, D.; Harvey, J.W.

    2008-01-01

    Muscle injury is common in Florida manatees (Trichechus manatus latirostris). Plasma aspartate amino-transferase (AST) is frequently used to assess muscular damage in capture myopathy and traumatic injury. Therefore, accurate measurement of AST and alanine aminotransferase (ALT) is important in managed, free-ranging animals, as well as in those rehabilitating from injury. Activities of these enzymes, however, are usually not increased in manatees with either acute or chronic muscle damage, despite marked increases in plasma creatine kinase activity. It is hypothesized that this absence of response is due to apoenzymes in the blood not detected by commonly used veterinary assays. Addition of coenzyme pyridoxal-5-phosphate (P5P or vitamin B6) should, therefore, result in higher measured enzyme activities. The objective of this study was to determine the most accurate, precise, and diagnostically useful method for aminotransferase measurement in manatees that can be used in veterinary practices and diagnostic laboratories. Additionally, appropriate collection and storage techniques were assessed. The use of an optimized commercial wet chemical assay with 100 ??mol P5P resulted in a positive bias of measured enzyme activities in a healthy population of animals. However, AST and ALT were still much lower than that typically observed in domestic animals and should not be used alone in the assessment of capture myopathy and muscular trauma. Additionally, the dry chemistry analyzer, typically used in clinics, reported significantly higher and less precise AST and ALT activities with poor correlation to those measured with wet chemical methods found in diagnostic laboratories. Therefore, these results cannot be clinically compared. Overall, the optimized wet chemical method was the most precise and diagnostically useful measurement of aminotransferase in samples. Additionally, there was a statistically significant difference between paired serum and plasma measurement

  1. HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporine A interaction and mechanism studies.

    PubMed

    Smith, P F; Eydelloth, R S; Grossman, S J; Stubbs, R J; Schwartz, M S; Germershausen, J I; Vyas, K P; Kari, P H; MacDonald, J S

    1991-06-01

    Recent clinical evidence indicates a potential for skeletal muscle toxicity after therapy with HMG-CoA reductase inhibitors (HMGRIs) in man. Although the incidence of drug-induced skeletal muscle toxicity is very low (0.1-0.2%) with monotherapy, it may increase following concomitant drug therapy with the immunosuppressant, cyclosporine A (CsA), and possibly with certain other hypolipidemic agents. In the Sprague-Dawley rat, very high, pharmacologically comparable dosages (150-1200 mg/kg/day) of structurally similar HMGRIs (lovastatin, simvastatin, pravastatin and L-647, 318) produced dose-related increases in the incidence and severity of skeletal muscle degeneration. Physical signs included inappetence, decreased activity, loss of body weight, localized alopecia and mortality. To evaluate the interaction between HMGRIs and CsA, a rat model of CsA-induced cholestasis was developed. In this 2-week model, the skeletal muscle toxicity of the HMGRIs was clearly potentiated by CsA (10 mg/kg/day). Doses of HMGRIs which did not produce skeletal muscle toxicity when given alone caused between 75 and 100% incidence of myopathy (very slight to marked skeletal muscle degeneration) when CsA was coadministered. Typical light microscopic changes included myofiber necrosis with interstitial edema and inflammatory infiltration in areas of acute injury. Histochemical characterization of the muscle lesion indicated that type 2B fibers (primarily glycolytic white fibers) were most sensitive to this toxicity but that, with prolonged administration, all fiber types were ultimately affected. Results of pharmacokinetic studies in rats treated with various HMGRIs +/- CsA indicated that coadministration of CsA alters the disposition of these compounds, resulting in increased systemic exposure (e.g., increased area under the plasma drug concentration vs. time curve-AUC) and consequent (up to 13-fold) increases in skeletal muscle drug levels. Evaluation of the potential interaction between

  2. Electrodiagnostic features of acute paralytic poliomyelitis associated with West Nile virus infection.

    PubMed

    Al-Shekhlee, Amer; Katirji, Bashar

    2004-03-01

    West Nile virus (WNV) infection is a potentially fatal disease, with meningoencephalitis being its most common neurological manifestation. Guillain-Barré syndrome (GBS) has also been described, but acute paralytic poliomyelitis has only recently been recognized. We report the clinical and electrodiagnostic findings of five patients with WNV infection, who presented with acute paralytic poliomyelitis. Three patients manifested focal asymmetrical weakness, and two had rapid ascending quadriplegia mimicking GBS. Electrodiagnostic studies during the acute illness showed normal sensory nerve action potentials, compound motor action potentials of normal or reduced amplitude, and no slowing of nerve conduction velocities. Depending on the timing of the examination, fibrillation potentials were widespread, including in those with focal weakness. Cervical magnetic resonance imaging in one patient showed abnormal T2-weighted signals in the spinal cord gray matter. On follow-up, signs of clinical improvement were seen in one patient, whereas two remained quadriplegic and ventilator-dependent 5 months after the onset. This report highlights the value of the electrodiagnostic studies in the diagnosis and prognosis of focal or generalized weakness due to acute paralytic poliomyelitis associated with WNV infection.

  3. Ileocolonic transfer of solid chyme in small intestinal neuropathies and myopathies

    SciTech Connect

    Greydanus, M.P.; Camilleri, M.; Colemont, L.J.; Phillips, S.F.; Brown, M.L.; Thomforde, G.M. )

    1990-07-01

    The aims of this study were to assess gastric emptying, small bowel transit and colonic filling in patients with motility disorders, with particular attention to the patterns of colonic filling. Gastrointestinal transit was assessed using a previously validated radiolabeled mixed meal. Fourteen patients with clinical and manometric features of chronic intestinal pseudoobstruction classified as intestinal neuropathy and 6 as intestinal myopathy, were studied. The results were compared with those from 10 healthy controls studied similarly. Gastric emptying and small bowel transit of solids were significantly slower in both groups of patients than in healthy controls (P less than 0.05). In health, the ileocolonic transit of solid chyme was characterized by intermittent bolus transfers. The mean size of boluses transferred to the colon (expressed as a percentage of ingested radiolabel) was significantly less (P less than 0.05) in patients with intestinal myopathy (10% +/- 4% (SEM)) than in healthy controls (25% +/- 4%) or in patients with intestinal neuropathy (25% +/- 4%). The intervals between bolus transfer of solids (plateaus in the colonic filling curve) were longer (P less than 0.05) in myopathies (212 +/- 89 minutes) than in health (45 +/- 7 minutes) or neuropathies (53 +/- 11 minutes). Thus, gastric emptying and small bowel transit were delayed in small bowel neuropathies and myopathies. Bolus filling of the colon was less frequent and less effective in patients with myopathic intestinal pseudoobstruction, whereas bolus transfer was preserved in patients with neuropathic intestinal pseudoobstruction.

  4. Mutation-Specific Effects on Thin Filament Length in Thin Filament Myopathy

    PubMed Central

    de Winter, Josine M.; Joureau, Barbara; Lee, Eun-Jeong; Kiss, Balázs; Yuen, Michaela; Gupta, Vandana A.; Pappas, Christopher T.; Gregorio, Carol C.; Stienen, Ger J. M.; Edvardson, Simon; Wallgren-Pettersson, Carina; Lehtokari, Vilma-Lotta; Pelin, Katarina; Malfatti, Edoardo; Romero, Norma B.; van Engelen, Baziel G.; Voermans, Nicol C.; Donkervoort, Sandra; Bönnemann, C. G.; Clarke, Nigel F.; Beggs, Alan H.; Granzier, Henk; Ottenheijm, Coen A. C.

    2016-01-01

    Objective Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation. Methods We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. Results Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force–sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin–thick filament overlap. Interpretation These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths. PMID:27074222

  5. Clinical Manifestation and a New "ISCU" Mutation in Iron-Sulphur Cluster Deficiency Myopathy

    ERIC Educational Resources Information Center

    Kollberg, Gittan; Tulinius, Mar; Melberg, Atle; Darin, Niklas; Andersen, Oluf; Holmgren, Daniel; Oldfors, Anders; Holme, Elisabeth

    2009-01-01

    Myopathy with deficiency of succinate dehydrogenase and aconitase is a recessively inherited disorder characterized by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur. The…

  6. Use of guidelines when planning home care of a girl with severe congenital myopathy.

    PubMed

    Gray, Kelly; Isaacs, David; Kilham, Henry; Tobin, Bernadette; Waters, Karen

    2016-01-01

    We use issues that arose in the management of a 4-year old girl with a congenital myopathy to consider the tension between respecting the choices and decisions of the child's parents and applying clinical practice guidelines that emphasise minimising risk to the child. This case raises the issue of when it is reasonable to override parents' choice of management options.

  7. Severe myopathy in mice lacking the MEF2/SRF-dependent gene leiomodin-3

    PubMed Central

    Cenik, Bercin K.; Garg, Ankit; McAnally, John R.; Shelton, John M.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.; Liu, Ning

    2015-01-01

    Maintenance of skeletal muscle structure and function requires a precise stoichiometry of sarcomeric proteins for proper assembly of the contractile apparatus. Absence of components of the sarcomeric thin filaments causes nemaline myopathy, a lethal congenital muscle disorder associated with aberrant myofiber structure and contractility. Previously, we reported that deficiency of the kelch-like family member 40 (KLHL40) in mice results in nemaline myopathy and destabilization of leiomodin-3 (LMOD3). LMOD3 belongs to a family of tropomodulin-related proteins that promote actin nucleation. Here, we show that deficiency of LMOD3 in mice causes nemaline myopathy. In skeletal muscle, transcription of Lmod3 was controlled by the transcription factors SRF and MEF2. Myocardin-related transcription factors (MRTFs), which function as SRF coactivators, serve as sensors of actin polymerization and are sequestered in the cytoplasm by actin monomers. Conversely, conditions that favor actin polymerization de-repress MRTFs and activate SRF-dependent genes. We demonstrated that the actin nucleator LMOD3, together with its stabilizing partner KLHL40, enhances MRTF-SRF activity. In turn, SRF cooperated with MEF2 to sustain the expression of LMOD3 and other components of the contractile apparatus, thereby establishing a regulatory circuit to maintain skeletal muscle function. These findings provide insight into the molecular basis of the sarcomere assembly and muscle dysfunction associated with nemaline myopathy. PMID:25774500

  8. Rehabilitation of Critical Illness Polyneuropathy and Myopathy Patients: An Observational Study

    ERIC Educational Resources Information Center

    Novak, Primoz; Vidmar, Gaj; Kuret, Zala; Bizovicar, Natasa

    2011-01-01

    Critical illness polyneuropathy and myopathy (CIPNM) frequently develops in patients hospitalized in intensive care units. The number of patients with CIPNM admitted to inpatient rehabilitation is increasing. The aim of this study was to comprehensively evaluate the outcome of their rehabilitation. Twenty-seven patients with CIPNM were included in…

  9. Aerobic Exercise and Pharmacological Therapies for Skeletal Myopathy in Heart Failure: Similarities and Differences

    PubMed Central

    Bacurau, Aline V.; Cunha, Telma F.; Souza, Rodrigo W.; Voltarelli, Vanessa A.; Gabriel-Costa, Daniele; Brum, Patricia C.

    2016-01-01

    Skeletal myopathy has been identified as a major comorbidity of heart failure (HF) affecting up to 20% of ambulatory patients leading to shortness of breath, early fatigue, and exercise intolerance. Neurohumoral blockade, through the inhibition of renin angiotensin aldosterone system (RAS) and β-adrenergic receptor blockade (β-blockers), is a mandatory pharmacological therapy of HF since it reduces symptoms, mortality, and sudden death. However, the effect of these drugs on skeletal myopathy needs to be clarified, since exercise intolerance remains in HF patients optimized with β-blockers and inhibitors of RAS. Aerobic exercise training (AET) is efficient in counteracting skeletal myopathy and in improving functional capacity and quality of life. Indeed, AET has beneficial effects on failing heart itself despite being of less magnitude compared with neurohumoral blockade. In this way, AET should be implemented in the care standards, together with pharmacological therapies. Since both neurohumoral inhibition and AET have a direct and/or indirect impact on skeletal muscle, this review aims to provide an overview of the isolated effects of these therapeutic approaches in counteracting skeletal myopathy in HF. The similarities and dissimilarities of neurohumoral inhibition and AET therapies are also discussed to identify potential advantageous effects of these combined therapies for treating HF. PMID:26904163

  10. Novel Pathogenic Variants in a French Cohort Widen the Mutational Spectrum of GNE Myopathy

    PubMed Central

    Cerino, Mathieu; Gorokhova, Svetlana; Béhin, Anthony; Urtizberea, Jon Andoni; Kergourlay, Virginie; Salvo, Eric; Bernard, Rafaëlle; Lévy, Nicolas; Bartoli, Marc; Krahn, Martin

    2015-01-01

    Background: GNE myopathy is a rare autosomal recessively inherited muscle disease resulting from mutations in the gene encoding GNE (UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase), a key enzyme in sialic acid biosynthesis. 154 different pathogenic variants have been previously associated with GNE myopathy. Objective: Describe novel pathogenic variants associated with GNE myopathy in a large French cohort. Methods: We analyzed mutational data from 32 GNE myopathy index patients. Novel, as well as previously published pathogenic variants, were examined for possible deleterious effects on splicing. Results: We describe 13 novel pathogenic variants in GNE, identified in the first large French cohort reported to date. We also find that 6 published pathogenic variants might have a previously unrecognized deleterious effect on splicing. Conclusions: Novel pathogenic GNE variants described here raise the total number of different pathogenic variants reported to 167, complementing the recently published GNE mutation update. Our novel findings on possible splice-disrupting effects by several variants suggest that the pathogenicity mechanism of these variants could be reinterpreted, expanding our knowledge about the GNE mutational spectrum. PMID:27858732

  11. Sporadic cardiac and skeletal myopathy caused by a de novo desmin mutation.

    PubMed

    Park, K Y; Dalakas, M C; Semino-Mora, C; Lee, H S; Litvak, S; Takeda, K; Ferrans, V J; Goldfarb, L G

    2000-06-01

    Desmin myopathy is a familial or sporadic disorder characterized by intracytoplasmic accumulation of desmin in the muscle cells. We and others have previously identified desmin gene mutations in patients with familial myopathy, but close to 45% of the patients do not report previous family history of the disease. The present study was conducted to determine the cause of desmin myopathy in a sporadic patient presenting with symmetrical muscle weakness and atrophy combined with atrioventricular conduction block requiring a permanent pacemaker. A novel heterozygous R406W mutation in the desmin gene was identified by sequencing cDNA and genomic DNA. Expression of a construct containing the patient's mutant desmin cDNA in SW13 (vim-) cells demonstrated a high pathogenic potential of the R406W mutation. This mutation was not found in the patient's father, mother or sister by sequencing and restriction analysis. Testing with five microsatellite markers and four intragenic single nucleotide polymorphisms excluded alternative paternity. Haplotype analysis indicates that the patient's father was germ-line mosaic for the desmin mutation. We conclude that de novo mutations in the desmin gene may be the cause of sporadic forms of desmin-related cardiac and skeletal myopathy.

  12. Metabolic Myopathies and Physical Activity: When Fatigue Is More Than Simple Exertion.

    ERIC Educational Resources Information Center

    Tarnopolsky, Mark A.

    2002-01-01

    When patients experience fatigue and muscle cramps beyond exercise adaptation, physicians should consider metabolic myopathies. The most common conditions seen in active patients are myoadenylate deaminase deficiency and disorders such as McArdle's disease. Targeted family histories and basic laboratory studies help rule out conditions mimicking…

  13. Mice lacking microRNA 133a develop dynamin 2–dependent centronuclear myopathy

    PubMed Central

    Liu, Ning; Bezprozvannaya, Svetlana; Shelton, John M.; Frisard, Madlyn I.; Hulver, Matthew W.; McMillan, Ryan P.; Wu, Yaru; Voelker, Kevin A.; Grange, Robert W.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.

    2011-01-01

    MicroRNAs modulate cellular phenotypes by inhibiting expression of mRNA targets. In this study, we have shown that the muscle-specific microRNAs miR-133a-1 and miR-133a-2 are essential for multiple facets of skeletal muscle function and homeostasis in mice. Mice with genetic deletions of miR-133a-1 and miR-133a-2 developed adult-onset centronuclear myopathy in type II (fast-twitch) myofibers, accompanied by impaired mitochondrial function, fast-to-slow myofiber conversion, and disarray of muscle triads (sites of excitation-contraction coupling). These abnormalities mimicked human centronuclear myopathies and could be ascribed, at least in part, to dysregulation of the miR-133a target mRNA that encodes dynamin 2, a GTPase implicated in human centronuclear myopathy. Our findings reveal an essential role for miR-133a in the maintenance of adult skeletal muscle structure, function, bioenergetics, and myofiber identity; they also identify a potential modulator of centronuclear myopathies. PMID:21737882

  14. Cyclophilin D, a target for counteracting skeletal muscle dysfunction in mitochondrial myopathy

    PubMed Central

    Gineste, Charlotte; Hernandez, Andres; Ivarsson, Niklas; Cheng, Arthur J.; Naess, Karin; Wibom, Rolf; Lesko, Nicole; Bruhn, Helene; Wedell, Anna; Freyer, Christoph; Zhang, Shi-Jin; Carlström, Mattias; Lanner, Johanna T.; Andersson, Daniel C.; Bruton, Joseph D.; Wredenberg, Anna; Westerblad, Håkan

    2015-01-01

    Muscle weakness and exercise intolerance are hallmark symptoms in mitochondrial disorders. Little is known about the mechanisms leading to impaired skeletal muscle function and ultimately muscle weakness in these patients. In a mouse model of lethal mitochondrial myopathy, the muscle-specific Tfam knock-out (KO) mouse, we previously demonstrated an excessive mitochondrial Ca2+ uptake in isolated muscle fibers that could be inhibited by the cyclophilin D (CypD) inhibitor, cyclosporine A (CsA). Here we show that the Tfam KO mice have increased CypD levels, and we demonstrate that this increase is a common feature in patients with mitochondrial myopathy. We tested the effect of CsA treatment on Tfam KO mice during the transition from a mild to terminal myopathy. CsA treatment counteracted the development of muscle weakness and improved muscle fiber Ca2+ handling. Importantly, CsA treatment prolonged the lifespan of these muscle-specific Tfam KO mice. These results demonstrate that CsA treatment is an efficient therapeutic strategy to slow the development of severe mitochondrial myopathy. PMID:26374844

  15. Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate

    PubMed Central

    Goldberger, Jeffrey J.; Arora, Rishi; Green, David; Greenland, Philip; Lee, Daniel C.; Lloyd-Jones, Donald M.; Markl, Michael; Ng, Jason; Shah, Sanjiv J.

    2015-01-01

    Atrial disease or myopathy forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. Current diagnostic approaches in patients with AF focus on identifying clinical predictors with evaluation of left atrial size by echocardiography serving as the sole measure specifically evaluating the atrium. Although the atrial substrate underlying AF is likely developing for years prior to the onset of AF, there is no current evaluation to identify the pre-clinical atrial myopathy. Atrial fibrosis is one component of the atrial substrate that has garnered recent attention based on newer MRI techniques that have been applied to visualize atrial fibrosis in humans with prognostic implications regarding success of treatment. Advanced ECG signal processing, echocardiographic techniques, and MRI imaging of fibrosis and flow provide up-to-date approaches to evaluate the atrial myopathy underlying AF. While thromboembolic risk is currently defined by clinical scores, their predictive value is mediocre. Evaluation of stasis via imaging and biomarkers associated with thrombogenesis may provide enhanced approaches to assess risk for stroke in patients with AF. Better delineation of the atrial myopathy that serves as the substrate for AF and thromboembolic complications might improve treatment outcomes. Furthermore, better delineation of the pathophysiologic mechanisms underlying the development of the atrial substrate for AF, particularly in its earlier stages, could help identify blood and imaging biomarkers that could be useful to assess risk for developing new onset AF and suggest specific pathways that could be targeted for prevention. PMID:26216085

  16. Cyclophilin D, a target for counteracting skeletal muscle dysfunction in mitochondrial myopathy.

    PubMed

    Gineste, Charlotte; Hernandez, Andres; Ivarsson, Niklas; Cheng, Arthur J; Naess, Karin; Wibom, Rolf; Lesko, Nicole; Bruhn, Helene; Wedell, Anna; Freyer, Christoph; Zhang, Shi-Jin; Carlström, Mattias; Lanner, Johanna T; Andersson, Daniel C; Bruton, Joseph D; Wredenberg, Anna; Westerblad, Håkan

    2015-12-01

    Muscle weakness and exercise intolerance are hallmark symptoms in mitochondrial disorders. Little is known about the mechanisms leading to impaired skeletal muscle function and ultimately muscle weakness in these patients. In a mouse model of lethal mitochondrial myopathy, the muscle-specific Tfam knock-out (KO) mouse, we previously demonstrated an excessive mitochondrial Ca(2+) uptake in isolated muscle fibers that could be inhibited by the cyclophilin D (CypD) inhibitor, cyclosporine A (CsA). Here we show that the Tfam KO mice have increased CypD levels, and we demonstrate that this increase is a common feature in patients with mitochondrial myopathy. We tested the effect of CsA treatment on Tfam KO mice during the transition from a mild to terminal myopathy. CsA treatment counteracted the development of muscle weakness and improved muscle fiber Ca(2+) handling. Importantly, CsA treatment prolonged the lifespan of these muscle-specific Tfam KO mice. These results demonstrate that CsA treatment is an efficient therapeutic strategy to slow the development of severe mitochondrial myopathy.

  17. Evaluation of ubiquinone concentration and mitochondrial function relative to cerivastatin-induced skeletal myopathy in rats.

    PubMed

    Schaefer, William H; Lawrence, Jeffery W; Loughlin, Amy F; Stoffregen, Dana A; Mixson, Lori A; Dean, Dennis C; Raab, Conrad E; Yu, Nathan X; Lankas, George R; Frederick, Clay B

    2004-01-01

    As a class, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors can potentially cause skeletal myopathy. One statin, cerivastatin, has recently been withdrawn from the market due to an unacceptably high incidence of rhabdomyolysis. The mechanism underlying statin-induced myopathy is unknown. This paper sought to investigate the relationship among statin-induced myopathy, mitochondrial function, and muscle ubiquinone levels. Rats were administered cerivastatin at 0.1, 0.5, and 1.0 (mg/kg)/day or dose vehicle (controls) by oral gavage for 15 days. Samples of type I-predominant skeletal muscle (soleus) and type II-predominant skeletal muscle [quadriceps and extensor digitorum longus (EDL)], and blood were collected on study days 5, 10, and 15 for morphological evaluation, clinical chemistry, mitochondrial function tests, and analysis of ubiquinone levels. No histological changes were observed in any of the animals on study days 5 or 10, but on study day 15, mid- and high-dose animals had necrosis and inflammation in type II skeletal muscle. Elevated creatine kinase (CK) levels in blood (a clinical marker of myopathy) correlated with the histopathological diagnosis of myopathy. Ultrastructural characterization of skeletal muscle revealed disruption of the sarcomere and altered mitochondria only in myofibers with degeneration, while adjacent myofibers were unaffected and had normal mitochondria. Thus, mitochondrial effects appeared not to precede myofiber degeneration. Mean coenzyme Q9 (CoQ9) levels in all dose groups were slightly decreased relative to controls in type II skeletal muscle, although the difference was not significantly different in most cases. Mitochondrial function in skeletal muscle was not affected by the changes in ubiquinone levels. The ubiquinone levels in high-dose-treated animals exhibiting myopathy were not significantly different from low-dose animals with no observable toxic effects. Furthermore, ubiquinone levels did not correlate

  18. The Clinical Phenotypes of the Juvenile Idiopathic Inflammatory Myopathies

    PubMed Central

    Shah, Mona; Mamyrova, Gulnara; Targoff, Ira N.; Huber, Adam M.; Malley, James D.; Rice, Madeline Murguia; Miller, Frederick W.; Rider, Lisa G.

    2015-01-01

    The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes and other systemic features. Although juvenile dermatomyositis (JDM), the most common form of JIIM, has been well-studied, the other major clinical subgroups of JIIM, including juvenile polymyositis (JPM) and juvenile myositis overlapping with another autoimmune or connective tissue disease (JCTM), have not been well characterized, and their similarity to the adult clinical subgroups is also unknown. We enrolled 436 patients with JIIM, including 354 classified as JDM, 33 as JPM and 49 as JCTM, in a nationwide registry study. The aim of this study was to compare demographics, clinical features, laboratory measures, including myositis autoantibodies, and outcomes, among these clinical subgroups, as well as with published data on adult IIM patients enrolled in a separate natural history study. Random forest classification and logistic regression modeling were used to compare clinical subgroups, following univariate analysis. JDM was characterized by typical rashes, including Gottron’s papules, heliotrope rash, malar rash, periungual capillary changes and other photosensitive and vasculopathic skin rashes. JPM was characterized by more severe weakness, higher creatine kinase levels, falling episodes and more frequent cardiac disease. JCTM had more frequent interstitial lung disease, Raynaud’s phenomenon, arthralgia and malar rash. Differences in autoantibody frequency were also evident, with anti-p155, anti-MJ and anti-Mi2 seen more frequently in patients with JDM, anti-signal recognition particle and anti-Jo1 in JPM, and anti-U1RNP, PM-Scl and other myositis-associated autoantibodies more commonly present in JCTM. Mortality was highest in JCTM, whereas hospitalizations and wheelchair usage were highest in JPM patients. Several demographic and clinical features were shared between juvenile and adult IIM subgroups

  19. Muscle-fiber transdifferentiation in an experimental model of respiratory chain myopathy

    PubMed Central

    2012-01-01

    Introduction Skeletal muscle fiber composition and muscle energetics are not static and change in muscle disease. This study was performed to determine whether a mitochondrial myopathy is associated with adjustments in skeletal muscle fiber-type composition. Methods Ten rats were treated with zidovudine, an antiretroviral nucleoside reverse transcriptase inhibitor that induces a myopathy by interfering with mitochondrial functions. Soleus muscles were examined after 21 weeks of treatment. Ten untreated rats served as controls. Results Zidovudine induced a myopathy with mitochondrial DNA depletion, abnormalities in mitochondrial ultrastructure, and reduced cytochrome c oxidase activity. Mitochondrial DNA was disproportionally more diminished in type I compared with type II fibers, whereas atrophy predominated in type II fibers. Compared with those of controls, zidovudine-exposed soleus muscles contained an increased proportion (256%) of type II fibers, whereas neonatal myosin heavy chains remained repressed, indicating fiber-type transformation in the absence of regeneration. Microarray gene-expression analysis confirmed enhanced fast-fiber isoforms, repressed slow-fiber transcripts, and reduced neonatal fiber transcripts in the mitochondrial myopathy. Respiratory chain transcripts were diminished, whereas the enzymes of glycolysis and glycogenolysis were enhanced, indicating a metabolic adjustment from oxidative to glycolytic capacities. A coordinated regulation was found of transcription factors known to orchestrate type II fiber formation (upregulation of MyoD, Six1, Six2, Eya1, and Sox6, and downregulation of myogenin and ERRγ). Conclusions The type I to type II fiber transformation in mitochondrial myopathy implicates mitochondrial function as a new regulator of skeletal muscle fiber type. PMID:23107834

  20. Phenotypes, genotypes, and prevalence of congenital myopathies older than 5 years in Denmark

    PubMed Central

    Werlauff, Ulla; Duno, Morten; Vissing, John

    2017-01-01

    Objective: Congenital myopathy as a nosologic entity has long been recognized, but knowledge of overall and subtype prevalence and phenotype-genotype relationship is scarce, especially in the adult population. Methods: A national cohort of 107 patients ≥5 years diagnosed with congenital myopathy were prospectively assessed clinically, histologically, and genetically. Results: Twenty-five patients were excluded because of atypical features or alternative etiologies. The remaining 82 were on average 28 years old. Histologic examination revealed 14 (17%) with core disease, 15 (18%) centronuclear myopathy, 12 (15%) nemaline rods, 27 (33%) congenital fiber-type disproportion or type I predominance, and 14 (17%) nonspecific myopathic changes. Genetic etiology was identified in 46 patients (56.1%); 22.0% were heterozygous or compound heterozygous for mutations in RYR1, 7.3% had DNM2 mutations, and 7.3% NEB mutations. Less than 5% had mutations in ACTA1, TPM2/3, MTM1, TTN, SEPN1, or SC4NA. A genetic cause was established in 83% with specific histology (cores/rods/centronuclear myopathy) vs 29% with unspecific histology. The detailed clinical examination found gene-dependent discrepancies in the pattern of muscle affection and walking ability. Although walking ability was delayed in patients with ACTA1, TPM2/3, and RYR1 mutations, it was within normal limits in patients with NEB and DNM2 mutations. Conclusions: We found that overall, genetic and histologic prevalence of congenital myopathy in Denmark differs from previous retrospective reports. Less RYR1 and more DNM2 and NEB mutations and less core histology were present in our cohort. These differences may be explained by our prospective design, the older cohort of patients, and by differences in genetic background. PMID:28357410

  1. Delayed diagnosis of late-onset Pompe disease in patients with myopathies of unknown origin and/or hyperCKemia.

    PubMed

    Pérez-López, Jordi; Selva-O'Callaghan, Albert; Grau-Junyent, Josep M; Gallego-Galindo, Luis; Coll, M Josep; García-Morillo, Salvador; Torralba-Cabeza, Miguel A; Vilardell-Tarrés, Miquel

    2015-04-01

    Pompe disease is a rare metabolic myopathy whose diagnosis is sometimes delayed despite being essential for improving clinical outcomes. We aimed to investigate the prevalence of late-onset Pompe disease among patients with a myopathy of unknown etiology, including polymyositis, or with idiopathic rise of creatine kinase (CK) levels, in a department of internal medicine. A cohort study was conducted in 241 subjects: 140 patients with myopathies of unknown origin or increased CK levels, 30 with polymyositis and 71 who constituted the control group of other myopathies. Acid α-glucosidase (GAA) activity was tested in dried blood spots. If a positive result was obtained, GAA activity in isolated lymphocytes and/or genetic testing was performed as a confirmatory diagnosis. Out of the 140 investigated patients, 2 patients with myopathies of unknown origin were confirmed to be positive for Pompe disease. Thus, late-onset Pompe disease should be considered among adult patients with myopathy of unknown origin.

  2. Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy.

    PubMed

    Kraeva, N; Heytens, L; Jungbluth, H; Treves, S; Voermans, N; Kamsteeg, E; Ceuterick-de Groote, C; Baets, J; Riazi, S

    2015-07-01

    Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.

  3. Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1

    PubMed Central

    Schessl, Joachim; Taratuto, Ana L.; Sewry, Caroline; Battini, Roberta; Chin, Steven S.; Maiti, Baijayanta; Dubrovsky, Alberto L.; Erro, Marcela G.; Espada, Graciela; Robertella, Monica; Saccoliti, Maria; Olmos, Patricia; Bridges, Leslie R.; Standring, Peter; Hu, Ying; Zou, Yaqun; Swoboda, Kathryn J.; Scavina, Mena; Goebel, Hans-Hilmar; Mitchell, Christina A.; Flanigan, Kevin M.; Muntoni, Francesco

    2009-01-01

    We recently identified the X-chromosomal four and a half LIM domain gene FHL1 as the causative gene for reducing body myopathy, a disorder characterized by progressive weakness and intracytoplasmic aggregates in muscle that exert reducing activity on menadione nitro-blue-tetrazolium (NBT). The mutations detected in FHL1 affected highly conserved zinc coordinating residues within the second LIM domain and lead to the formation of aggregates when transfected into cells. Our aim was to define the clinical and morphological phenotype of this myopathy and to assess the mutational spectrum of FHL1 mutations in reducing body myopathy in a larger cohort of patients. Patients were ascertained via the detection of reducing bodies in muscle biopsy sections stained with menadione-NBT followed by clinical, histological, ultrastructural and molecular genetic analysis. A total of 11 patients from nine families were included in this study, including seven sporadic patients with early childhood onset disease and four familial cases with later onset. Weakness in all patients was progressive, sometimes rapidly so. Respiratory failure was common and scoliosis and spinal rigidity were significant in some of the patients. Analysis of muscle biopsies confirmed the presence of aggregates of FHL1 positive material in all biopsies. In two patients in whom sequential biopsies were available the aggregate load in muscle sections appeared to increase over time. Ultrastructural analysis revealed that cytoplasmic bodies were regularly seen in conjunction with the reducing bodies. The mutations detected were exclusive to the second LIM domain of FHL1 and were found in both sporadic as well as familial cases of reducing body myopathy. Six of the nine mutations affected the crucial zinc coordinating residue histidine 123. All mutations in this residue were de novo and were associated with a severe clinical course, in particular in one male patient (H123Q). Mutations in the zinc coordinating residue

  4. Exertional rhabdomyolysis: physiological response or manifestation of an underlying myopathy?

    PubMed Central

    Scalco, Renata S; Snoeck, Marc; Quinlivan, Ros; Treves, Susan; Laforét, Pascal; Jungbluth, Heinz; Voermans, Nicol C

    2016-01-01

    Exertional rhabdomyolysis is characterised by muscle breakdown associated with strenuous exercise or normal exercise under extreme circumstances. Key features are severe muscle pain and sudden transient elevation of serum creatine kinase (CK) levels with or without associated myoglobinuria. Mild cases may remain unnoticed or undiagnosed. Exertional rhabdomyolysis is well described among athletes and military personnel, but may occur in anybody exposed to unaccustomed exercise. In contrast, exertional rhabdomyolysis may be the first manifestation of a genetic muscle disease that lowers the exercise threshold for developing muscle breakdown. Repeated episodes of exertional rhabdomyolysis should raise the suspicion of such an underlying disorder, in particular in individuals in whom the severity of the rhabdomyolysis episodes exceeds the expected response to the exercise performed. The present review aims to provide a practical guideline for the acute management and postepisode counselling of patients with exertional rhabdomyolysis, with a particular emphasis on when to suspect an underlying genetic disorder. The pathophysiology and its clinical features are reviewed, emphasising four main stepwise approaches: (1) the clinical significance of an acute episode, (2) risks of renal impairment, (3) clinical indicators of an underlying genetic disorders and (4) when and how to recommence sport activity following an acute episode of rhabdomyolysis. Genetic backgrounds that appear to be associated with both enhanced athletic performance and increased rhabdomyolysis risk are briefly reviewed. PMID:27900193

  5. A mitochondrial tRNA aspartate mutation causing isolated mitochondrial myopathy.

    PubMed

    Seneca, Sara; Goemans, Nathalie; Van Coster, Rudy; Givron, Patrice; Reybrouck, Tony; Sciot, Raf; Meulemans, Ann; Smet, Joel; Van Hove, Johan L K

    2005-08-30

    Several mutations in mitochondrial transfer RNA (tRNA) genes can cause mitochondrial myopathy. We describe a young girl who presented with pronounced exercise intolerance. The anaerobic threshold and the maximal oxygen consumption were decreased. She had decreased complex I and IV enzyme activity and ragged red fibers on muscle biopsy. An A to G transition at nucleotide position 7526 in tRNA Aspartate (tRNA(Asp)) gene was heteroplasmic in several of the patient's tissues. We were unable to detect the mutation in muscle tissue from the patient's mother. This case adds a new genetic etiology for mitochondrial myopathy. It also illustrates for patients with combined deficiency of the complex I and IV enzyme activity the value of sequencing in the affected tissue muscle, and not only in blood, all mitochondrial tRNA genes including those not commonly affected, such as in this case mt tRNA(Asp).

  6. [An autosomal recessive syndrome with myopathy and central and peripheral nervous system involvement (author's transl)].

    PubMed

    Warter, J M; Marescaux, C; Coquillat, G; Walter, P; Micheletti, G; Rohmer, F

    1981-01-01

    Three of 11 children, offspring of a consanguineous marriage, presented a progressive myopathy and seizures, associated with symptoms suggesting both central and peripheral nervous system involvement. The ultrastructural muscular lesions were not specific. The association of severe impairment of muscle tissue and of central nervous system is rare, being described in centronuclear myopathy, cerebromuscular dystrophy, Kearns-Sayre syndrome and in a few isolated cases. Clinically only these isolated observations and especially the Kearns-Sayre syndrome demonstrate analogies to our observations. These data lead us to the discussion of the specificity of ultrastructural lesions, especially mitochondrial abnormalities. Some authors consider these abnormalities to be the biochemical hallmark for ophthalmoplegia plus, whereas for others, especially Drachman, they are an inconstant and nonspecific finding, merely the consequence and not the cause of this disease. These observations argue for the relationship between muscular pathology and nervous system dysfunction.

  7. Ranolazine-induced myopathy in a patient on chronic statin therapy.

    PubMed

    Correa, Daniel; Landau, Mark

    2013-03-01

    We present a case demonstrating clinical, electrophysiological, serological, and radiological evidence of a myopathy induced by ranolazine, in a patient otherwise asymptomatic on chronic statin therapy. The patient developed proximal weakness, serum creatine kinase levels of 1875 U/L, electromyography with muscle membrane instability and small short-duration motor unit potentials, and magnetic resonance imaging evidence of muscle edema. The manifestations began within one week of initiation of ranolazine and improved within days after discontinuation. Ranolazine is a weak inhibitor of CYP3A4 known to increase the serum level of simvastatin and its active metabolite 2-fold. We postulate that the addition of ranolazine to a medical regimen that included atorvastatin induced a myoncecrotic myopathy.

  8. Camptocormia and dropped head syndrome as a clinic picture of myotonic myopathy.

    PubMed

    Kocaaga, Zehra; Bal, Serpil; Turan, Yasemin; Gurgan, Alev; Esmeli, Figen

    2008-12-01

    Dropped head syndrome is primarily based on weakness localized at neck extensors. It may result from motor neuron disease, myasthenia gravis, and chronic inflammatory demyelinating polyneuropathy and also from various neuromuscular diseases including inflammatory, dystrophic and metabolic myopathies. Camptocormia (CC) on the other hand is an unusual condition characterized by progressive weakness of the extensor vertebral muscles and results in involuntary trunk flexion. CC may emerge as a clinical feature of many different conditions such as several myopathies and Parkinson's disease. The association of dropped head syndrome with CC has been rarely published in the literature. However, this is the only case presenting with concomitant dropped head syndrome and CC as a clinical picture of myotonic dystrophy (MD). In this report we aimed to represent a female patient, who was diagnosed as having myotonic dystrophy, with concurrent dropped head syndrome and CC.

  9. A myopathy associated with protozoan schizonts in chickens in commercial farms in peninsular Malaysia.

    PubMed

    Opitz, H M; Jakob, H J; Wiensenhuetter, E; Devi, V V

    1982-01-01

    A myopathy associated with elongated intramuscular protozoan schizonts of uncertain classification was observed in chickens in commercial farms. Of 152 affected fowls originating from 21 flocks in 12 farms, 149 were 24 weeks of age or older and 136 were broiler breeder birds. Both sexes were affected. The disease was only observed during the months of October, November and December, 1976 and 1977. The monthly mortality rate in affected adult flocks rose by 0.5% to 4% and the egg production declined by 5% to 15% during this period. Most affected birds were in good body condition or overweight. Gross lesions were usually present in all skeletal muscles and the cardiac muscle. They resembled nutritional myopathy, sarcosporidiosis, leucocytozoonosis or haemorrhagic syndrome. Microscopically visible elongated schizonts were demonstrated in skeletal muscles and the cardiac muscle in 49 of 55 birds examined histologically. The possible aetiology with respect to known parasites of muscles in fowls is discussed.

  10. Relationship of Skeletal Muscle Development and Growth to Breast Muscle Myopathies: A Review.

    PubMed

    Velleman, Sandra G

    2015-12-01

    Selection in meat-type birds has focused on growth rate, muscling, and feed conversion. These strategies have made substantial improvements but have affected muscle structure, repair mechanisms, and meat quality, especially in the breast muscle. The increase in muscle fiber diameters has reduced available connective tissue spacing, reduced blood supply, and altered muscle metabolism in the breast muscle. These changes have increased muscle fiber degeneration and necrosis but have limited muscle repair mechanisms mediated by the adult myoblast (satellite cell) population of cells, likely resulting in the onset of myopathies. This review focuses on muscle growth mechanisms and how changes in the cellular development of the breast muscle may be associated with breast muscle myopathies occurring in meat-type birds.

  11. Glutaric aciduria type II presenting as myopathy and rhabdomyolysis in a teenager.

    PubMed

    Prasad, Manish; Hussain, Shanawaz

    2015-01-01

    Late-onset glutaric aciduria type II has been described recently as a rare but treatable cause of proximal myopathy in teenagers and adults. It is an autosomal recessive disease affecting fatty acid, amino acid, and choline metabolism. This is usually a result of 2 defective flavoproteins: either electron transfer flavoprotein (ETF) or electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). We present a 14-year-old boy with a background of autistic spectrum disorder who presented with severe muscle weakness and significant rhabdomyolysis. Before the onset of muscle weakness, he was very active but was completely bedridden at presentation. Diagnosis was established quickly by urine organic acid and plasma acylcarnitine analysis. He has shown significant improvement after starting oral riboflavin supplementation and is now fully mobile. This case highlights that late-onset glutaric aciduria type II is an important differential diagnosis to consider in teenagers presenting with proximal myopathy and rhabdomyolysis and it may not be associated with hypoglycemia.

  12. A PATTERN RECOGNITION APPROACH TO THE PATIENT WITH A SUSPECTED MYOPATHY

    PubMed Central

    Barohn, Richard J.; Dimachkie, Mazen M.; Jackson, Carlayne E.

    2014-01-01

    Myopathies are a heterogeneous group of disorders that can be challenging to diagnose. The purpose of this review is to provide a diagnostic approach based predominantly upon the clinical history and neurologic examination. Laboratory testing that can be subsequently used to confirm the suspected diagnosis based upon this pattern recognition approach will also be discussed. Over the past decade, there have been numerous discoveries allowing clinicians to diagnose myopathies with genetic testing. Unfortunately, some of the testing, particularly molecular genetics, is extremely expensive and frequently not covered by insurance. Careful consideration of the distribution of muscle weakness and attention to common patterns of involvement in the context of other aspects of the neurologic examination and laboratory evaluation should assist the clinician in making a timely and accurate diagnosis, and sometimes can minimize the expense of further testing PMID:25037080

  13. Late-onset polyglucosan body myopathy in five patients with a homozygous mutation in GYG1

    PubMed Central

    Akman, H. Orhan; Aykit, Yavuz; Amuk, Ozge Ceren; Malfatti, Edoardo; Romero, Norma B.; Maioli, Maria Antonietta; Piras, Rachele; DiMauro, Salvatore; Marrosu, Gianni

    2015-01-01

    Five Sardinian patients presented in their 5th or 6th decade with progressive limb girdle muscle weakness but their muscle biopsies showed vacuolar myopathy. The more or less abundant subsarcolemmal and intermyofibrillar vacuoles showed intense, partially α-amylase resistant, PAS-positive deposits consistent with polyglucosan. The recent description of late-onset polyglucosan myopathy has prompted us to find new genetic defects in the gene (GYG1) encoding glycogenin-1, the crucial primer enzyme of glycogen synthesis in muscle. We found a single homozygous intronic mutation harbored by five patients, who, except for two siblings, appear to be unrelated but all five live in central or south Sardinian villages. PMID:26652229

  14. Hereditary inclusion-body myopathy: clues on pathogenesis and possible therapy.

    PubMed

    Broccolini, Aldobrando; Gidaro, Teresa; Morosetti, Roberta; Mirabella, Massimiliano

    2009-09-01

    Hereditary inclusion-body myopathy (h-IBM), or distal myopathy with rimmed vacuoles (DMRV), is an autosomal recessive disorder with onset in early adult life and a progressive course leading to severe disability. h-IBM/DMRV is due to mutations of a gene (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been unambiguously clarified how GNE gene mutations impair muscle metabolism. Although numerous studies have indicated a key role of hyposialylation of glycoproteins in h-IBM/DMRV pathogenesis, others have demonstrated new and unpredicted functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h-IBM/DMRV and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of this disorder.

  15. Salvaging hope: Is increasing NAD(+) a key to treating mitochondrial myopathy?

    PubMed

    Lightowlers, Robert N; Chrzanowska-Lightowlers, Zofia M A

    2014-06-01

    Mitochondrial diseases can arise from mutations either in mitochondrial DNA or in nuclear DNA encoding mitochondrially destined proteins. Currently, there is no cure for these diseases although treatments to ameliorate a subset of the symptoms are being developed. In this issue of EMBO Molecular Medicine, Khan et al (2014) use a mouse model to test the efficacy of a simple dietary supplement of nicotinamide riboside to treat and prevent mitochondrial myopathies.

  16. Paraneoplastic Necrotizing Autoimmune Myopathy in a Patient Undergoing Laparoscopic Pancreatoduodenectomy for Distal Cholangiocarcinoma

    PubMed Central

    van Dijk, Stefan; van der Kooi, Anneke J.; Aronica, Eleonora; van Gulik, Thomas M.; Busch, Olivier R.; Besselink, Marc G.

    2016-01-01

    A 73-year-old male presented with jaundice and severe muscle weakness. He was diagnosed with distal cholangiocarcinoma and paraneoplastic necrotizing autoimmune myopathy (NAM). Treatment of NAM consisted of dexamethasone pulse therapy, prednisone, and single-dose intravenous immunoglobulin. The distal cholangiocarcinoma was resected through a total laparoscopic pancreatoduodenectomy. After hospital discharge, muscle strength initially increased postoperatively; however, pneumonia resulted in the deterioration of his general condition and death 5 months after the diagnosis of paraneoplastic NAM. PMID:27843429

  17. Novel myosin-based therapies for congenital cardiac and skeletal myopathies

    PubMed Central

    Ochala, Julien; Sun, Yin-Biao

    2016-01-01

    The dysfunction in a number of inherited cardiac and skeletal myopathies is primarily due to an altered ability of myofilaments to generate force and motion. Despite this crucial knowledge, there are, currently, no effective therapeutic interventions for these diseases. In this short review, we discuss recent findings giving strong evidence that genetically or pharmacologically modulating one of the myofilament proteins, myosin, could alleviate the muscle pathology. This should constitute a research and clinical priority. PMID:27412953

  18. Myosin Storage Myopathy in C. elegans and Human Cultured Muscle Cells

    PubMed Central

    Dahl-Halvarsson, Martin; Pokrzywa, Malgorzata; Rauthan, Manish; Pilon, Marc

    2017-01-01

    Myosin storage myopathy is a protein aggregate myopathy associated with the characteristic subsarcolemmal accumulation of myosin heavy chain in muscle fibers. Despite similar histological findings, the clinical severity and age of onset are highly variable, ranging from no weakness to severe impairment of ambulation, and usually childhood-onset to onset later in life. Mutations located in the distal end of the tail of slow/ß-cardiac myosin heavy chain are associated with myosin storage myopathy. Four missense mutations (L1793P, R1845W, E1883K and H1901L), two of which have been reported in several unrelated families, are located within or closed to the assembly competence domain. This location is critical for the proper assembly of sarcomeric myosin rod filaments. To assess the mechanisms leading to protein aggregation in myosin storage myopathy and to evaluate the impact of these mutations on myosin assembly and muscle function, we expressed mutated myosin proteins in cultured human muscle cells and in the nematode Caenorhabditis elegans. While L1793P mutant myosin protein efficiently incorporated into the sarcomeric thick filaments, R1845W and H1901L mutants were prone to formation of myosin aggregates without assembly into striated sarcomeric thick filaments in cultured muscle cells. In C. elegans, mutant alleles of the myosin heavy chain gene unc-54 corresponding to R1845W, E1883K and H1901L, were as effective as the wild-type myosin gene in rescuing the null mutant worms, indicating that they retain functionality. Taken together, our results suggest that the basis for the pathogenic effect of the R1845W and H1901L mutations are primarily structural rather than functional. Further analyses are needed to identify the primary trigger for the histological changes seen in muscle biopsies of patients with L1793P and E1883K mutations. PMID:28125727

  19. Idiopathic Inflammatory Myopathies: an Update on Classification and Treatment with Special Focus on Juvenile Forms.

    PubMed

    Pagnini, Ilaria; Vitale, Antonio; Selmi, Carlo; Cimaz, Rolando; Cantarini, Luca

    2017-02-01

    Juvenile inflammatory myopathies represent a heterogeneous group of rare and potentially fatal disorders of unknown aetiology, characterised by inflammation and proximal and symmetric muscle weakness. Beyond many similarities, specific clinical, laboratoristic and histopathologic features underlie different subsets with distinguishing demographic, prognostic and therapeutic peculiarities. Over time, several forms of inflammatory idiopathic myopathies have been described, including macrophagic myofascitis, immune-mediated necrozing myopathy and the spectrum of amyopathic dermatomyositis that include hypomyopathic dermatomyositis, inclusion body myositis and cancer-associated myositis occurring almost exclusively in adults. However, juvenile dermatomyositis is the most frequent in childhood, whereas polymyositis is relatively more frequent in adults. The aetiology is nowadays widely unclear; however, current theories contemplate a combination of environmental triggers, immune dysfunction and specific tissue responses involving muscle, skin and small vessels endothelium in genetically susceptible individuals. Myositis-specific autoantibodies, found almost exclusively in patients with myositis and myositis-associated autoantibodies, detectable both among patients with myositis and in subjects suffering from other autoimmune diseases, have an important clinical role because of their relation to specific clinical features, response to therapy and prognosis. The gold standard treatment for juvenile dermatomyositis is represented by corticosteroids, along with adjunctive steroid-sparing immunosuppressive therapies, which are used to counteract disease activity, prevent mortality, and reduce long-term disability. Further treatment approach such as biologic agents and autologous stem cell transplantation are emerging during the last years, in particular in patients difficult to treat and with poor prognosis. Therefore, a highly medical specialised approach is required for

  20. Whole-body MRI for full assessment and characterization of diffuse inflammatory myopathy

    PubMed Central

    Elessawy, Saleh Saleh; Abdel Razek, Eman; Tharwat, Samar

    2016-01-01

    Background Conventional magnetic resonance imaging (MRI) is a highly valuable tool for full assessment of the extent of bilateral symmetrical diffuse inflammatory myopathy, owing to its high sensitivity in the detection of edema which correlates with, and sometimes precedes, clinical findings. Purpose To evaluate the use of whole-body (WB)-MRI in characterization and full assessment of the extent and distribution of diffuse inflammatory myopathy. Material and Methods A prospective study on 15 patients presenting with clinical evidence of inflammatory myopathy. It included 4 boys/men and 11 girls/women (age range, 6–44 years; mean age, 25.5 years). 1.5 T WB-MRI was performed and the distribution and extent of disease severity was assessed according to muscle edema on STIR images. Results Four cases of dermatomyositis showed lower limb disease predilection with edema in gluteal, thigh, and calf muscles. The same finding was seen in one case with recurrent polymyositis and three cases with overlap myositis with systemic lupus erythematosus (SLE). Bilateral upper and lower limb myositis was demonstrated in three cases of polymyositis and one case of overlap myositis with scleroderma. Bilateral edema involving all scanned muscle groups was detected in three cases of polymyositis with paraneoplastic syndrome, SLE, and severe active dermatomyositis (including the neck muscles). Conclusion WB-MRI is the diagnostic modality of choice for cases of inflammatory myopathy. It accurately detects the most severely affected muscles candidate for biopsy and provides a reliable baseline study for follow-up of disease progression as well as response to treatment. PMID:27708860

  1. Myopathy, muscle atrophy and tongue lipid composition in MuSK myasthenia gravis.

    PubMed

    Nikolić, Ana V; Bačić, Goran G; Daković, Marko Ž; Lavrnić, Slobodan Đ; Rakočević Stojanović, Vidosava M; Basta, Ivana Z; Lavrnić, Dragana V

    2015-09-01

    Myasthenia gravis (MG) associated with anti-muscle-specific tyrosine kinase (MuSK) antibodies differs in many aspects from typical presentation of acetylcholine receptor (AChR)-positive MG. Myopathy and muscle atrophy are observed in MuSK-positive MG patients, unlike AChR-positive patients with MG. That is why the aim of this study was to assess the presence of myopathy and muscle atrophy as well as the tongue lipid composition in our cohort of MuSK-positive MG patients. Clinical examination, electromyography (EMG) and proton magnetic resonance spectroscopy were performed in 31 MuSK-positive and 28 AChR-positive MG patients. Myopathic EMG was more frequent in MuSK compared to AChR MG patients. In AChR MG patients, myopathic EMG in facial muscles was more frequent after long-term corticosteroid treatment, which was not the case with MuSK-positive MG patients. Facial and/or tongue muscle atrophy was registered in 23 % of MuSK MG patients. Longer disease duration was observed in patients with clinical signs of tongue and/or facial muscle atrophy compared to those with normal tongue muscle. Intramyocellular lipid deposition in the tongue was present in 85.2 % of MuSK and 20 % of AChR MG patients. Female MuSK MG patients had more frequently electrophysiological signs of myopathy on the facial muscles and signs of intramyocellular lipid deposition in the tongue, compared to male patients with MuSK-positive MG. Myopathy, muscle atrophy and intramyocellular lipid deposition in the tongue are more frequent in MuSK-positive compared to AChR-positive MG patients.

  2. Effect of bezafibrate treatment on late-onset mitochondrial myopathy in mice.

    PubMed

    Yatsuga, Shuichi; Suomalainen, Anu

    2012-02-01

    Mitochondrial dysfunction is an important cause of metabolic disorders of children and adults, with no effective therapy options. Recently, induction of mitochondrial biogenesis, by transgenic overexpression of PGC1-alpha [peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1-alpha], was reported to delay progression of early-onset cytochrome-c-oxidase (COX) deficiency in skeletal muscle of two mouse models: a muscle-specific knock-out of COX10 (COX10-mKO) and a constitutive knock-out of Surf1 (Surf1-KO). A pan-PPAR agonist, bezafibrate, could similarly delay myopathy progression in COX10-mKOs, but not in SURF1-KOs. We asked whether bezafibrate affected disease progression in late-onset adult-type mitochondrial myopathy mice. These 'Deletor mice' express a dominant patient mutation in Twinkle-helicase, leading to accumulation of multiple mtDNA deletions and subsequent progressive respiratory chain (RC) deficiency with COX-negative muscle fibers at 12 months of age. The primary and secondary molecular findings in Deletor mice mimic closely those in patients with Twinkle myopathy. We applied 0.5% bezafibrate diet to Deletors for 22 weeks, starting at disease manifestation, mimicking patient treatment after diagnosis. Bezafibrate delayed significantly the accumulation of COX-negative fibers and multiple mtDNA deletions. However, mitochondrial biogenesis was not induced: mitochondrial DNA copy number, transcript and RC protein amounts decreased in both Deletors and wild-type mice. Furthermore, bezafibrate induced severe lipid oxidation effects, with hepatomegaly and loss of adipose tissue, the mechanism involving lipid mobilization by high hepatic expression of FGF21 cytokine. However, as bezafibrate has been tolerated well by humans, the beneficial muscle findings in Deletor mice support consideration of bezafibrate trials on adult patients with mitochondrial myopathy.

  3. Abnormalities in the expression of nebulin in chromosome-2 linked nemaline myopathy.

    PubMed

    Sewry, C A; Brown, S C; Pelin, K; Jungbluth, H; Wallgren-Pettersson, C; Labeit, S; Manzur, A; Muntoni, F

    2001-03-01

    Nemaline myopathy is clinically and genetically heterogeneous. The most common autosomal recessive form affecting infants (NEM2) links to chromosome 2q, and is caused by mutations in the gene for nebulin. We have examined the immunocytochemical expression of nebulin in skeletal muscle in 11 cases of nemaline myopathy, from ten families, with linkage compatible to chromosome 2q.22, the locus for nebulin. Mutations in the gene for nebulin have been found in eight of these cases. Immunolabelling with polyclonal antibodies to C-terminal regions of nebulin was compared with antibodies to fibre-type-specific myofibrillar proteins, including myosin heavy chain isoforms and alpha-actinin isoforms. No cases showed a complete absence of C-terminal nebulin, and no enhancement of labelling of the rods was seen with conventional fluorescence microscopy. In control muscle an antibody to the M176-181 repeat region of nebulin showed higher expression in fibres with slow myosin, while ones to the serine-rich domain and to the SH3 domain showed uniform expression. In some cases of nemaline myopathy differences in these patterns were observed. Two siblings with a homozygous mutation in exon 185, that produces a stop codon, showed an absence of labelling only with the SH3 antibody, and other cases showed uneven labelling with this antibody or some fibres devoid of label. Fibre type correlations also showed differences from controls, as some fibres had a fast isoform of one protein but a slow isoform of another. These results indicate that analysis of nebulin expression may detect abnormalities in some cases linked to the corresponding locus and may help to direct molecular analysis. In addition, they may also be relevant to studies of fibre type plasticity and diversity in nemaline myopathy.

  4. KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy

    PubMed Central

    Garg, Ankit; O’Rourke, Jason; Long, Chengzu; Doering, Jonathan; Ravenscroft, Gianina; Bezprozvannaya, Svetlana; Nelson, Benjamin R.; Beetz, Nadine; Li, Lin; Chen, She; Laing, Nigel G.; Grange, Robert W.; Bassel-Duby, Rhonda; Olson, Eric N.

    2014-01-01

    Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40 (KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in KLHL40-deficient patients. We determined that KLHL40 localizes to the sarcomere I band and A band and binds to nebulin (NEB), a protein frequently implicated in NM, as well as a putative thin filament protein, leiomodin 3 (LMOD3). KLHL40 belongs to the BTB-BACK-kelch (BBK) family of proteins, some of which have been shown to promote degradation of their substrates. In contrast, we found that KLHL40 promotes stability of NEB and LMOD3 and blocks LMOD3 ubiquitination. Accordingly, NEB and LMOD3 were reduced in skeletal muscle of both Klhl40–/– mice and KLHL40-deficient patients. Loss of sarcomere thin filament proteins is a frequent cause of NM; therefore, our data that KLHL40 stabilizes NEB and LMOD3 provide a potential basis for the development of NM in KLHL40-deficient patients. PMID:24960163

  5. Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review.

    PubMed

    Canestaro, William J; Austin, Melissa A; Thummel, Kenneth E

    2014-11-01

    Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1.

  6. Subcellular Localization of Matrin 3 Containing Mutations Associated with ALS and Distal Myopathy

    PubMed Central

    Gallego-Iradi, M. Carolina; Clare, Alexis M.; Brown, Hilda H.; Janus, Christopher; Lewis, Jada; Borchelt, David R.

    2015-01-01

    Background Mutations in Matrin 3 [MATR3], an RNA- and DNA-binding protein normally localized to the nucleus, have been linked to amyotrophic lateral sclerosis (ALS) and distal myopathies. In the present study, we have used transient transfection of cultured cell lines to examine the impact of different disease-causing mutations on the localization of Matrin 3 within cells. Results Using CHO and human H4 neuroglioma cell models, we find that ALS/myopathy mutations do not produce profound changes in the localization of the protein. Although we did observe variable levels of Matrin 3 in the cytoplasm either by immunostaining or visualization of fluorescently-tagged protein, the majority of cells expressing either wild-type (WT) or mutant Matrin 3 showed nuclear localization of the protein. When cytoplasmic immunostaining, or fusion protein fluorescence, was seen in the cytoplasm, the stronger intensity of staining or fluorescence was usually evident in the nucleus. In ~80% of cells treated with sodium arsenite (Ars) to induce cytoplasmic stress granules, the nuclear localization of WT and F115C mutant Matrin 3 was not disturbed. Notably, over-expression of mutant Matrin 3 did not induce the formation of obvious large inclusion-like structures in either the cytoplasm or nucleus. Conclusions Our findings indicate that mutations in Matrin 3 that are associated with ALS and myopathy do not dramatically alter the normal localization of the protein or readily induce inclusion formation. PMID:26528920

  7. A novel perspective for burn-induced myopathy: Membrane repair defect

    PubMed Central

    Wang, Chao; Wang, Hongyu; Wu, Dan; Hu, Jianhong; Wu, Wei; Zhang, Yong; Peng, Xi

    2016-01-01

    Myopathy is a common complication of severe burn patients. One potential cause of this myopathy could be failure of the plasma membrane to undergo repair following injuries generated from toxin or exercise. The aim of this study is to assess systemic effect on muscle membrane repair deficiency in burn injury. Skeletal muscle fibers isolated from burn-injured mice were damaged with a UV laser and dye influx imaged confocally to evaluate membrane repair capacity. Membrane repair failure was also tested in burn-injured mice subjected to myotoxin or treadmill exercise. We further used C2C12 myotubules and animal models to investigate the role of MG53 in development of burn-induced membrane repair defect. We demonstrated that skeletal muscle myofibers in burn-injured mice showed significantly more dye uptake after laser damage than controls, indicating a membrane repair deficiency. Myotoxin or treadmill exercise also resulted in a higher-grade repair defect in burn-injured mice. Furthermore, we observed that burn injury induced a significant decrease in MG53 levels and its dimerization in skeletal muscles. Our findings highlight a new mechanism that implicates membrane repair failure as an underlying cause of burn-induced myopathy. And, the disorders in MG53 expression and MG53 dimerization are involved in this cellular pathology. PMID:27545095

  8. A new motor performance test in a prospective study on children with suspected myopathy.

    PubMed

    van den Beld, Willeke A; van der Sanden, Gitty A C; Feuth, Ton; Janssen, Anjo J W M; Sengers, Rob C A; Verbeek, André L M; Gabreëls, Fons J M

    2006-09-01

    In the development of a new diagnostic motor performance test to spare more children from painful muscle biopsy, seven functional items were used to measure muscle strength and muscle endurance in a prospective study on new patients. Over a 2-year period, 22 patients (12 males, 10 females; mean age 8y 1mo [SD 2y 6mo], range 4-11y) were recruited for the study. They had all been referred with suspected myopathy. The motor performance test was administered before muscle biopsy. Validity of the seven items was assessed using logistic regression analysis and receiver operating characteristic (ROC) analysis. Two items were withdrawn from the test because they were not suitable for children aged 4 to 5 years. The five remaining items were: Heels, Circuit, Stairs, Jump, and Gowers. A full logistic regression model including these five items was fitted to the total population of 90 patients suspected of having myopathy (from this study and our previous study) to make the best prediction of whether myopathy was present. The ROC area under the curve of the diagnostic prediction model was 0.92 (95% confidence interval [CI] 0.87-0.98) and 0.89 (95% CI 0.87-0.92) after bootstrap correction. This indicated the high diagnostic power that can be expected for future, similar patients. This non-invasive and child-friendly motor performance test can improve diagnostic procedure and, therefore, spare more children from unnecessary muscle biopsy.

  9. Oculopharyngeal Weakness, Hypophrenia, Deafness, and Impaired Vision: A Novel Autosomal Dominant Myopathy with Rimmed Vacuoles

    PubMed Central

    Chen, Ting; Lu, Xiang-Hui; Wang, Hui-Fang; Ban, Rui; Liu, Hua-Xu; Shi, Qiang; Wang, Qian; Yin, Xi; Pu, Chuan-Qiang

    2016-01-01

    Background: Myopathies with rimmed vacuoles are a heterogeneous group of muscle disorders with progressive muscle weakness and varied clinical manifestations but similar features in muscle biopsies. Here, we describe a novel autosomal dominant myopathy with rimmed vacuoles in a large family with 11 patients of three generations affected. Methods: A clinical study including family history, obstetric, pediatric, and development history was recorded. Clinical examinations including physical examination, electromyography (EMG), serum creatine kinase (CK), bone X-rays, and brain magnetic resonance imaging (MRI) were performed in this family. Open muscle biopsies were performed on the proband and his mother. To find the causative gene, the whole-exome sequencing was carried out. Results: Disease onset was from adolescence to adulthood, but the affected patients of the third generation presented an earlier onset and more severe clinical manifestations than the older generations. Clinical features were characterized as dysarthria, dysphagia, external ophthalmoplegia, limb weakness, hypophrenia, deafness, and impaired vision. However, not every patient manifested all symptoms. Serum CK was mildly elevated and EMG indicated a myopathic pattern. Brain MRI showed cerebellum and brain stem mildly atrophy. Rimmed vacuoles and inclusion bodies were observed in muscle biopsy. The whole-exome sequencing was performed, but the causative gene has not been found. Conclusions: We reported a novel autosomal dominant myopathy with rimmed vacuoles characterized by dysarthria, dysphagia, external ophthalmoplegia, limb weakness, hypophrenia, deafness, and impaired vision, but the causative gene has not been found and needs further study. PMID:27453229

  10. Beyond mice: Emerging and transdisciplinary models for the study of early-onset myopathies.

    PubMed

    Jagla, Krzysztof; Kalman, Benoit; Boudou, Thomas; Hénon, Sylvie; Batonnet-Pichon, Sabrina

    2017-04-01

    The use of the adapted models to decipher patho-physiological mechanisms of human diseases is always a great challenge. This is of particular importance for early-onset myopathies, in which pathological mutations often impact not only on muscle structure and function but also on developmental processes. Mice are currently the main animal model used to study neuromuscular disorders including the early-onset myopathies. However strategies based on simple animal models and on transdisciplinary approaches exploring mechanical muscle cell properties emerge as attractive, non-exclusive alternatives. These new ways provide valuable opportunities to improve our knowledge on how mechanical, biochemical, and genetic/epigenetic cues modulate the formation, organization and function of muscle tissues. Here we provide an overview of how single cell and micro-tissue engineering in parallel to non-mammalian, Drosophila and zebrafish models could contribute to filling gaps in our understanding of pathogenic mechanisms underlying early-onset myopathies. We also discuss their potential impact on designing new diagnostic and therapeutic strategies.

  11. Novel pathogenic variants and genes for myopathies identified by whole exome sequencing

    PubMed Central

    Hunter, Jesse M; Ahearn, Mary Ellen; Balak, Christopher D; Liang, Winnie S; Kurdoglu, Ahmet; Corneveaux, Jason J; Russell, Megan; Huentelman, Matthew J; Craig, David W; Carpten, John; Coons, Stephen W; DeMello, Daphne E; Hall, Judith G; Bernes, Saunder M; Baumbach-Reardon, Lisa

    2015-01-01

    Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes. PMID:26247046

  12. Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.

    PubMed

    Merlini, Luciano; Angelin, Alessia; Tiepolo, Tania; Braghetta, Paola; Sabatelli, Patrizia; Zamparelli, Alessandra; Ferlini, Alessandra; Maraldi, Nadir M; Bonaldo, Paolo; Bernardi, Paolo

    2008-04-01

    Ullrich congenital muscular dystrophy and Bethlem myopathy are skeletal muscle diseases that are due to mutations in the genes encoding collagen VI, an extracellular matrix protein forming a microfibrillar network that is particularly prominent in the endomysium of skeletal muscle. Myoblasts from patients affected by Ullrich congenital muscular dystrophy display functional and ultrastructural mitochondrial alterations and increased apoptosis due to inappropriate opening of the permeability transition pore, a mitochondrial inner membrane channel. These alterations could be normalized by treatment with cyclosporin A, a widely used immunosuppressant that desensitizes the permeability transition pore independently of calcineurin inhibition. Here, we report the results of an open pilot trial with cyclosporin A in five patients with collagen VI myopathies. Before treatment, all patients displayed mitochondrial dysfunction and increased frequency of apoptosis, as determined in muscle biopsies. Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration, which also increased muscle regeneration. These findings demonstrate that collagen VI myopathies can be effectively treated with drugs acting on the pathogenic mechanism downstream of the genetic lesion, and they represent an important proof of principle for the potential therapy of genetic diseases.

  13. Technological quality, mineral profile, and sensory attributes of broiler chicken breasts affected by White Striping and Wooden Breast myopathies.

    PubMed

    Tasoniero, G; Cullere, M; Cecchinato, M; Puolanne, E; Dalle Zotte, A

    2016-11-01

    The aim of the research was to study the impact of white striping and wooden breast myopathies on the technological quality, mineral, and sensory profile of poultry meat. With this purpose, a total of 138 breasts were selected for a control group with normal breasts (N), a group of breasts characterised by white striping (WS) myopathy, and a group of breasts having both white striping and wooden breast myopathies (WSWB). Data revealed that the simultaneous presence of the two myopathies, with respect to the WS lesion individually considered, had a further detrimental effect on pH (6.04 vs. 5.96; P < 0.05), yellowness (11.4 vs. 10.3; P < 0.01), cooking losses (30.4 vs. 27.6%; P < 0.05), toughness instrumental values (22.8 vs. 20.0 N; P < 0.01), and perception (6.22 vs. 5.56; P < 0.01). In addition, mineral contents suggest that a defective ions regulation is also present in white striping and wooden breast myopathies.

  14. Diagnosis of myocardial involvement in patients with systemic myopathies with 15-(p-(I-123)iodophenyl) pentadecanoic acid (IPPA) SPECT

    SciTech Connect

    Kropp, J.; Briele, B.; Smekal, A.V.; Hotze, A.L.; Biersack, H.J.; Koehler, U.; Zierz, St. ); Knapp, F.F. )

    1992-01-01

    Involvement of the myocardium in non-infectious myopathies presents in most cases as systolic dysfunction or a disturbed cardiac rhythm. We are interested in exploring how often cardiac involvement can be evaluated with various diagnostic techniques in patients with proven myopathy. We investigated 41 patients with myopathies of various etiology, including mitochondrial and congenital myopathies, Curshmann-Steinert disease, muscular dystrophy, and others. Myopathy was proven by muscular biopsy usually from the bicep. Fatty acid imaging was performed with 15-(p-(I-123)iodophenyl)pentadecanoic acid (IP-PA) and sequential SPECT-scintigraphy with a 180 deg. rotation starting at the 45 deg. RAO position. 190 MBq were injected at the maximal stage of a submaximal exercise. Filtered backprojection and reorientation of the slices were achieved by standard techniques. The quantitative comparison of the oblique slices (bulls-eye technique) of the SPECT-studies revealed turnover-rates as a qualitative measure of {beta}-oxidation. Serum levels of lactate (L), pyruvate (P), glucose (G) and triglycerides (TG) were measured at rest and stress. Ventricular function was investigated by radionuclide ventriculography (MUGA) at rest and under stress with Tc-99m labeled red blood cells. In addition, ECG, 24 hour-ECG, and echocardiography were also performed with standard techniques.

  15. Diagnosis of myocardial involvement in patients with systemic myopathies with 15-(p-[I-123]iodophenyl) pentadecanoic acid (IPPA) SPECT

    SciTech Connect

    Kropp, J.; Briele, B.; Smekal, A.V.; Hotze, A.L.; Biersack, H.J.; Koehler, U.; Zierz, St.; Knapp, F.F.

    1992-03-01

    Involvement of the myocardium in non-infectious myopathies presents in most cases as systolic dysfunction or a disturbed cardiac rhythm. We are interested in exploring how often cardiac involvement can be evaluated with various diagnostic techniques in patients with proven myopathy. We investigated 41 patients with myopathies of various etiology, including mitochondrial and congenital myopathies, Curshmann-Steinert disease, muscular dystrophy, and others. Myopathy was proven by muscular biopsy usually from the bicep. Fatty acid imaging was performed with 15-(p-[I-123]iodophenyl)pentadecanoic acid (IP-PA) and sequential SPECT-scintigraphy with a 180 deg. rotation starting at the 45 deg. RAO position. 190 MBq were injected at the maximal stage of a submaximal exercise. Filtered backprojection and reorientation of the slices were achieved by standard techniques. The quantitative comparison of the oblique slices (bulls-eye technique) of the SPECT-studies revealed turnover-rates as a qualitative measure of {beta}-oxidation. Serum levels of lactate (L), pyruvate (P), glucose (G) and triglycerides (TG) were measured at rest and stress. Ventricular function was investigated by radionuclide ventriculography (MUGA) at rest and under stress with Tc-99m labeled red blood cells. In addition, ECG, 24 hour-ECG, and echocardiography were also performed with standard techniques.

  16. SLCO1B1 genetic variant associated with statin-induced myopathy: a proof-of-concept study using the clinical practice research datalink.

    PubMed

    Carr, D F; O'Meara, H; Jorgensen, A L; Campbell, J; Hobbs, M; McCann, G; van Staa, T; Pirmohamed, M

    2013-12-01

    This study aimed to determine whether patients with statin-induced myopathy could be identified using the United Kingdom Clinical Practice Research Datalink, whether DNA could be obtained, and whether previously reported associations of statin myopathy with the SLCO1B1 c.521T>C and COQ2 rs4693075 polymorphisms could be replicated. Seventy-seven statin-induced myopathy patients (serum creatine phosphokinase (CPK) > 4× upper limit of normal (ULN)) and 372 statin-tolerant controls were identified and recruited. Multiple logistic regression analysis showed the SLCO1B1 c.521T>C single-nucleotide polymorphism to be a significant risk factor (P = 0.009), with an odds ratio (OR) per variant allele of 2.06 (1.32-3.15) for all myopathy and 4.09 (2.06-8.16) for severe myopathy (CPK > 10× ULN, and/or rhabdomyolysis; n = 23). COQ2 rs4693075 was not associated with myopathy. Meta-analysis showed an association between c.521C>T and simvastatin-induced myopathy, although power for other statins was limited. Our data replicate the association of SLCO1B1 variants with statin-induced myopathy. Furthermore, we demonstrate how electronic medical records provide a time- and cost-efficient means of recruiting patients with severe adverse drug reactions for pharmacogenetic studies.

  17. Chronic intestinal pseudo-obstruction caused by an intestinal inflammatory myopathy: case report and review of the literature.

    PubMed

    Dewit, S; de Hertogh, G; Geboes, K; Tack, J

    2008-04-01

    Chronic intestinal pseudo-obstruction (CIP) is an uncommon disorder that may be of primary or secondary origin. We report a case of a 37-year-old woman with CIP due to inflammatory disorder of unknown origin involving the skin (eosinophilic fasciitis), the lungs (decreased diffusion capacity) and the gastrointestinal tract. History, clinical examination, plain abdominal film, barium X-ray and colonoscopy established a diagnosis of recurrent pseudo-obstruction. A full-thickness biopsy was performed during explorative laparotomy, and histological examination revealed findings compatible with an inflammatory myopathy due to a dense lymphoid infiltrate and extensive loss of the muscularis propria layers. Immunosuppressive therapy with cyclosporin was initiated, with significant clinical improvement. This case illustrates another form of CIP, characterized by an inflammatory myopathy, which is histologically distinct from other known visceral myopathies and neuropathies.

  18. Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy.

    PubMed

    Osaki, Yoshinori; Nakagawa, Yoshimi; Miyahara, Shoko; Iwasaki, Hitoshi; Ishii, Akiko; Matsuzaka, Takashi; Kobayashi, Kazuto; Yatoh, Shigeru; Takahashi, Akimitsu; Yahagi, Naoya; Suzuki, Hiroaki; Sone, Hirohito; Ohashi, Ken; Ishibashi, Shun; Yamada, Nobuhiro; Shimano, Hitoshi

    2015-10-23

    HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs.

  19. Centronuclear myopathy related to dynamin 2 mutations: Clinical, morphological, muscle imaging and genetic features of an Italian cohort

    PubMed Central

    Catteruccia, Michela; Fattori, Fabiana; Codemo, Valentina; Ruggiero, Lucia; Maggi, Lorenzo; Tasca, Giorgio; Fiorillo, Chiara; Pane, Marika; Berardinelli, Angela; Verardo, Margherita; Bragato, Cinzia; Mora, Marina; Morandi, Lucia; Bruno, Claudio; Santoro, Lucio; Pegoraro, Elena; Mercuri, Eugenio; Bertini, Enrico; D’Amico, Adele

    2013-01-01

    Mutations in dynamin 2 (DNM2) gene cause autosomal dominant centronuclear myopathy and occur in around 50% of patients with centronuclear myopathy. We report clinical, morphological, muscle imaging and genetic data of 10 unrelated Italian patients with centronuclear myopathy related to DNM2 mutations. Our results confirm the clinical heterogeneity of this disease, underlining some peculiar clinical features, such as severe pulmonary impairment and jaw contracture that should be considered in the clinical follow-up of these patients. Muscle MRI showed a distinct pattern of involvement, with predominant involvement of soleus and tibialis anterior in the lower leg muscles, followed by hamstring muscles and adductor magnus at thigh level and gluteus maximus. The detection of three novel DNM2 mutations and the first case of somatic mosaicism further expand the genetic spectrum of the disease. PMID:23394783

  20. Concomitant Acute Transverse Myelitis and Sensory Motor Axonal Polyneuropathy in Two Children: Two Case Reports

    PubMed Central

    Chung, Hyung; Joa, Kyung-Lim; Kim, Hyo-Sang; Kim, Chang-Hwan; Jung, Han-Young

    2015-01-01

    Acute transverse myelitis (ATM) is an upper motor neuron disease of the spinal cord, and concomitant association of peripheral polyneuropathy, particularly the axonal type, is rarely reported in children. Our cases presented with ATM complicated with axonal type polyneuropathy. Axonal type polyneuropathy may be caused by acute motor-sensory axonal neuropathy (AMSAN) or critical illness polyneuropathy and myopathy (CIPNM). These cases emphasize the need for nerve and muscle biopsies to make the differential diagnosis between AMSAN and CIPNM in patients with ATM complicated with axonal polyneuropathy. PMID:25750885

  1. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute cystitis; Acute bladder infection; Acute bacterial cystitis ... cause. Menopause also increases the risk for a urinary tract infection. The following also increase your chances of having ...

  2. A fatal case of cor pulmonale with undetected chronic hypoventilation in an infant with a known congenital myopathy.

    PubMed

    Holst, John M; Willis, Mary J

    2012-01-01

    The authors of this paper wish to present a case of fatal cor pulmonale with right ventricular hypertrophy complicated by a congenital myopathy. It is our intention to demonstrate the importance of vigilant clinical assessment of children with a congenital myopathy, regardless of the exact etiology of their disease, or family history of disease severity. This case highlights the risk for fatal complications if hypoventilation and respiratory insufficiency go unrecognized in myopathic children. Consequently, we recommend respiratory and cardiac monitoring surveillance as well as appropriate referral to specialists in the management of such children.

  3. The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

    PubMed Central

    Friedrich, O.; Reid, M. B.; Van den Berghe, G.; Vanhorebeek, I.; Hermans, G.; Rich, M. M.; Larsson, L.

    2015-01-01

    Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca2+ dysregulation is present through altered Ca2+ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models. PMID:26133937

  4. A Peculiar Formula of Essential Amino Acids Prevents Rosuvastatin Myopathy in Mice

    PubMed Central

    D'Antona, Giuseppe; Tedesco, Laura; Ruocco, Chiara; Corsetti, Giovanni; Ragni, Maurizio; Fossati, Andrea; Saba, Elisa; Fenaroli, Francesca; Montinaro, Mery; Carruba, Michele O.; Valerio, Alessandra

    2016-01-01

    Abstract Aims: Myopathy, characterized by mitochondrial oxidative stress, occurs in ∼10% of statin-treated patients, and a major risk exists with potent statins such as rosuvastatin (Rvs). We sought to determine whether a peculiar branched-chain amino acid-enriched mixture (BCAAem), found to improve mitochondrial function and reduce oxidative stress in muscle of middle-aged mice, was able to prevent Rvs myopathy. Results: Dietary supplementation of BCAAem was able to prevent the structural and functional alterations of muscle induced by Rvs in young mice. Rvs-increased plasma 3-methylhistidine (a marker of muscular protein degradation) was prevented by BCAAem. This was obtained without changes of Rvs ability to reduce cholesterol and triglyceride levels in blood. Rather, BCAAem promotes de novo protein synthesis and reduces proteolysis in cultured myotubes. Morphological alterations of C2C12 cells induced by statin were counteracted by amino acids, as were the Rvs-increased atrogin-1 mRNA and protein levels. Moreover, BCAAem maintained mitochondrial mass and density and citrate synthase activity in skeletal muscle of Rvs-treated mice beside oxygen consumption and ATP levels in C2C12 cells exposed to statin. Notably, BCAAem assisted Rvs to reduce oxidative stress and to increase the anti-reactive oxygen species (ROS) defense system in skeletal muscle. Innovation and Conclusions: The complex interplay between proteostasis and antioxidant properties may underlie the mechanism by which a specific amino acid formula preserves mitochondrial efficiency and muscle health in Rvs-treated mice. Strategies aimed at promoting protein balance and controlling mitochondrial ROS level may be used as therapeutics for the treatment of muscular diseases involving mitochondrial dysfunction, such as statin myopathy. Antioxid. Redox Signal. 25, 595–608. PMID:27245589

  5. BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome.

    PubMed

    Kostera-Pruszczyk, Anna; Suszek, Małgorzata; Płoski, Rafał; Franaszczyk, Maria; Potulska-Chromik, Anna; Pruszczyk, Piotr; Sadurska, Elżbieta; Karolczak, Justyna; Kamińska, Anna M; Rędowicz, Maria Jolanta

    2015-12-01

    BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C > T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for α-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of α-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far.

  6. The genetic basis of pectoralis major myopathies in modern broiler chicken lines

    PubMed Central

    Bailey, Richard A.; Watson, Kellie A.; Bilgili, S. F.; Avendano, Santiago

    2015-01-01

    This is the first report providing estimates of the genetic basis of breast muscle myopathies (BMM) and their relationship with growth and yield in broiler chickens. In addition, this paper addresses the hypothesis that genetic selection for increase breast yield has contributed to the onset of BMM. Data were analyzed from ongoing recording of BMM within the Aviagen breeding program. This study focused on three BMM: deep pectoral myopathy (DPM; binary trait), white striping (WS; 4 categories) and wooden breast (WB; 3 categories). Data from two purebred commercial broiler lines (A and B) were utilized providing greater than 40,000 meat quality records per line. The difference in selection history between these two lines has resulted in contrasting breast yield (BY): 29% for Line A and 21% for Line B. Data were analyzed to estimate genetic parameters using a multivariate animal model including six traits: body weight (BW), processing body weight (PW), BY, DPM, WB, and WS, in addition to the appropriate fixed effects and permanent environmental effect of the dam. Results indicate similar patterns of heritability and genetic correlations for the two lines. Heritabilities (h2) of BW, PW and BY ranged from 0.271–0.418; for DPM and WB h2 <0.1; and for WS h2 ≤0.338. Genetic correlations between the BMM and BW, PW, or BY were ≤0.132 in Line A and ≤0.248 in Line B. This paper demonstrates the polygenic nature of these traits and the low genetic relationships with BW, PW, and BY, which facilitates genetic improvement across all traits in a balanced breeding program. It also highlights the importance of understanding the environmental and/or management factors that contribute greater than 65% of the variance in the incidence of white striping of breast muscle and more than 90% of the variance of the incidence of wooden breast and deep pectoral myopathy in broiler chickens. PMID:26476091

  7. The genetic basis of pectoralis major myopathies in modern broiler chicken lines.

    PubMed

    Bailey, Richard A; Watson, Kellie A; Bilgili, S F; Avendano, Santiago

    2015-12-01

    This is the first report providing estimates of the genetic basis of breast muscle myopathies (BMM) and their relationship with growth and yield in broiler chickens. In addition, this paper addresses the hypothesis that genetic selection for increase breast yield has contributed to the onset of BMM. Data were analyzed from ongoing recording of BMM within the Aviagen breeding program. This study focused on three BMM: deep pectoral myopathy (DPM; binary trait), white striping (WS; 4 categories) and wooden breast (WB; 3 categories). Data from two purebred commercial broiler lines (A and B) were utilized providing greater than 40,000 meat quality records per line. The difference in selection history between these two lines has resulted in contrasting breast yield (BY): 29% for Line A and 21% for Line B. Data were analyzed to estimate genetic parameters using a multivariate animal model including six traits: body weight (BW), processing body weight (PW), BY, DPM, WB, and WS, in addition to the appropriate fixed effects and permanent environmental effect of the dam. Results indicate similar patterns of heritability and genetic correlations for the two lines. Heritabilities (h2) of BW, PW and BY ranged from 0.271-0.418; for DPM and WB h2<0.1; and for WS h2≤0.338. Genetic correlations between the BMM and BW, PW, or BY were ≤0.132 in Line A and ≤0.248 in Line B. This paper demonstrates the polygenic nature of these traits and the low genetic relationships with BW, PW, and BY, which facilitates genetic improvement across all traits in a balanced breeding program. It also highlights the importance of understanding the environmental and/or management factors that contribute greater than 65% of the variance in the incidence of white striping of breast muscle and more than 90% of the variance of the incidence of wooden breast and deep pectoral myopathy in broiler chickens.

  8. Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report

    PubMed Central

    Rais, Theodore

    2015-01-01

    The relationship between autism spectrum disorders and mitochondrial dysfunction, including mitochondrial myopathies and other mitochondrial diseases, is an area of ongoing research. All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized. Nevertheless, autism spectrum disorders have been linked to many specific genes associated with mitochondrial function, especially to genes involved in mitochondrial tRNA and the electron transport chain, both particularly vulnerable to point mutations, and clinical research also supports a relationship between the two pathologies. Although only a small minority of patients with autism have a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms, and these symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians. The authors report the case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler-Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction. This case illustrates the need for a high index of suspicion for mitochondrial disease in patients with autism, as they have two orders of magnitude greater risk for such diseases than the general population. The literature shows that mitochondrial disease is underdiagnosed in autism spectrum disorder patients and should not be viewed as a “zebra” (i.e., an obscure diagnosis that is made when a more common explanation is more likely). PMID:26634179

  9. Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report.

    PubMed

    Brown, Bradley D; Rais, Theodore

    2015-01-01

    The relationship between autism spectrum disorders and mitochondrial dysfunction, including mitochondrial myopathies and other mitochondrial diseases, is an area of ongoing research. All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized. Nevertheless, autism spectrum disorders have been linked to many specific genes associated with mitochondrial function, especially to genes involved in mitochondrial tRNA and the electron transport chain, both particularly vulnerable to point mutations, and clinical research also supports a relationship between the two pathologies. Although only a small minority of patients with autism have a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms, and these symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians. The authors report the case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler-Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction. This case illustrates the need for a high index of suspicion for mitochondrial disease in patients with autism, as they have two orders of magnitude greater risk for such diseases than the general population. The literature shows that mitochondrial disease is underdiagnosed in autism spectrum disorder patients and should not be viewed as a "zebra" (i.e., an obscure diagnosis that is made when a more common explanation is more likely).

  10. Modulating myosin restores muscle function in a mouse model of nemaline myopathy

    PubMed Central

    Lindqvist, Johan; Levy, Yotam; Pati‐Alam, Alisha; Hardeman, Edna C.; Gregorevic, Paul

    2016-01-01

    Objective Nemaline myopathy, one of the most common congenital myopathies, is associated with mutations in various genes including ACTA1. This disease is also characterized by various forms/degrees of muscle weakness, with most cases being severe and resulting in death in infancy. Recent findings have provided valuable insight into the underlying pathophysiological mechanisms. Mutations in ACTA1 directly disrupt binding interactions between actin and myosin, and consequently the intrinsic force‐generating capacity of muscle fibers. ACTA1 mutations are also associated with variations in myofiber size, the mechanisms of which have been unclear. In the present study, we sought to test the hypotheses that the compromised functional and morphological attributes of skeletal muscles bearing ACTA1 mutations (1) would be directly due to the inefficient actomyosin complex and (2) could be restored by manipulating myosin expression. Methods We used a knockin mouse model expressing the ACTA1 His40Tyr actin mutation found in human patients. We then performed in vivo intramuscular injections of recombinant adeno‐associated viral vectors harboring a myosin transgene known to facilitate muscle contraction. Results We observed that in the presence of the transgene, the intrinsic force‐generating capacity was restored and myofiber size was normal. Interpretation This demonstrates a direct link between disrupted attachment of myosin molecules to actin monomers and muscle fiber atrophy. These data also suggest that further therapeutic interventions should primarily target myosin dysfunction to alleviate the pathology of ACTA1‐related nemaline myopathy. Ann Neurol 2016;79:717–725 PMID:26891371

  11. Chronically ischemic mouse skeletal muscle exhibits myopathy in association with mitochondrial dysfunction and oxidative damage.

    PubMed

    Pipinos, Iraklis I; Swanson, Stanley A; Zhu, Zhen; Nella, Aikaterini A; Weiss, Dustin J; Gutti, Tanuja L; McComb, Rodney D; Baxter, B Timothy; Lynch, Thomas G; Casale, George P

    2008-07-01

    A myopathy characterized by mitochondrial pathology and oxidative stress is present in patients with peripheral arterial disease (PAD). Patients with PAD differ in disease severity, mode of presentation, and presence of comorbid conditions. In this study, we used a mouse model of hindlimb ischemia to isolate and directly investigate the effects of chronic inflow arterial occlusion on skeletal muscle microanatomy, mitochondrial function and expression, and oxidative stress. Hindlimb ischemia was induced by staged ligation/division of the common femoral and iliac arteries in C57BL/6 mice, and muscles were harvested 12 wk later. Muscle microanatomy was examined by bright-field microscopy, and mitochondrial content was determined as citrate synthase activity in muscle homogenates and ATP synthase expression by fluorescence microscopy. Electron transport chain (ETC) complexes I through IV were analyzed individually by respirometry. Oxidative stress was assessed as total protein carbonyls and 4-hydroxy-2-nonenal (HNE) adducts and altered expression and activity of manganese superoxide dismutase (MnSOD). Ischemic muscle exhibited histological features of myopathy and increased mitochondrial content compared with control muscle. Complex-dependent respiration was significantly reduced for ETC complexes I, III, and IV in ischemic muscle. Protein carbonyls, HNE adducts, and MnSOD expression were significantly increased in ischemic muscle. MnSOD activity was not significantly changed, suggesting MnSOD inactivation. Using a mouse model, we have demonstrated for the first time that inflow arterial occlusion alone, i.e., in the absence of other comorbid conditions, causes myopathy with mitochondrial dysfunction and increased oxidative stress, recapitulating the muscle pathology of PAD patients.

  12. Histomorphologic and ultrastructural recovery of myopathy in rats treated with low-level laser therapy.

    PubMed

    Servetto, Natalia; Cremonezzi, David; Simes, Juan Carlos; Di Pietro, Antonio; Campana, Vilma R

    2017-03-09

    The purpose of the present work was to study the effect of low-level laser therapy (LLLT): helium-neon (He-Ne) and gallium arsenide (Ga-As) laser on the histomorphology of muscle and mitochondria in experimental myopathy in rats. Thirty Suquía strain female rats were distributed in groups: (A) control (intact), (B) injured, (C) injured and treated with He-Ne laser, (D) injured and treated with Ga-As laser, (E) irradiated with He-Ne laser on the non-injured muscle, and (F) irradiated with Ga-As laser on the non-injured muscle. Myopathy was induced by injecting 0.05 mg/rat/day of adrenaline in the left gastrocnemius muscle at the same point on five consecutive days, in groups B, C, and D. LLLT was applied with 9.5 J cm(-2) daily for seven consecutive days in groups C, D, E, and F. The muscles were examined with optic and electronic microscopy. The inflammation was classified as absent, mild, and intense and the degree of mitochondrial alteration was graded I, II, III, and IV. Categorical data were statistically analyzed by Chi-square and the Fisher-Irwin Bilateral test, setting significant difference at p < 0.05. The damage found in muscle and mitochondria histomorphology in animals with induced myopathy (B) was intense or severe inflammation with grade III or IV of mitochondrial alteration. They underwent significant regression (p < 0.001) compared with the groups treated with He-Ne (C) and Ga-As (D) laser, in which mild or moderate inflammation was seen and mitochondrial alteration grades I and II, recovering normal myofibrillar architecture. No differences were found between the effects caused by the two lasers, or between groups A, E, and F. Group A was found to be different from B, C, and D (p < 0.001). LLLT in experimental myopathy caused significant muscular and mitochondrial morphologic recovery.

  13. Suspected myofibrillar myopathy in Arabian horses with a history of exertional rhabdomyolysis

    PubMed Central

    VALBERG, S. J.; McKENZIE, E. C.; EYRICH, L. V.; SHIVERS, J.; BARNES, N. E.; FINNO, C. J.

    2016-01-01

    Summary Reasons for performing study Although exertional rhabdomyolysis (ER) is common in Arabian horses, there are no dedicated studies describing histopathological characteristics of muscle from Arabian horses with ER. Objectives To prospectively identify distinctive histopathological features of muscle from Arabian endurance horses with a history of ER (pro-ER) and to retrospectively determine their prevalence in archived samples from Arabian horses with exertional myopathies (retro-ER). Study design Prospective and retrospective histopathological description. Methods Middle gluteal muscle biopsies obtained from Arabian controls (n = 14), pro-ER (n = 13) as well as archived retro-ER (n = 25) muscle samples previously classified with type 2 polysaccharide storage myopathy (15/25), recurrent exertional rhabdomyolysis (7/25) and no pathology (3/25) were scored for histopathology and immunohistochemical staining of cytoskeletal proteins. Glutaraldehyde-fixed samples (2 pro-ER, one control) were processed for electron microscopy. Pro-ER and retro-ER groups were compared with controls using Mann–Whitney U and Fisher's exact tests. Results Centrally located myonuclei in mature myofibres were found in significantly more (P<0.05) pro-ER (12/13) and retro-ER (21/25) horses than controls (4/14). Degenerating myofibres were not evident in any biopsies. Retro-ER horses had amylase-resistant polysaccharide (6/25, P<0.05) and higher scores for cytoplasmic glycogen, rimmed vacuoles and rod-like bodies. A few control horses (3/14) and significantly (P<0.05) more pro-ER (12/13) and retro-ER (18/25) horses had disrupted myofibrillar alignment and large desmin and αβ-crystallin positive cytoplasmic aggregates. Prominent Z-disc degeneration and focal myofibrillar disruption with regional accumulation of β-glycogen particles were identified on electron microscopy of the 2 pro-ER samples. Conclusions In a subset of Arabian horses with intermittent episodes of exertional

  14. Dominantly inherited proximal myotonic myopathy and leukoencephalopathy in a family with an incidental CLCN1 mutation

    PubMed Central

    Mastaglia, F; Harker, N; Phillips, B; Day, T; Hankey, G; Laing, N; Fabian, V; Kakulas, B

    1998-01-01

    A two generation family of Greek origin with mild myotonia, predominantly proximal muscle weakness, and cataracts compatible with the syndrome of proximal myotonic myopathy, is reported. In addition, brain MRI showed a diffuse leukoencephalopathy in the propositus. Molecular genetic studies showed the R894X mutation in exon 23 of the muscle chloride channel gene in the propositus but in only one of her two clinically affected offspring, indicating that it is not the mutation causing disease in this family.

 PMID:9576553

  15. Dysregulated innate immune function in the aetiopathogenesis of idiopathic inflammatory myopathies.

    PubMed

    Day, Jessica; Otto, Sophia; Proudman, Susanna; Hayball, John D; Limaye, Vidya

    2017-01-01

    The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of systemic muscle conditions that are believed to be autoimmune in nature. They have distinct pathological features, but the aetiopathogenesis of each subtype remains largely unknown. Recently, there has been increased interest in the complex role the innate immune system plays in initiating and perpetuating these conditions, and how this may differ between subtypes. This article summarises the traditional paradigms of IIM pathogenesis and reviews the accumulating evidence for disturbances in innate immune processes in these rare, but debilitating chronic conditions.

  16. [Reduced synthesis of coenzyme Q10 may cause statin related myopathy].

    PubMed

    Nielsen, Mette Lundgren; Pareek, Manan; Henriksen, Jan Erik

    2011-11-14

    Statin treatment can cause muscular side effects. It has been suggested that the mechanism is reduced synthesis of coenzyme Q10 (coQ10) and a subsequent dysfunction of the respiratory chain. A literature review resulted in insufficient evidence supporting this theory. It is uncertain whether intramuscular levels of coQ10 and mitochondrial function are affected by statin therapy and whether the symptoms of myopathy can be alleviated with coQ10 supplementation. Nevertheless, due to a favourable safety profile, coQ10 can be tested in patients whose muscular symptoms cannot be managed otherwise.

  17. Muscle spindles exhibit core lesions and extensive degeneration of intrafusal fibers in the Ryr1{sup I4895T/wt} mouse model of core myopathy

    SciTech Connect

    Zvaritch, Elena; MacLennan, David H.

    2015-04-24

    Muscle spindles from the hind limb muscles of adult Ryr1{sup I4895T/wt} (IT/+) mice exhibit severe structural abnormalities. Up to 85% of the spindles are separated from skeletal muscle fascicles by a thick layer of connective tissue. Many intrafusal fibers exhibit degeneration, with Z-line streaming, compaction and collapse of myofibrillar bundles, mitochondrial clumping, nuclear shrinkage and pyknosis. The lesions resemble cores observed in the extrafusal myofibers of this animal model and of core myopathy patients. Spindle abnormalities precede those in extrafusal fibers, indicating that they are a primary pathological feature in this murine Ryr1-related core myopathy. Muscle spindle involvement, if confirmed for human core myopathy patients, would provide an explanation for an array of devastating clinical features characteristic of these diseases and provide novel insights into the pathology of RYR1-related myopathies. - Highlights: • Muscle spindles exhibit structural abnormalities in a mouse model of core myopathy. • Myofibrillar collapse and mitochondrial clumping is observed in intrafusal fibers. • Myofibrillar degeneration follows a pattern similar to core formation in extrafusal myofibers. • Muscle spindle abnormalities are a part of the pathological phenotype in the mouse model of core myopathy. • Direct involvement of muscle spindles in the pathology of human RYR1-related myopathies is proposed.

  18. An analysis of the sensitivity and specificity of MHC-I and MHC-II immunohistochemical staining in muscle biopsies for the diagnosis of inflammatory myopathies.

    PubMed

    Rodríguez Cruz, Pedro M; Luo, Yue-Bei; Miller, James; Junckerstorff, Reimar C; Mastaglia, Frank L; Fabian, Victoria

    2014-12-01

    Although there have been several previous reports of immunohistochemical staining for MHC antigens in muscle biopsies, there appears to be a lack of consensus about its routine use in the diagnostic evaluation of biopsies from patients with suspected inflammatory myopathy. Positive MHC-I staining is nonspecific but is widely used as a marker for inflammatory myopathy, whilst the role of MHC-II staining is not clearly defined. We investigated the sensitivity and specificity of MHC-I and MHC-II immunostaining for the diagnosis of inflammatory myopathy in a large group of biopsies from a single reference laboratory. Positive staining for MHC-I was found to have a high sensitivity in biopsies from patients with inflammatory myopathy but a very low specificity, as it was also common in other non-inflammatory myopathies and neurogenic disorders. On the other hand, MHC-II positivity had a much higher specificity in all major subgroups of inflammatory myopathy, especially inclusion body myositis. The findings indicate that the combination of MHC-I and MHC-II staining results in a higher degree of specificity for the diagnosis of inflammatory myopathy and that in biopsies with inflammation, positive MHC-II staining strongly supports the diagnosis of an immune-mediated myopathy. We recommend that immunohistochemical staining for both MHC-I and MHC-II should be included routinely in the diagnostic evaluation of muscle biopsies from patients with suspected inflammatory myopathy. However, as the sensitivity and interpretation of MHC staining may depend on the technique used, further studies are needed to compare procedures in different centres and develop standardised protocols.

  19. Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy

    PubMed Central

    Childers, Martin K; Joubert, Romain; Poulard, Karine; Moal, Christelle; Grange, Robert W; Doering, Jonathan A; Lawlor, Michael W; Rider, Branden E.; Jamet, Thibaud; Danièle, Nathalie; Martin, Samia; Rivière, Christel; Soker, Thomas; Hammer, Caroline; Van Wittenberghe, Laetitia; Lockard, Mandy; Guan, Xuan; Goddard, Melissa; Mitchell, Erin; Barber, Jane; Williams, J. Koudy; Mack, David L; Furth, Mark E; Vignaud, Alban; Masurier, Carole; Mavilio, Fulvio; Moullier, Philippe; Beggs, Alan H; Buj-Bello, Anna

    2014-01-01

    Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype-8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged lifespan to more than one year in the absence of toxicity, humoral and cell-mediated immune response. These results demonstrate the therapeutic efficacy of AAV-mediated gene therapy for myotubular myopathy in small and large animal models, and provide proof of concept for future clinical trials in XLMTM patients. PMID:24452262

  20. Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.

    PubMed

    Childers, Martin K; Joubert, Romain; Poulard, Karine; Moal, Christelle; Grange, Robert W; Doering, Jonathan A; Lawlor, Michael W; Rider, Branden E; Jamet, Thibaud; Danièle, Nathalie; Martin, Samia; Rivière, Christel; Soker, Thomas; Hammer, Caroline; Van Wittenberghe, Laetitia; Lockard, Mandy; Guan, Xuan; Goddard, Melissa; Mitchell, Erin; Barber, Jane; Williams, J Koudy; Mack, David L; Furth, Mark E; Vignaud, Alban; Masurier, Carole; Mavilio, Fulvio; Moullier, Philippe; Beggs, Alan H; Buj-Bello, Anna

    2014-01-22

    Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype 8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology, and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged life span to more than 1 year in the absence of toxicity or a humoral or cell-mediated immune response. These results demonstrate the therapeutic efficacy of AAV-mediated gene therapy for myotubular myopathy in small- and large-animal models, and provide proof of concept for future clinical trials in XLMTM patients.

  1. [A case of inflammatory myopathy with widely skin rash following use of supplements containing Spirulina].

    PubMed

    Konno, Takuya; Umeda, Yoshitaka; Umeda, Maiko; Kawachi, Izumi; Oyake, Mutsuo; Fujita, Nobuya

    2011-05-01

    A 49-year old woman noticed her skin rash several days after taking supplements containing Spirulina, a planktonic blue-green alga. Her skin rash was spreading over large parts of her body, even after stop ingestion two months later. Five months later, she developed muscle weakness of neck flexor and left proximal upper extremity. On admission, creatine kinase (CK) was elevated to 1,268 IU/ml in the serum. A muscle specimen revealed many necrotizing muscle fibers and the infiltration of mononuclear cells in the peri- and endomysium including a lot of eosinophils. Immunohistochemical staining showed the infiltration of CD4 positive cells in the peri- and endomysium and that of CD20 positive B cells in the perivascular regions. She was diagnosed as having inflammatory myopathy with widely skin rash. Therapy with administration of prednisolone and cyclophosphamide followed by methyl-prednisolone pulse improved her clinical symptoms. There is a similar report describing a case of dermatomyositis after ingestion of Spirulina, which is known to have immune-stimulating property such as accelerating tumor necrosis factor (TNF)-alpha production. Also, TNF-alpha single nucleotide polymorphisms (TNF-308A) was demonstrated to have strong association with onset of myositis in Caucasians. The use of Spirulina could result in inflammatory myopathy under some specific conditions.

  2. Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach.

    PubMed

    Han, X; Quinney, S K; Wang, Z; Zhang, P; Duke, J; Desta, Z; Elmendorf, J S; Flockhart, D A; Li, L

    2015-09-01

    Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System.

  3. Distinct inflammatory properties of late-activated macrophages in inflammatory myopathies

    PubMed Central

    Rostasy, KM; Schmidt, J; Bahn, E; Pfander, T; Piepkorn, M; Wilichowski, E; Schulz-Schaeffer, J

    2008-01-01

    Summary Distinct mechanisms such as humeral immunity in dermatomyositis (DM) and T-cell-mediated cytotoxicity in polymyositis (PM) contribute to the pathology of inflammatory myopathies. In addition, different subsets of macrophages are present in both diseases. Herein, the characteristics of 25F9-positive macrophages in skeletal muscle inflammation are outlined. Muscle biopsies of subjects with DM and PM were studied by immunohistochemical multi-labelling using the late-activation marker 25F9, together with markers characterizing macrophage function including IFN-γ, iNOS, and TGF-β. In PM, a robust expression of IFN-γ, iNOS, and TGF-β was observed in inflammatory cells. Double- and serial-labelling revealed that a subset of 25F9-positive macrophages in the vicinity of injured muscle fibres expressed iNOS and TGF-β, but not IFN-γ. In DM, IFN-γ, iNOS and TGF-β were also expressed in inflammatory cells in the endomysium. Double- and serial-labelling studies in DM indicated that 25F9-positive macrophages expressed TGF-β and to a lesser degree iNOS, but not IFN-γ. In conclusion, our data suggest that late-activated macrophages contribute to the pathology of inflammatory myopathies. PMID:19364061

  4. Distinct inflammatory properties of late-activated macrophages in inflammatory myopathies.

    PubMed

    Rostasy, K M; Schmidt, J; Bahn, E; Pfander, T; Piepkorn, M; Wilichowski, E; Schulz-Schaeffer, J

    2008-10-01

    Distinct mechanisms such as humeral immunity in dermatomyositis (DM) and T-cell-mediated cytotoxicity in polymyositis (PM) contribute to the pathology of inflammatory myopathies. In addition, different subsets of macrophages are present in both diseases. Herein, the characteristics of 25F9-positive macrophages in skeletal muscle inflammation are outlined. Muscle biopsies of subjects with DM and PM were studied by immunohistochemical multi-labelling using the late-activation marker 25F9, together with markers characterizing macrophage function including IFN-gamma, iNOS, and TGF-beta. In PM, a robust expression of IFN-gamma, iNOS, and TGF-beta was observed in inflammatory cells. Double- and serial-labelling revealed that a subset of 25F9-positive macrophages in the vicinity of injured muscle fibres expressed iNOS and TGF-beta, but not IFN-gamma. In DM, IFN-gamma, iNOS and TGF-beta were also expressed in inflammatory cells in the endomysium. Double- and serial-labelling studies in DM indicated that 25F9-positive macrophages expressed TGF-beta and to a lesser degree iNOS, but not IFN-gamma. In conclusion, our data suggest that late-activated macrophages contribute to the pathology of inflammatory myopathies.

  5. HSPB7 interacts with dimerized FLNC and its absence results in progressive myopathy in skeletal muscles

    PubMed Central

    Juo, Liang-Yi; Liao, Wern-Chir; Shih, Yen-Ling; Yang, Bih-Ying; Liu, An-Bang

    2016-01-01

    ABSTRACT HSPB7 belongs to the small heat-shock protein (sHSP) family, and its expression is restricted to cardiac and skeletal muscles from embryonic stages to adulthood. Here, we found that skeletal-muscle-specific ablation of the HspB7 does not affect myogenesis during embryonic stages to postnatal day 1 (P1), but causes subsequent postnatal death owing to a respiration defect, with progressive myopathy phenotypes in the diaphragm. Deficiency of HSPB7 in the diaphragm muscle resulted in muscle fibrosis, sarcomere disarray and sarcolemma integrity loss. We identified dimerized filamin C (FLNC) as an interacting partner of HSPB7. Immunofluorescence studies demonstrated that the aggregation and mislocalization of FLNC occurred in the muscle of HspB7 mutant adult mice. Furthermore, the components of dystrophin glycoprotein complex, γ- and δ-sarcoglycan, but not dystrophin, were abnormally upregulated and mislocalized in HSPB7 mutant muscle. Collectively, our findings suggest that HSPB7 is essential for maintaining muscle integrity, which is achieved through its interaction with FLNC, in order to prevent the occurrence and progression of myopathy. PMID:26929074

  6. Effects of exercise training on neurovascular control and skeletal myopathy in systolic heart failure

    PubMed Central

    Middlekauff, Holly R.; Gomes-Santos, Igor L.; Antunes-Correa, Ligia M.

    2015-01-01

    Neurohormonal excitation and dyspnea are the hallmarks of heart failure (HF) and have long been associated with poor prognosis in HF patients. Sympathetic nerve activity (SNA) and ventilatory equivalent of carbon dioxide (VE/VO2) are elevated in moderate HF patients and increased even further in severe HF patients. The increase in SNA in HF patients is present regardless of age, sex, and etiology of systolic dysfunction. Neurohormonal activation is the major mediator of the peripheral vasoconstriction characteristic of HF patients. In addition, reduction in peripheral blood flow increases muscle inflammation, oxidative stress, and protein degradation, which is the essence of the skeletal myopathy and exercise intolerance in HF. Here we discuss the beneficial effects of exercise training on resting SNA in patients with systolic HF and its central and peripheral mechanisms of control. Furthermore, we discuss the exercise-mediated improvement in peripheral vasoconstriction in patients with HF. We will also focus on the effects of exercise training on ventilatory responses. Finally, we review the effects of exercise training on features of the skeletal myopathy in HF. In summary, exercise training plays an important role in HF, working synergistically with pharmacological therapies to ameliorate these abnormalities in clinical practice. PMID:25681428

  7. Constitutive Activation of the Calcium Sensor STIM1 Causes Tubular-Aggregate Myopathy

    PubMed Central

    Böhm, Johann; Chevessier, Frédéric; De Paula, André Maues; Koch, Catherine; Attarian, Shahram; Feger, Claire; Hantaï, Daniel; Laforêt, Pascal; Ghorab, Karima; Vallat, Jean-Michel; Fardeau, Michel; Figarella-Branger, Dominique; Pouget, Jean; Romero, Norma B.; Koch, Marc; Ebel, Claudine; Levy, Nicolas; Krahn, Martin; Eymard, Bruno; Bartoli, Marc; Laporte, Jocelyn

    2013-01-01

    Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly progressive muscle weakness. We identified dominant STIM1 mutations as a genetic cause of tubular-aggregate myopathy (TAM). Stromal interaction molecule 1 (STIM1) is the main Ca2+ sensor in the endoplasmic reticulum, and all mutations were found in the highly conserved intraluminal Ca2+-binding EF hands. Ca2+ stores are refilled through a process called store-operated Ca2+ entry (SOCE). Upon Ca2+-store depletion, wild-type STIM1 oligomerizes and thereby triggers extracellular Ca2+ entry. In contrast, the missense mutations found in our four TAM-affected families induced constitutive STIM1 clustering, indicating that Ca2+ sensing was impaired. By monitoring the calcium response of TAM myoblasts to SOCE, we found a significantly higher basal Ca2+ level in TAM cells and a dysregulation of intracellular Ca2+ homeostasis. Because recessive STIM1 loss-of-function mutations were associated with immunodeficiency, we conclude that the tissue-specific impact of STIM1 loss or constitutive activation is different and that a tight regulation of STIM1-dependent SOCE is fundamental for normal skeletal-muscle structure and function. PMID:23332920

  8. [Patient of myofibrillar myopathy associated with muscle cramp and distal muscle involvement].

    PubMed

    Okada, Yoichiro; Ayaki, Takashi; Matsumoto, Riki; Ito, Hidefumi; Takahashi, Ryosuke; Nakano, Satoshi

    2012-01-01

    A 53-year-old man presented mild, but gradually worsening, distal-dominant upper bilateral limbs weakness and muscle cramp in both legs from the age of 30. He had no obvious muscle atrophy during the course of the disease. Muscle biopsy of the right lateral vastus muscle showed myopathic changes with round or helical hyaline inclusions in eosinophilic on H&E staining and dark green on modified Gomori trichrome. There were also non-rimmed vacuoles. NADH-TR showed lack of enzymic activity in areas corresponding to the inclusions. Immunohistochemistry demonstrated abnormal accumulation of desmin and myotilin in fibers with inclusions. Given these pathological findings, he was diagnosed with myofibrillar myopathy (MFM). Because MFM is genetically heterogeneous, its clinical manifestations are reported as variable. While MFM patients are sometimes reported to develop serious conditions such as severe weakness, cardiomyopathy or respiratory failure, which require a pacemaker or mechanical ventilator, our case only had mild distal dominant limb weakness and muscle cramps. Our patient suggests that we must consider MFM as a differential diagnosis in adult onset distal myopathies.

  9. A statin-dependent QTL for GATM expression is associated with statin-induced myopathy.

    PubMed

    Mangravite, Lara M; Engelhardt, Barbara E; Medina, Marisa W; Smith, Joshua D; Brown, Christopher D; Chasman, Daniel I; Mecham, Brigham H; Howie, Bryan; Shim, Heejung; Naidoo, Devesh; Feng, QiPing; Rieder, Mark J; Chen, Yii-Der I; Rotter, Jerome I; Ridker, Paul M; Hopewell, Jemma C; Parish, Sarah; Armitage, Jane; Collins, Rory; Wilke, Russell A; Nickerson, Deborah A; Stephens, Matthew; Krauss, Ronald M

    2013-10-17

    Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.

  10. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

    PubMed Central

    Yuen, Michaela; Sandaradura, Sarah A.; Dowling, James J.; Kostyukova, Alla S.; Moroz, Natalia; Quinlan, Kate G.; Lehtokari, Vilma-Lotta; Ravenscroft, Gianina; Todd, Emily J.; Ceyhan-Birsoy, Ozge; Gokhin, David S.; Maluenda, Jérome; Lek, Monkol; Nolent, Flora; Pappas, Christopher T.; Novak, Stefanie M.; D’Amico, Adele; Malfatti, Edoardo; Thomas, Brett P.; Gabriel, Stacey B.; Gupta, Namrata; Daly, Mark J.; Ilkovski, Biljana; Houweling, Peter J.; Davidson, Ann E.; Swanson, Lindsay C.; Brownstein, Catherine A.; Gupta, Vandana A.; Medne, Livija; Shannon, Patrick; Martin, Nicole; Bick, David P.; Flisberg, Anders; Holmberg, Eva; Van den Bergh, Peter; Lapunzina, Pablo; Waddell, Leigh B.; Sloboda, Darcée D.; Bertini, Enrico; Chitayat, David; Telfer, William R.; Laquerrière, Annie; Gregorio, Carol C.; Ottenheijm, Coen A.C.; Bönnemann, Carsten G.; Pelin, Katarina; Beggs, Alan H.; Hayashi, Yukiko K.; Romero, Norma B.; Laing, Nigel G.; Nishino, Ichizo; Wallgren-Pettersson, Carina; Melki, Judith; Fowler, Velia M.; MacArthur, Daniel G.; North, Kathryn N.; Clarke, Nigel F.

    2014-01-01

    Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle. PMID:25250574

  11. Phenotypes of Myopathy-Related Beta-Tropomyosin Mutants in Human and Mouse Tissue Cultures

    PubMed Central

    Abdul-Hussein, Saba; Rahl, Karin; Moslemi, Ali-Reza; Tajsharghi, Homa

    2013-01-01

    Mutations in TPM2 result in a variety of myopathies characterised by variable clinical and morphological features. We used human and mouse cultured cells to study the effects of β-TM mutants. The mutants induced a range of phenotypes in human myoblasts, which generally changed upon differentiation to myotubes. Human myotubes transfected with the E41K-β-TMEGFP mutant showed perinuclear aggregates. The G53ins-β-TMEGFP mutant tended to accumulate in myoblasts but was incorporated into filamentous structures of myotubes. The K49del-β-TMEGFP and E122K-β-TMEGFP mutants induced the formation of rod-like structures in human cells. The N202K-β-TMEGFP mutant failed to integrate into thin filaments and formed accumulations in myotubes. The accumulation of mutant β-TMEGFP in the perinuclear and peripheral areas of the cells was the striking feature in C2C12. We demonstrated that human tissue culture is a suitable system for studying the early stages of altered myofibrilogenesis and morphological changes linked to myopathy-related β-TM mutants. In addition, the histopathological phenotype associated with expression of the various mutant proteins depends on the cell type and varies with the maturation of the muscle cell. Further, the phenotype is a combinatorial effect of the specific amino acid change and the temporal expression of the mutant protein. PMID:24039757

  12. Identification and Mechanistic Investigation of Drug–Drug Interactions Associated With Myopathy: A Translational Approach

    PubMed Central

    Han, X; Quinney, SK; Wang, Z; Zhang, P; Duke, J; Desta, Z; Elmendorf, JS; Flockhart, DA

    2015-01-01

    Myopathy is a group of muscle diseases that can be induced or exacerbated by drug–drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine–simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System. PMID:25975815

  13. Treatment options for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.

    PubMed

    Santa, Kristin M

    2010-11-01

    Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare neurodegenerative disease caused by the decreased ability of cells to produce sufficient energy in the form of adenosine 5'-triphosphate. Although it is one of the most common maternally inherited mitochondrial disorders, its exact incidence is unknown. Caused most frequently by an A-to-G point mutation at the 3243 position in the mitochondrial DNA, MELAS syndrome has a broad range of clinical manifestations and a highly variable course. The classic neurologic characteristics include encephalopathy, seizures, and stroke-like episodes. In addition to its neurologic manifestations, MELAS syndrome exhibits multisystem effects including cardiac conduction defects, diabetes mellitus, short stature, myopathy, and gastrointestinal disturbances. Unfortunately, no consensus guidelines outlining standard drug regimens exist for this syndrome. Many of the accepted therapies used in treating MELAS syndrome have been identified through a small number of clinical trials or isolated case reports. Currently, the drugs most often used include antioxidants and various vitamins aimed at minimizing the demands on the mitochondria and supporting and maximizing their function. Some of the most frequently prescribed agents include coenzyme Q(10), l-arginine, B vitamins, and levocarnitine. Although articles describing MELAS syndrome are available, few specifically target education for clinical pharmacists. This article will provide pharmacists with a practical resource to enhance their understanding of MELAS syndrome in order to provide safe and effective pharmaceutical care.

  14. Intensive care unit acquired weakness in children: Critical illness polyneuropathy and myopathy

    PubMed Central

    Kukreti, Vinay; Shamim, Mosharraf; Khilnani, Praveen

    2014-01-01

    Background and Aims: Intensive care unit acquired weakness (ICUAW) is a common occurrence in patients who are critically ill. It is most often due to critical illness polyneuropathy (CIP) or to critical illness myopathy (CIM). ICUAW is increasingly being recognized partly as a consequence of improved survival in patients with severe sepsis and multi-organ failure, partly related to commonly used agents such as steroids and muscle relaxants. There have been occasional reports of CIP and CIM in children, but little is known about their prevalence or clinical impact in the pediatric population. This review summarizes the current understanding of pathophysiology, clinical presentation, diagnosis and treatment of CIP and CIM in general with special reference to published literature in the pediatric age group. Subjects and Methods: Studies were identified through MedLine and Embase using relevant MeSH and Key words. Both adult and pediatric studies were included. Results: ICUAW in children is a poorly described entity with unknown incidence, etiology and unclear long-term prognosis. Conclusions: Critical illness polyneuropathy and myopathy is relatively rare, but clinically significant sequelae of multifactorial origin affecting morbidity, length of intensive care unit (ICU) stay and possibly mortality in critically ill children admitted to pediatric ICU. PMID:24678152

  15. Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations

    PubMed Central

    Savarese, Marco; Di Fruscio, Giuseppina; Tasca, Giorgio; Ruggiero, Lucia; Janssens, Sandra; De Bleecker, Jan; Delpech, Marc; Musumeci, Olimpia; Toscano, Antonio; Angelini, Corrado; Sacconi, Sabrina; Santoro, Lucio; Ricci, Enzo; Claes, Kathleen; Politano, Luisa; Nigro, Vincenzo

    2015-01-01

    We studied 786 undiagnosed patients with LGMD or nonspecific myopathic features to investigate the role of ANO5 mutations in limb-girdle muscular dystrophies (LGMDs) and in nonspecific myopathies using the next generation sequencing (NGS) approach. In 160 LGMD patients, we first sequenced hotspot exons 5 and 20 and then sequenced the remaining part of the coding region. Another 626 patients, recruited using broader inclusion criteria, were directly analyzed by targeted NGS. By combining NGS and Sanger sequencing, we identified 33/786 (4%) patients carrying putative pathogenic changes in both alleles and 23 ANO5 heterozygotes (3%). The phenotypic spectrum is broader than expected, from hyperCKemia to myopathies, with lack of genotype/phenotype correlations. In particular, this is currently the largest screening of the ANO5 gene. The large number of heterozygotes for damaging mutations suggests that anoctaminopathies should be frequent and often nonpenetrant. We propose the multiple genetic testing by targeted NGS as a first step to analyze patients with nonspecific myopathic presentations. This represents a straightforward approach to overcome the difficulties of clinical heterogeneity of ANO5 patients, and to test, at the same time, many other genes involved in neuromuscular disorders. PMID:25891276

  16. Microneedle Electrode Array for Electrical Impedance Myography to Characterize Neurogenic Myopathy.

    PubMed

    Li, Zhao; Li, Yi; Liu, Mingsheng; Cui, Liying; Yu, Yude

    2016-05-01

    Electrical impedance myography (EIM) is a noninvasive technique for neuromuscular assessment, wherein a low-intensity alternating current is applied to a muscle, and the consequent surface voltage patterns are evaluated. Commercial wet electrodes are most commonly used for EIM. However, these electrodes are not suitable for use on small muscles, as they do not effectively solve the problem of high electrode-skin contact impedance (ESCI) that negatively influences the quality of recorded biopotentials. To address this problem, we fabricated a novel microneedle electrode array (MEA) that consists of 124-µm-long microneedles. Compared to wet electrodes, the MEA could pierce through the outer skin surface in a painless and micro-invasive manner, and could thus effectively reduce ESCI. The MEA has excellent test-retest reproducibility, with intraclass correlation coefficients exceeding 0.920. When used in combination with EIM, the MEA differentiated the affected muscles from the unaffected muscles in patients with neurogenic myopathy, by using EIM parameters of reactance and phase (p = 0.023 and 0.008, respectively). Thus, the novel MEA is a practical and reusable device for EIM assessment in cases of neurogenic myopathy. However, further refinement of the electrode is needed to enhance the clinical application of the system.

  17. Anemia, myopathy, and pansteatitis in vitamin E-deficient captive marmosets (Callithrix spp.).

    PubMed

    Juan-Sallés, C; Prats, N; Resendes, A; Domingo, M; Hilton, D; Ruiz, J M; Garner, M M; Valls, X; Marco, A J

    2003-09-01

    Five young adult pet marmosets (Callithrix spp.) were presented with weight loss (5/5); fecal retention (3/5); diarrhea (2/5); impaired locomotion (3/5); anemia (4/4); hypoproteinemia or hypoalbuminemia (3/4); elevations of creatine phosphokinase, lactic dehydrogenase, and alanine aminotransferase (3/4); and renal failure with hypercholesterolemia (2/4). All anemic marmosets had low serum vitamin E levels. The anemia responded to vitamin E and selenium therapy in two marmosets. One of the five marmosets died before presentation, and two others died despite therapy. The two marmosets necropsied had degenerative myopathy, pyogranulomatous pansteatitis, and increased erythrophagocytosis and hemosiderosis. The striated muscle and adipose tissue of both marmosets were negative for coxsackievirus ribonucleic acid by in situ hybridization. These findings suggest that vitamin E deficiency may be involved in the development of anemia, myopathy, and steatitis in callitrichids; however, in some marmosets, underlying diseases such as chronic colitis may have influenced the development of anemia and impaired vitamin E status.

  18. Semitendinosus myopathy and treatment with adipose-derived stem cells in working German shepherd police dogs.

    PubMed

    Gibson, Melissa A; Brown, S Gary; Brown, Nancy O

    2017-03-01

    Semitendinosus myopathy has been treated with numerous surgical and non-surgical therapies resulting in recurrence of lameness within 2 to 9 months. Eleven cases of semitendinosus myopathy diagnosed in 8 working police dogs that were treated with adipose-derived mesenchymal stem cells were retrospectively evaluated. At short-term follow-up < 6 mo, ultrasound and gait evaluations revealed a mean reduction in the overall intramuscular lesion size of 54.82% (SD +/- 18.02; range: 30.5% to 82.7%) and reduction in the Visual Assessment Score (VAS) of 1 to 3 points. At long-term follow-up > 1 y, in 8 cases the dogs had a normal gait and in 3 cases the dogs had an improved gait compared with initial examination, and all 8 dogs returned to active police work. Fisher's exact test resulted in P = 0.000008 when comparing published historical reports and these 11 cases for resolution of lameness and return to active duty.

  19. A centronuclear myopathy--dynamin 2 mutation impairs autophagy in mice.

    PubMed

    Durieux, Anne-Cécile; Vassilopoulos, Stéphane; Lainé, Jeanne; Fraysse, Bodvaël; Briñas, Laura; Prudhon, Bernard; Castells, Josiane; Freyssenet, Damien; Bonne, Gisèle; Guicheney, Pascale; Bitoun, Marc

    2012-06-01

    Dynamin 2 (Dnm2) is involved in endocytosis and intracellular membrane trafficking through its function in vesicle formation from distinct membrane compartments. Heterozygous (HTZ) mutations in the DNM2 gene cause dominant centronuclear myopathy or Charcot-Marie-Tooth neuropathy. We generated a knock-in Dnm2R465W mouse model expressing the most frequent human mutation and recently reported that HTZ mice progressively developed a myopathy. We investigated here the cause of neonatal lethality occurring in homozygous (HMZ) mice. We show that HMZ mice present at birth with a reduced body weight, hypoglycemia, increased liver glycogen content and hepatomegaly, in agreement with a defect in neonatal autophagy. In vitro studies performed in HMZ embryonic fibroblasts point out to a decrease in the autophagy flux prior to degradation at the autolysosome. We show that starved HMZ cells have a higher number of immature autophagy-related structures probably due to a defect of acidification. Our results highlight the role of Dnm2 in the cross talk between endosomal and autophagic pathways and evidence a new role of Dnm2-dependent membrane trafficking in autophagy which may be relevant in DNM2-related human diseases.

  20. Mice lacking TR4 nuclear receptor develop mitochondrial myopathy with deficiency in complex I.

    PubMed

    Liu, Su; Lee, Yi-Fen; Chou, Samuel; Uno, Hideo; Li, Gonghui; Brookes, Paul; Massett, Michael P; Wu, Qiao; Chen, Lu-Min; Chang, Chawnshang

    2011-08-01

    The estimated incidence of mitochondrial diseases in humans is approximately 1:5000 to 1:10,000, whereas the molecular mechanisms for more than 50% of human mitochondrial disease cases still remain unclear. Here we report that mice lacking testicular nuclear receptor 4 (TR4(-/-)) suffered mitochondrial myopathy, and histological examination of TR4(-/-) soleus muscle revealed abnormal mitochondrial accumulation. In addition, increased serum lactate levels, decreased mitochondrial ATP production, and decreased electron transport chain complex I activity were found in TR4(-/-) mice. Restoration of TR4 into TR4(-/-) myoblasts rescued mitochondrial ATP generation capacity and complex I activity. Further real-time PCR quantification and promoter studies found TR4 could modulate complex I activity via transcriptionally regulating the complex I assembly factor NDUFAF1, and restoration of NDUFAF1 level in TR4(-/-) myoblasts increased mitochondrial ATP generation capacity and complex I activity. Together, these results suggest that TR4 plays vital roles in mitochondrial function, which may help us to better understand the pathogenesis of mitochondrial myopathy, and targeting TR4 via its ligands/activators may allow us to develop better therapeutic approaches.

  1. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.

    PubMed

    Khan, Nahid A; Auranen, Mari; Paetau, Ilse; Pirinen, Eija; Euro, Liliya; Forsström, Saara; Pasila, Lotta; Velagapudi, Vidya; Carroll, Christopher J; Auwerx, Johan; Suomalainen, Anu

    2014-06-01

    Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy.

  2. Red yeast rice and coenzyme Q10 as safe alternatives to surmount atorvastatin-induced myopathy in hyperlipidemic rats.

    PubMed

    Abdelbaset, Marwan; Safar, Marwa M; Mahmoud, Sawsan S; Negm, Seham A; Agha, Azza M

    2014-06-01

    Statins are the first line treatment for the management of hyperlipidemia. However, the primary adverse effect limiting their use is myopathy. This study examines the efficacy and safety of red yeast rice (RYR), a source of natural statins, as compared with atorvastatin, which is the most widely used synthetic statin. Statin interference with the endogenous synthesis of coenzyme Q10 (CoQ10) prompted the hypothesis that its deficiency may be implicated in the pathogenesis of statin-associated myopathy. Hence, the effects of combination of CoQ10 with either statin have been evaluated. Rats were rendered hyperlipidemic through feeding them a high-fat diet for 90 days, during the last 30 days of the diet they were treated daily with either atorvastatin, RYR, CoQ10, or combined regimens. Lipid profile, liver function tests, and creatine kinase were monitored after 15 and 30 days of drug treatments. Heart contents of CoQ9 and CoQ10 were assessed and histopathological examination of the liver and aortic wall was performed. RYR and CoQ10 had the advantage over atorvastatin in that they lower cholesterol without elevating creatine kinase, a hallmark of myopathy. RYR maintained normal levels of heart ubiquinones, which are essential components for energy production in muscles. In conclusion, RYR and CoQ10 may offer alternatives to overcome atorvastatin-associated myopathy.

  3. [Interindividual differences in the response to statin therapy and gene polymorphisms related to myopathy during statin therapy].

    PubMed

    Dendramis, Gregory

    2011-03-01

    The enzyme HMG-CoA reductase (HMGCR), the main site of action of statins, undergoes alternative splicing of exon 13, which encodes the binding domain of statins to the enzyme. The resulting isoform, called HMGCRv1, shows altered enzyme activity and sensitivity to statins compared to the classical isoform. This translates into interindividual differences in the response to treatment with these drugs. A recent discovery in the field of genetics has brought about the identification of the single nucleotide polymorphism rs4363657 of the SLCO1B1 gene located on chromosome 12. This polymorphism is strongly associated with myopathy induced by statins. From the available literature, a clinical study has evaluated the relationship between gene polymorphisms and myopathy during statin therapy. The study involved 12 000 patients treated with simvastatin at a dose of 80 mg/day. The odds ratio for myopathy was 4.5 (95% confidence interval 2.6-7.7) per copy of the C allele, and 16.9 (95% confidence interval 4.7-61.1) in CC as compared with TT homozygotes. Myopathy could be attributed to the C variant in more than 60% of cases. Genomic typing may allow the identification of these variants, leading to a tailored statin therapy with higher benefits to the patients and less adverse side effects.

  4. A novel DNAJB6 mutation causes dominantly-inherited distal-onset myopathy and compromises DNAJB6 function.

    PubMed

    Tsai, Pei-Chien; Tsai, Yu-Shuen; Soong, Bing-Wen; Huang, Yen-Hua; Wu, Hung-Ta; Chen, Ying-Hao; Lin, Kon-Ping; Liao, Yi-Chu; Lee, Yi-Chung

    2017-02-23

    Mutations in the DNAJB6 gene have been identified as a rare cause of dominantly-inherited limb-girdle muscular dystrophy or distal-onset myopathy. To identify the genetic cause of distal-onset myopathy in a Taiwanese family of Han Chinese origin, we performed exome sequencing for the two affected individuals and identified a heterozygous mutation, c.287C>T (p.Pro96Leu) in the DNAJB6 gene that co-segregated with myopathy in the family. Notably, this mutation is novel and localizes within the glycine and phenylalanine-rich (G/F) domain and alters an amino acid residue previously reported with a different mutation. Furthermore, in vitro functional studies demonstrated that the c.287C>T (p.Pro96Leu) mutation possessed a dominant negative effect on the anti-aggregation function of DNAJB6 protein. Taken together, these findings expand the molecular spectrum of DNAJB6 mutations and also emphasize the pathogenic role of DNAJB6 dysfunction in distal-onset myopathy.

  5. [Phosphorus NMR spectroscopy. Its value in the diagnosis of metabolic myopathies. A case of Mac Ardle's disease].

    PubMed

    Kaminsky, P; Melone, M; Brunotte, F; Escanye, J M; Robin, B; Floquet, J; Duc, M L; Robert, J; Duc, M

    1990-06-09

    Phosphorus nuclear magnetic resonance spectroscopy is a non-invasive method used to study muscle bioenergetics in vivo. A new case of Mc Ardle's disease (myophosphorylase deficiency) is reported here. In a context of metabolic myopathy this method can provide a diagnosis of glycogenosis. The spectra obtained at exercise and during recovery determine the degree of enzyme deficiency with satisfactory precision.

  6. Muscle weakness in respiratory and peripheral skeletal muscles in a mouse model for nebulin-based nemaline myopathy.

    PubMed

    Joureau, Barbara; de Winter, Josine M; Stam, Kelly; Granzier, Henk; Ottenheijm, Coen A C

    2017-01-01

    Nemaline myopathy is among the most common non-dystrophic congenital myopathies, and is characterized by the presence of nemaline rods in skeletal muscles fibers, general muscle weakness, and hypotonia. Although respiratory failure is the main cause of death in nemaline myopathy, only little is known regarding the contractile strength of the diaphragm, the main muscle of inspiration. To investigate diaphragm contractility, in the present study we took advantage of a mouse model for nebulin-based nemaline myopathy that we recently developed. In this mouse model, exon 55 of Neb is deleted (Neb(ΔExon55)), a mutation frequently found in patients. Diaphragm contractility was determined in permeabilized muscle fibers and was compared to the contractility of permeabilized fibers from three peripheral skeletal muscles: soleus, extensor digitorum longus, and gastrocnemius. The force generating capacity of diaphragm muscle fibers of Neb(ΔExon55) mice was reduced to 25% of wildtype levels, indicating severe contractile weakness. The contractile weakness of diaphragm fibers was more pronounced than that observed in soleus muscle, but not more pronounced than that observed in extensor digitorum longus and gastrocnemius muscles. The reduced muscle contractility was at least partly caused by changes in cross-bridge cycling kinetics which reduced the number of bound cross-bridges. The severe diaphragm weakness likely contributes to the development of respiratory failure in Neb(ΔExon55) mice and might explain their early, postnatal death.

  7. Dietary nitrate does not reduce oxygen cost of exercise or improve muscle mitochondrial function in mitochondrial myopathy patients.

    PubMed

    Nabben, Miranda; Schmitz, Joep P J; Ciapaite, Jolita; Le Clercq, Carlijn M P; van Riel, Natal A; Haak, Harm R; Nicolay, Klaas; de Coo, Irenaeus F; Smeets, Hubert J M; Praet, Stephan F; van Loon, Luc J C; Prompers, Jeanine J

    2017-02-08

    Muscle weakness and exercise intolerance negatively affect the quality of life of mitochondrial myopathy patients. Short-term dietary nitrate supplementation has been shown to improve exercise performance and reduce oxygen cost of exercise in healthy humans and trained athletes. We investigated if 1 week of dietary inorganic nitrate supplementation decreases the oxygen cost of exercise and improves mitochondrial function in mitochondrial myopathy patients. Ten mitochondrial myopathy patients (40 ± 5 years, maximal whole-body oxygen uptake = 21.2 ± 3.2 mL/min/kg body weight, maximal workload = 122 ± 26 W) received 8.5 mg/kg body weight/day of inorganic nitrate (~7 mmol) for 8 days. Whole-body oxygen consumption at 50% of the maximal workload, in vivo skeletal muscle oxidative capacity (evaluated from post-exercise phosphocreatine recovery using (31)P magnetic resonance spectroscopy) and ex vivo mitochondrial oxidative capacity in permeabilized skinned muscle fibers (measured with high-resolution respirometry) were determined before and after nitrate supplementation. Despite a 6-fold increase in plasma nitrate levels, nitrate supplementation did not affect whole-body oxygen cost during submaximal exercise. Additionally, no beneficial effects of nitrate were found on in vivo or ex vivo muscle mitochondrial oxidative capacity. This is the first time that the therapeutic potential of dietary nitrate for mitochondrial myopathy patients was evaluated. We conclude that 1 week of dietary nitrate supplementation does not reduce oxygen cost of exercise or improve mitochondrial function in the group of patients tested.

  8. The myopathy of peripheral arterial occlusive disease: part 1. Functional and histomorphological changes and evidence for mitochondrial dysfunction.

    PubMed

    Pipinos, Iraklis I; Judge, Andrew R; Selsby, Joshua T; Zhu, Zhen; Swanson, Stanley A; Nella, Aikaterini A; Dodd, Stephen L

    In recent years, an increasing number of studies have demonstrated that a myopathy is present, contributes, and, to a certain extent, determines the pathogenesis of peripheral arterial occlusive disease (PAD). These works provide evidence that a state of repetitive cycles of exercise-induced ischemia followed by reperfusion at rest operates in PAD patients and mediates a large number of structural and metabolic changes in the muscle, resulting in reduced strength and function. The key players in this process appear to be defective mitochondria that, through multilevel failure in their roles as energy, oxygen radical species, and apoptosis regulators, produce and sustain a progressive decline in muscle performance. In this 2-part review, we highlight the currently available evidence that characterizes the nature and mechanisms responsible for this myopathy. In part 1, the authors review the functional and histomorphological characteristics of the myopathy and focus on the biochemistry and bioenergetics of its mitochondriopathy. In part 2, they then review accumulating evidence that oxidative stress related to ischemia reperfusion is probably the major operating mechanism of PAD myopathy. Important new findings of a possible neuropathy and a shift in muscle fiber type are also reviewed. Learning more about these mechanisms will enhance our understanding of the degree to which they are preventable and treatable.

  9. Two Cases of Chronic Intestinal Pseudo-obstruction: A Comparison of Staining Characteristics of Enteric Visceral Myopathy With Hirschsprung Disease.

    PubMed

    Chaffin, Joanna; Lee, Jeffrey R; Rao, Satish S C; Sharma, Suash J

    2016-09-01

    Chronic intestinal pseudo-obstruction (CIPO), a rare, debilitating disorder of bowel motility dysfunction, is largely a clinical diagnosis, without any universally accepted diagnostic criteria. Three subgroups are generally acknowledged based on the cell-type affected: enteric visceral myopathy (the most common subgroup), neuropathy, and mesenchymopathy. A fourth subgroup includes abnormalities of neurohormonal peptides. Although immunohistochemical staining is reportedly useful for identifying the mesenchymopathic type, its role in diagnosing enteric visceral myopathy and neuropathy has been fraught with difficulties. We present two cases of chronic intestinal pseudo-obstruction that are clinically and histopathologically suggestive of type III visceral enteric myopathy, aiming to expound upon the diagnostic and pathogenic features. We found that the outer-longitudinal layer of the muscularis propria was more severely affected as compared with the inner circular layer. To investigate the value of this finding, we performed immunostains in the one case in which a paraffin block was available. We found increased peripherin and calretinin immunopositive nerve fibers in the outer layer as compared with inner, but without any significant increase in S-100 positivity or alteration in neuronal morphology of myenteric plexus, a novel finding. This differential staining pattern was completely different from Hirschsprung disease, in which we found rare to absent peripherin and calretinin staining. It is unclear if this increase in the outer layer in visceral myopathy reflects a reactive change or dysfunctional axons. In addition, the history of volvulus in one patient and transmural inflammatory changes in the second raise concerns about the higher propensity of clinical complications secondary to the attenuated outer muscular layer. This study suggests that enteric visceral myopathy has histologic and staining characteristics different from Hirschsprung disease, a finding

  10. Roles of proinflammatory cytokines and the Fas/Fas ligand interaction in the pathogenesis of inflammatory myopathies.

    PubMed

    Kondo, Masahiro; Murakawa, Yohko; Harashima, Nanae; Kobayashi, Shotai; Yamaguchi, Shuhei; Harada, Mamoru

    2009-09-01

    Within the lesions of inflammatory myopathies, muscle fibres and invading mononuclear cells express Fas and Fas ligand (FasL), respectively. However, the roles of the Fas/FasL interaction in the pathogenesis of inflammatory myopathies are not fully understood. In the present study, we investigated the roles of proinflammatory cytokines and the Fas/FasL system in the pathogenesis of inflammatory myopathies. In vitro culturing of muscle cells with the proinflammatory cytokines interferon-gamma, tumour necrosis factor-alpha, and interleukin (IL)-1beta synergistically increased Fas expression, susceptibility to Fas-mediated apoptosis, and the expression of cytoplasmic caspases 8 and 3. In addition, culturing of muscle cells with activated CD4(+) T cells induced muscle cell apoptosis, which was partially inhibited by anti-FasL antibody. We also tested the possibility that T helper (Th) 17, which is an IL-17-producing helper T-cell subset that plays crucial roles in autoimmune and inflammatory responses, participates in the pathogenesis of inflammatory myopathies. Interestingly, in vitro culturing of dendritic cells with anti-Fas immunoglobulin M (IgM) or activated CD4(+) T cells induced the expression of mRNA for IL-23p19, but not for IL-12p35, in addition to proinflammatory cytokines. Furthermore, IL-23p19 and IL-17 mRNAs were detected in the majority of biopsy samples from patients with inflammatory myopathies. Taken together, these results suggest that proinflammatory cytokines enhance Fas-mediated apoptosis of muscle cells, and that the Fas/FasL interaction between invading dendritic cells and CD4(+) T cells induces local production of IL-23 and proinflammatory cytokines, which can promote the proliferation of Th17 cells and enhance Fas-mediated apoptosis of muscle cells, respectively.

  11. Myopathy in Marinesco-Sjögren syndrome links endoplasmic reticulum chaperone dysfunction to nuclear envelope pathology.

    PubMed

    Roos, Andreas; Buchkremer, Stephan; Kollipara, Laxmikanth; Labisch, Thomas; Gatz, Christian; Zitzelsberger, Manuela; Brauers, Eva; Nolte, Kay; Schröder, J Michael; Kirschner, Janbernd; Jesse, Christopher Marvin; Goebel, Hans Hilmar; Goswami, Anand; Zimmermann, Richard; Zahedi, René Peiman; Senderek, Jan; Weis, Joachim

    2014-05-01

    Marinesco-Sjögren syndrome (MSS) features cerebellar ataxia, mental retardation, cataracts, and progressive vacuolar myopathy with peculiar myonuclear alterations. Most MSS patients carry homozygous or compound heterozygous SIL1 mutations. SIL1 is a nucleotide exchange factor for the endoplasmic reticulum resident chaperone BiP which controls a plethora of essential processes in the endoplasmic reticulum. In this study we made use of the spontaneous Sil1 mouse mutant woozy to explore pathomechanisms leading to Sil1 deficiency-related skeletal muscle pathology. We found severe, progressive myopathy characterized by alterations of the sarcoplasmic reticulum, accumulation of autophagic vacuoles, mitochondrial changes, and prominent myonuclear pathology including nuclear envelope and nuclear lamina alterations. These abnormalities were remarkably similar to the myopathy in human patients with MSS. In particular, the presence of perinuclear membranous structures which have been reported as an ultrastructural hallmark of MSS-related myopathy could be confirmed in woozy muscles. We found that these structures are derived from the nuclear envelope and nuclear lamina and associate with proliferations of the sarcoplasmic reticulum. In line with impaired function of BiP secondary to loss of its nucleotide exchange factor Sil1, we observed activation of the unfolded protein response and the endoplasmic-reticulum-associated protein degradation-pathway. Despite initiation of the autophagy-lysosomal system, autophagic clearance was found ineffective which is in agreement with the formation of autophagic vacuoles. This report identifies woozy muscle as a faithful phenocopy of the MSS myopathy. Moreover, we provide a link between two well-established disease mechanisms in skeletal muscle, dysfunction of chaperones and nuclear envelope pathology.

  12. Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy.

    PubMed

    Nalbandian, Angèle; Khan, Arif A; Srivastava, Ruchi; Llewellyn, Katrina J; Tan, Baichang; Shukr, Nora; Fazli, Yasmin; Kimonis, Virginia E; BenMohamed, Lbachir

    2017-02-01

    Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCP(R155H/+) heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β((+))F4/80((+))Ly6C((+)) inflammatory macrophages that infiltrate the muscles of VCP(R155H/+) mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β((+))F4/80((+))Ly6C((+)) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCP(R155H/+) mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80((+))Ly6C((+))IL-1β((+)) macrophage infiltrates in the muscle, and significantly ameliorated muscle strength. Together, these results suggest that (i) NLRP3 inflammasome and local IL-1β((+))F4/80((+))Ly6C((+)) inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.

  13. A Comprehensive Overview on Myositis-Specific Antibodies: New and Old Biomarkers in Idiopathic Inflammatory Myopathy.

    PubMed

    Satoh, Minoru; Tanaka, Shin; Ceribelli, Angela; Calise, S John; Chan, Edward K L

    2017-02-01

    Autoantibodies specific for idiopathic inflammatory myopathy (myositis-specific autoantibodies (MSAs)) are clinically useful biomarkers to help the diagnosis of polymyositis/dermatomyositis (PM/DM). Many of these are also associated with a unique clinical subset of PM/DM, making them useful in predicting and monitoring certain clinical manifestations. Classic MSAs known for over 30 years include antibodies to Jo-1 (histidyl transfer RNA (tRNA) synthetase) and other aminoacyl tRNA synthetases (ARS), anti-Mi-2, and anti-signal recognition particle (SRP). Anti-Jo-1 is the first autoantibodies to ARS detected in 15-25 % of patients. In addition to anti-Jo-1, antibodies to seven other aminoacyl tRNA synthetases (ARS) have been reported with prevalence, usually 1-5 % or lower. Patients with any anti-ARS antibodies are associated with anti-synthetase syndrome characterized by myositis, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon, and others. Several recent studies suggested heterogeneity in clinical features among different anti-ARS antibody-positive patients and anti-ARS may also be found in idiopathic ILD without myositis. Anti-Mi-2 is a classic marker for DM and associated with good response to steroid treatment and good prognosis. Anti-SRP is specific for PM and associated with treatment-resistant myopathy histologically characterized as necrotizing myopathy. In addition to classic MSAs, several new autoantibodies with strong clinical significance have been described in DM. Antibodies to transcription intermediary factor 1γ/α (TIF1γ/α, p155/140) are frequently found in DM associated with malignancy while anti-melanoma differentiation-associated gene 5 (MDA5; CADM140) are associated with clinically amyopathic DM (CADM) complicated by rapidly progressive ILD. Also, anti-MJ/nuclear matrix protein 2 (NXP-2) and anti-small ubiquitin-like modifier-1 (SUMO-1) activating enzyme (SAE) are recognized as new DM-specific autoantibodies. Addition of

  14. A novel large deletion in the RYR1 gene in a Belgian family with late-onset and recessive core myopathy.

    PubMed

    Remiche, Gauthier; Kadhim, Hazim; Abramowicz, Marc; Mavroudakis, Nicolas; Monnier, Nicole; Lunardi, Joël

    2015-05-01

    We report a novel and particularly unusual type of mutation, namely, large deletion in the RYR1 gene, in a Belgian family with myopathy: Patients were found to be compound heterozygous and presented a clinico-pathological phenotype characterized by late-onset and recessive myopathy with cores. We depict the clinical, electrophysiological, pathological and molecular genetic characteristics of family members. To date, large deletions in the RYR1 gene have been reported in only two cases. Both involved different mutations and, in sharp contrast to our cases, presented with a very early-onset, neonatal, and a very severe or lethal phenotype. Overview of reported clinico-pathologic phenotypes, also highlights the rarity of combined late-onset/recessive co-occurrence in this group of myopathies with cores. Finally, this report underlines the broadening spectrum in this group of myopathologic disorders and highlights the concept of 'RYR1-associated/related core myopathies'.

  15. Muscle spindles exhibit core lesions and extensive degeneration of intrafusal fibers in the Ryr1(I4895T/wt) mouse model of core myopathy.

    PubMed

    Zvaritch, Elena; MacLennan, David H

    2015-04-24

    Muscle spindles from the hind limb muscles of adult Ryr1(I4895T/wt) (IT/+) mice exhibit severe structural abnormalities. Up to 85% of the spindles are separated from skeletal muscle fascicles by a thick layer of connective tissue. Many intrafusal fibers exhibit degeneration, with Z-line streaming, compaction and collapse of myofibrillar bundles, mitochondrial clumping, nuclear shrinkage and pyknosis. The lesions resemble cores observed in the extrafusal myofibers of this animal model and of core myopathy patients. Spindle abnormalities precede those in extrafusal fibers, indicating that they are a primary pathological feature in this murine Ryr1-related core myopathy. Muscle spindle involvement, if confirmed for human core myopathy patients, would provide an explanation for an array of devastating clinical features characteristic of these diseases and provide novel insights into the pathology of RYR1-related myopathies.

  16. [McArdle disease presenting with rhabdomyolisis and acute kidney injury].

    PubMed

    Costa, Rui; Castro, Rui; Costa, Alexandre; Taipa, Ricardo; Vizcaíno, Ramon; Morgado, Teresa

    2013-01-01

    McArdle disease typically presents in childhood or young adults with myalgia, exercise intolerance, cramps and myoglobinuria. Deficiency of myophosphorylase enzyme results in inability to degrade glycogen stores, causing glycogen accumulation in muscle tissue and energy deficit. Evolution with rhabdomiolysis may occur and can be complicated with acute kidney injury but rarely, in about 11% of cases, is the initial disease manifestation. We report a case of McArdle Disease in a 38-year-old male patient. The disease went unrecognized despite previous symptoms (myalgia, exercise intolerance and single myoglobinuria episode) until an episode of rhabdomyolisis complicated with oliguric acute kidney injury requiring hemodialysis. The kidney biopsy showed evidence of acute tubular necrosis. Despite normalization of renal function, muscle lysis markers remained abnormal. Metabolic myopathy was suspected and a muscle biopsy was performed. It showed subsarcolemic glycogen deposition and absence of myophosphorylase activity. This case-report underlines the importance of considering metabolic myopathy in patients with acute kidney injury and severe rhabdomyolisis.

  17. Acute Bronchitis

    MedlinePlus

    ... can also cause acute bronchitis. To diagnose acute bronchitis, your health care provider will ask about your symptoms and listen to your breathing. You may also have other tests. Treatments include rest, fluids, and aspirin (for adults) or ...

  18. A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy.

    PubMed

    Okamoto, Nobuhiko; Toribe, Yasuhisa; Nakajima, Tohru; Okinaga, Takeshi; Kurosawa, Kenji; Nonaka, Ikuya; Shimokawa, Osamu; Matsumoto, Noamichi

    2002-01-01

    Chromosome 1p36 deletion syndrome is characterized by hypotonia, moderate to severe developmental and growth retardation, and characteristic craniofacial dysmorphism. Muscle hypotonia and delayed motor development are almost constant features of the syndrome. We report a 4-year-old Japanese girl with 1p36 deletion syndrome whose muscle pathology showed congenital fiber type disproportion (CFTD) myopathy. This is the first case report of 1p36 deletion associated with CFTD. This association may indicate that one of the CFTD loci is located at 1p36. Ski proto-oncogene -/- mice have phenotypes that resemble some of the features observed in patients with 1p36 deletion syndrome. Because fluorescent in situ hybridization analysis revealed that the human SKI gene is deleted in our patient, some genes in 1p36, including SKI proto-oncogene, may be involved in muscle hypotonia and delayed motor development in this syndrome.

  19. Multiple Viral Determinants Mediate Myopathogenicity in Coxsackievirus B1-Induced Chronic Inflammatory Myopathy

    PubMed Central

    Tam, Patricia E.; Weber-Sanders, Melissa L.; Messner, Ronald P.

    2003-01-01

    Mice infected with myopathic coxsackievirus B1 Tucson (CVB1T) develop chronic inflammatory myopathy (CIM) consisting of hind limb weakness and inflammation. Amyopathic virus variants are infectious but attenuated for CIM. In this report, viral clones, chimeras, and sequencing were used to identify viral determinants of CIM. Chimeras identified several regions involved in CIM and localized a weakness determinant to nucleotides 2493 to 3200 of VP1. Sequencing of multiple clones and viruses identified five candidate determinants that were strictly conserved in myopathic viruses with one located in the 5′ untranslated region (UTR), three in the VP1 capsid, and one in the 3C protease. Taken together, these studies implicate Tyr-87 and/or Val-136 as candidate determinants of weakness. They also indicate that there are at least two determinants of inflammation and one additional determinant of weakness encoded by myopathic CVB1T. PMID:14557670

  20. Ascending paresis as presentation of an unusual association between necrotizing autoimmune myopathy and systemic lupus erythematosus.

    PubMed

    García-Reynoso, Marco Julio; Veramendi-Espinoza, Liz Eliana; Ruiz-Garcia, Henry Jeison

    2014-01-01

    A 45 year-old man went to the emergency room due to disease duration of 15 days of insidious onset and progressive course. It began with symmetrical weakness and pain in feet and ankles that extends upward to the knees. Later, this progressed to paraparesis with Creatine phosphokinase levels of 44,270 U/L and respiratory failure that required mechanical ventilation. Electromyography and muscle biopsy of quadriceps were made. The patient responded to corticotherapy in pulses and supporting management. The presentation of ascending paresis suggested the diagnosis of Guillain-Barré syndrome. However, the degree of muscle involvement with rhabdomyolysis explains the neurological damage by itself. The biopsy revealed pathological criteria for necrotizing autoimmune myopathy (NAM), as well as other clinical and laboratory evidence. Patient disease continued and reached criteria for systemic lupus erythematosus (SLE). To our best knowledge, this is the first report of the NAM and SLE association.

  1. Adult-onset nemaline myopathy in a dog presenting with persistent atrial standstill and primary hypothyroidism.

    PubMed

    Nakamura, R K; Russell, N J; Shelton, G D

    2012-06-01

    A nine-year-old neutered female mixed breed dog presented for evaluation following a five-day history of lethargy, inappetence, weakness, abdominal distension and generalised muscle atrophy. Persistent vatrial standstill with a junctional rhythm was identified on electrocardiogram. Echocardiogram identified moderate dilation of all cardiac chambers and mild thickening of the mitral and tricuspid valves. Serology was negative for Neospora caninum and Toxoplasma gondii. Permanent pacemaker implantation was performed in addition to endomyocardial and skeletal muscle biopsies. Cryosections from the biceps femoris muscle showed numerous nemaline rod bodies while endomyocardial biopsies were possibly consistent with end-stage myocarditis. Rod bodies have rarely been reported in the veterinary literature. To the authors' knowledge, this is the first report of adult-onset nemaline rod myopathy and hypothyroidism with concurrent cardiac disease in a dog.

  2. Late Na+ current and protracted electrical recovery are critical determinants of the aging myopathy

    PubMed Central

    Signore, Sergio; Sorrentino, Andrea; Borghetti, Giulia; Cannata, Antonio; Meo, Marianna; Zhou, Yu; Kannappan, Ramaswamy; Pasqualini, Francesco; O'Malley, Heather; Sundman, Mark; Tsigkas, Nikolaos; Zhang, Eric; Arranto, Christian; Mangiaracina, Chiara; Isobe, Kazuya; Sena, Brena F.; Kim, Junghyun; Goichberg, Polina; Nahrendorf, Matthias; Isom, Lori L.; Leri, Annarosa; Anversa, Piero; Rota, Marcello

    2015-01-01

    The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na+ current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca2+ cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca2+ transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly. PMID:26541940

  3. Mitochondrial Myopathy in Follow-up of a Patient With Chronic Fatigue Syndrome

    PubMed Central

    Galán, Fernando; de Lavera, Isabel; Cotán, David; Sánchez-Alcázar, José A.

    2015-01-01

    Introduction. Symptoms of mitochondrial diseases and chronic fatigue syndrome (CFS) frequently overlap and can easily be mistaken. Methods. We report the case of a patient diagnosed with CFS and during follow-up was finally diagnosed with mitochondrial myopathy by histochemical study of muscle biopsy, spectrophotometric analysis of the complexes of the mitochondrial respiratory chain, and genetic studies. Results. The results revealed 3% fiber-ragged blue and a severe deficiency of complexes I and IV and several mtDNA variants. Mother, sisters, and nephews showed similar symptoms, which strongly suggests a possible maternal inheritance. The patient and his family responded to treatment with high doses of riboflavin and thiamine with a remarkable and sustained fatigue and muscle symptoms improvement. Conclusions. This case illustrates that initial symptoms of mitochondrial disease in adults can easily be mistaken with CFS, and in these patients a regular reassessment and monitoring of symptoms is recommended to reconfirm or change the diagnosis. PMID:26904705

  4. Inflammatory myopathy in a patient with Aicardi-Goutières syndrome.

    PubMed

    Tumienė, Birutė; Voisin, Norine; Preikšaitienė, Eglė; Petroška, Donatas; Grikinienė, Jurgita; Samaitienė, Rūta; Utkus, Algirdas; Reymond, Alexandre; Kučinskas, Vaidutis

    2017-03-01

    Aicardi-Goutières syndrome (AGS) is an inflammatory disorder belonging to the recently characterized group of type I interferonopathies. The most consistently affected tissues in AGS are the central nervous system and skin, but various organ systems and tissues have been reported to be affected, pointing to the systemic nature of the disease. Here we describe a patient with AGS due to a homozygous p.Arg114His mutation in the TREX1 gene. The histologically proven inflammatory myopathy in our patient expands the range of clinical features of AGS. Histological signs of muscle biopsies in the proband, and in two other AGS patients described earlier, are similar to those seen in various autoimmune myositises and could be ascribed to inapproapriate IFN I activation. In view of signs of possible mitochondrial damage in AGS, we propose that mitochondrial DNA could be a trigger of autoimmune responses in AGS.

  5. Aborted Sudden Cardiac Death and a Mother with Suspected Metabolic Myopathy

    PubMed Central

    Finsterer, Josef; Stöllberger, Claudia; Keller, Hans

    2014-01-01

    Aborted sudden cardiac death (SCD) has not been reported as initial manifestation of cardiac involvement in metabolic myopathy (MM). A 20-year-old female with a previous history of three syncopes, hyperhidrosis, and recurrent tick bites experienced aborted SCD. Her mother presented with MM, and a history of pituitary adenoma, nephroptosis, arterial hypertension, depression, migraine, goiter, pancreatitis, osteoporosis, hyperhidrosis, multiple muscle ruptures, and hyperlipidemia. After a few days of disorientation and amnesia, the young female recovered completely. Clinical neurological examination was noticeable for partial ophthalmoparesis and mild hyperprolactinemia. She received an implantable cardioverter defibrillator, which did not discharge so far. Recurrent syncopes and aborted SCD may be the initial manifestation of MM with multiple organ involvement. The family history is important in cases with aborted SCD to guide the diagnostic work-up. Phenotypic heterogeneity between the family members may be an indicator of MM. PMID:25187745

  6. Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.

    PubMed

    Momma, Kazunari; Noguchi, Satoru; Malicdan, May Christine V; Hayashi, Yukiko K; Minami, Narihiro; Kamakura, Keiko; Nonaka, Ikuya; Nishino, Ichizo

    2012-01-01

    Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45-48 in DMD gene. All patients having rimmed vacuoles showed milder clinical features compared to those without rimmed vacuoles. Interestingly, the rimmed vacuoles in Becker muscular dystrophy muscles seem to represent autophagic vacuoles and are also associated with polyubiquitinated protein aggregates. These findings support the notion that rimmed vacuoles can appear in Becker muscular dystrophy, and may be related to the chronic changes in muscle pathology induced by certain mutations in the DMD gene.

  7. Biomarkers and Autoantibodies of Interstitial Lung Disease with Idiopathic Inflammatory Myopathies

    PubMed Central

    Yoshifuji, Hajime

    2015-01-01

    Various autoantibodies are seen in idiopathic inflammatory myopathies. Among myositis-specific antibodies, anti-aminoacyl-tRNA synthetase and anti-melanoma differentiation-associated protein 5 (MDA5) antibodies are associated with interstitial lung disease (ILD). Anti-MDA5 antibodies are associated with dermatomyositis (DM) or clinically amyopathic DM complicated with rapidly progressive ILD. In anti-MDA5-positive patients, a random ground-glass attenuation pattern is a characteristic finding of ILD in chest high-resolution computed tomography. Conversely, anti-aminoacyl-tRNA synthetase antibodies are not associated with rapidly progressive ILD but with chronic ILD. DM or clinically amyopathic DM patients with anti-MDA5, and characteristic high-resolution computed tomography findings are highly likely to have devastating ILD and need aggressive treatment. PMID:27081322

  8. Exertional myopathy in a grizzly bear (Ursus arctos) captured by leghold snare.

    PubMed

    Cattet, Marc; Stenhouse, Gordon; Bollinger, Trent

    2008-10-01

    We diagnosed exertional myopathy (EM) in a grizzly bear (Ursus arctos) that died approximately 10 days after capture by leghold snare in west-central Alberta, Canada, in June 2003. The diagnosis was based on history, post-capture movement data, gross necropsy, histopathology, and serum enzyme levels. We were unable to determine whether EM was the primary cause of death because autolysis precluded accurate evaluation of all tissues. Nevertheless, comparison of serum aspartate aminotransferase and creatine kinase concentrations and survival between the affected bear and other grizzly bears captured by leghold snare in the same research project suggests EM also occurred in other bears, but that it is not generally a cause of mortality. We propose, however, occurrence of nonfatal EM in grizzly bears after capture by leghold snare has potential implications for use of this capture method, including negative effects on wildlife welfare and research data.

  9. [Myopathy-lipomatosis associated with A8344G mitochondrial DNA mutation].

    PubMed

    Auré, K; Sternberg, D; Maisonobe, T; Herson, S; Jardel, C; Blondy, P; Lombès, A; Eymard, B; Laforêt, P

    2003-12-01

    We report the clinical features of two unrelated patients, a 51-year-old woman and a 54-year-old man, presenting proximal myopathy with lipomatosis. In both patients, muscle biopsies showed numerous ragged-red fibers. Molecular analysis were performed with denaturating gradient gel electrophoresis (DGGE) on muscle, blood, hair, buccal and urinary cells. The A8344G mutation of the tRNA-lysine gene of the mitochondrial DNA was detected in all tissues at high levels (more than 80 p cent). None of the patients had a contributive family history, and signs of central nervous system involvement were absent. These observations confirm that lipomatosis may be encountered in mitochondrial disorders and is tightly associated with the A8344G mutation.

  10. [How can we diagnose and better understand inflammatory myopathies? The usefulness of auto-antibodies].

    PubMed

    Sibilia, Jean; Chatelus, Emmanuel; Meyer, Alain; Gottenberg, Jacques-Eric; Sordet, Christelle; Goetz, Joëlle

    2010-10-01

    The inflammatory myopathies are a group of quite proteiform, systemic auto-immune diseases which include polymyositis, dermatomyositis and inclusion body myopathies. To facilitate the diagnosis, classification criteria (Bohan and Peter, 1975) have been proposed, based essentially on clinical criteria. In addition, over the past fifteen years, auto-antibodies characterizing certain forms of inflammatory myopathy have been identified. One distinguishes schematically: auto-antibodies specific for myositis and auto-antibodies sometimes associated with myositis. Concerning the myositis specific auto-antibodies (MSA), schematically there are a dozen specificities which are classed according to the cellular distribution of the auto-antigen. The most characteristic are certainly the auto-antibodies directed against cytoplasmic antigens: the anti-tRNA synthetases (anti-Jo-1 (PL-1), anti-PL-7, PL-12, EJ, OJ, JS, KS, ZO, YRS), anti-SRP (signal recognition particle), anti-Mas and anti-KJ, anti-Fer (eEF1), anti-Wa and anti-CADM p140. Other auto-antibodies are directed against nuclear auto-antigens: the anti-Mi-2, anti-PMS (PMS1, PMS2) and related antibodies (MLH1, DNA PKcs…), anti-56 kDa, anti-MJ (NXP-2), anti-SAE and anti-p155/p140 (TIF-1γ). Concerning the auto-antibodies sometimes associated with myositis (myositis associated auto-antibodies or MAA), they can also be observed in other auto-immune diseases. These auto-antibodies are directed against nuclear or nucleolar auto-antigens: the anti-PM-Scl, anti-Ku, anti-RNP (U1 RNP and U2 RNP, U4/U6 RNP and U5 RNP), anti-Ro 52 kDa and more rarely, anti-Ro 60 kDa and anti-La. The auto-antibodies related to myositis are biological tools which are of interest in two main ways. They have allowed us to sort out the nosology of these inflammatory myopathies, in particular by defining anti-tRNA synthetase syndrome. It now remains to determine how they might be employed to complement the classical clinico-biological diagnostic criteria

  11. A novel mitochondrial MTND5 frameshift mutation causing isolated complex I deficiency, renal failure and myopathy.

    PubMed

    Alston, Charlotte L; Morak, Monika; Reid, Christopher; Hargreaves, Iain P; Pope, Simon A S; Land, John M; Heales, Simon J; Horvath, Rita; Mundy, Helen; Taylor, Robert W

    2010-02-01

    Isolated complex I deficiency is the most commonly reported enzyme defect in paediatric mitochondrial disorders, and may arise due to mutations in nuclear-encoded structural or assembly genes, or the mitochondrial genome. We present the clinical, biochemical and molecular genetic data in a young girl whose clinical picture is dominated by chronic renal failure, myopathy and persistent lactic acidosis. An isolated complex I deficiency in muscle was identified due to a novel mutation (m.12425delA) in the MTND5 gene. This single nucleotide deletion is heteroplasmic and detectable in several tissues from the proband but not her mother, suggesting a de novo mutation event. The description of the first frameshift mutation in a mitochondrial complex I gene affirms mitochondrial DNA mutations as an important cause of isolated complex I deficiency in children and the importance of whole mitochondrial genome sequencing in the diagnostic work-up to elucidate the underlying molecular genetic abnormality and provide important genetic advice.

  12. Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.

    PubMed

    Ravenscroft, Gianina; Miyatake, Satoko; Lehtokari, Vilma-Lotta; Todd, Emily J; Vornanen, Pauliina; Yau, Kyle S; Hayashi, Yukiko K; Miyake, Noriko; Tsurusaki, Yoshinori; Doi, Hiroshi; Saitsu, Hirotomo; Osaka, Hitoshi; Yamashita, Sumimasa; Ohya, Takashi; Sakamoto, Yuko; Koshimizu, Eriko; Imamura, Shintaro; Yamashita, Michiaki; Ogata, Kazuhiro; Shiina, Masaaki; Bryson-Richardson, Robert J; Vaz, Raquel; Ceyhan, Ozge; Brownstein, Catherine A; Swanson, Lindsay C; Monnot, Sophie; Romero, Norma B; Amthor, Helge; Kresoje, Nina; Sivadorai, Padma; Kiraly-Borri, Cathy; Haliloglu, Goknur; Talim, Beril; Orhan, Diclehan; Kale, Gulsev; Charles, Adrian K; Fabian, Victoria A; Davis, Mark R; Lammens, Martin; Sewry, Caroline A; Manzur, Adnan; Muntoni, Francesco; Clarke, Nigel F; North, Kathryn N; Bertini, Enrico; Nevo, Yoram; Willichowski, Ekkhard; Silberg, Inger E; Topaloglu, Haluk; Beggs, Alan H; Allcock, Richard J N; Nishino, Ichizo; Wallgren-Pettersson, Carina; Matsumoto, Naomichi; Laing, Nigel G

    2013-07-11

    Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.

  13. Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy

    PubMed Central

    Ravenscroft, Gianina; Miyatake, Satoko; Lehtokari, Vilma-Lotta; Todd, Emily J.; Vornanen, Pauliina; Yau, Kyle S.; Hayashi, Yukiko K.; Miyake, Noriko; Tsurusaki, Yoshinori; Doi, Hiroshi; Saitsu, Hirotomo; Osaka, Hitoshi; Yamashita, Sumimasa; Ohya, Takashi; Sakamoto, Yuko; Koshimizu, Eriko; Imamura, Shintaro; Yamashita, Michiaki; Ogata, Kazuhiro; Shiina, Masaaki; Bryson-Richardson, Robert J.; Vaz, Raquel; Ceyhan, Ozge; Brownstein, Catherine A.; Swanson, Lindsay C.; Monnot, Sophie; Romero, Norma B.; Amthor, Helge; Kresoje, Nina; Sivadorai, Padma; Kiraly-Borri, Cathy; Haliloglu, Goknur; Talim, Beril; Orhan, Diclehan; Kale, Gulsev; Charles, Adrian K.; Fabian, Victoria A.; Davis, Mark R.; Lammens, Martin; Sewry, Caroline A.; Manzur, Adnan; Muntoni, Francesco; Clarke, Nigel F.; North, Kathryn N.; Bertini, Enrico; Nevo, Yoram; Willichowski, Ekkhard; Silberg, Inger E.; Topaloglu, Haluk; Beggs, Alan H.; Allcock, Richard J.N.; Nishino, Ichizo; Wallgren-Pettersson, Carina; Matsumoto, Naomichi; Laing, Nigel G.

    2013-01-01

    Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM. PMID:23746549

  14. Calcium homeostasis alterations in a mouse model of the Dynamin 2-related centronuclear myopathy

    PubMed Central

    Fraysse, Bodvaël; Guicheney, Pascale

    2016-01-01

    ABSTRACT Autosomal dominant centronuclear myopathy (CNM) is a rare congenital myopathy characterized by centrally located nuclei in muscle fibers. CNM results from mutations in the gene encoding dynamin 2 (DNM2), a large GTPase involved in endocytosis, intracellular membrane trafficking, and cytoskeleton regulation. We developed a knock-in mouse model expressing the most frequent DNM2-CNM mutation; i.e. the KI-Dnm2R465W model. Heterozygous (HTZ) KI-Dnm2 mice progressively develop muscle atrophy, impairment of contractile properties, histopathological abnormalities, and elevated cytosolic calcium concentration. Here, we aim at better characterizing the calcium homeostasis impairment in extensor digitorum longus (EDL) and soleus muscles from adult HTZ KI-Dnm2 mice. We demonstrate abnormal contractile properties and cytosolic Ca2+ concentration in EDL but not soleus muscles showing that calcium impairment is correlated with muscle weakness and might be a determinant factor of the spatial muscle involvement. In addition, the elevated cytosolic Ca2+ concentration in EDL muscles is associated with an increased sarcolemmal permeability to Ca2+ and releasable Ca2+ content from the sarcoplasmic reticulum. However, amplitude and kinetics characteristics of the calcium transient appear unchanged. This suggests that calcium defect is probably not a primary cause of decreased force generation by compromised sarcomere shortening but may be involved in long-term deleterious consequences on muscle physiology. Our results highlight the first pathomechanism which may explain the spatial muscle involvement occurring in DNM2-related CNM and open the way toward development of a therapeutic approach to normalize calcium content. PMID:27870637

  15. The Effect of Nutritional Status in the Pathogenesis of Critical Illness Myopathy (CIM).

    PubMed

    Ogilvie, Hannah; Larsson, Lars

    2014-05-30

    The muscle wasting and loss of specific force associated with Critical Illness Myopathy (CIM) is, at least in part, due to a preferential loss of the molecular motor protein myosin. This acquired myopathy is common in critically ill immobilized and mechanically ventilated intensive care patients (ICU). There is a growing understanding of the mechanisms underlying CIM, but the role of nutritional factors triggering this serious complication of modern intensive care remains unknown. This study aims at establishing the effect of nutritional status in the pathogenesis of CIM. An experimental ICU model was used where animals are mechanically ventilated, pharmacologically paralysed post-synaptically and extensively monitored for up to 14 days. Due to the complexity of the experimental model, the number of animals included is small. After exposure to this ICU condition, animals develop a phenotype similar to patients with CIM. The results from this study show that the preferential myosin loss, decline in specific force and muscle fiber atrophy did not differ between low vs. eucaloric animals. In both experimental groups, passive mechanical loading had a sparing effect of muscle weight independent on nutritional status. Thus, this study confirms the strong impact of the mechanical silencing associated with the ICU condition in triggering CIM, overriding any potential effects of caloric intake in triggering CIM. In addition, the positive effects of passive mechanical loading on muscle fiber size and force generating capacity was not affected by the nutritional status in this study. However, due to the small sample size these pilot results need to be validated in a larger cohort.

  16. Deletion of hexose-6-phosphate dehydrogenase activates the unfolded protein response pathway and induces skeletal myopathy.

    PubMed

    Lavery, Gareth G; Walker, Elizabeth A; Turan, Nil; Rogoff, Daniela; Ryder, Jeffery W; Shelton, John M; Richardson, James A; Falciani, Francesco; White, Perrin C; Stewart, Paul M; Parker, Keith L; McMillan, Daniel R

    2008-03-28

    Hexose-6-phosphate dehydrogenase (H6PD) is the initial component of a pentose phosphate pathway inside the endoplasmic reticulum (ER) that generates NADPH for ER enzymes. In liver H6PD is required for the 11-oxoreductase activity of 11beta-hydroxysteroid dehydrogenase type 1, which converts inactive 11-oxo-glucocorticoids to their active 11-hydroxyl counterparts; consequently, H6PD null mice are relatively insensitive to glucocorticoids, exhibiting fasting hypoglycemia, increased insulin sensitivity despite elevated circulating levels of corticosterone, and increased basal and insulin-stimulated glucose uptake in muscles normally enriched in type II (fast) fibers, which have increased glycogen content. Here, we show that H6PD null mice develop a severe skeletal myopathy characterized by switching of type II to type I (slow) fibers. Running wheel activity and electrically stimulated force generation in isolated skeletal muscle are both markedly reduced. Affected muscles have normal sarcomeric structure at the electron microscopy level but contain large intrafibrillar membranous vacuoles and abnormal triads indicative of defects in structure and function of the sarcoplasmic reticulum (SR). SR proteins involved in calcium metabolism, including the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), calreticulin, and calsequestrin, show dysregulated expression. Microarray analysis and real-time PCR demonstrate overexpression of genes encoding proteins in the unfolded protein response pathway. We propose that the absence of H6PD induces a progressive myopathy by altering the SR redox state, thereby impairing protein folding and activating the unfolded protein response pathway. These studies thus define a novel metabolic pathway that links ER stress to skeletal muscle integrity and function.

  17. Clinical course and treatment of anti-HMGCR antibody–associated necrotizing autoimmune myopathy

    PubMed Central

    Ramanathan, Sudarshini; Langguth, Daman; Hardy, Todd A.; Garg, Nidhi; Bundell, Chris; Rojana-Udomsart, Arada; Dale, Russell C.; Robertson, Thomas; Mammen, Andrew L.

    2015-01-01

    Objective: We examined a cohort of Australian patients with statin exposure who developed a necrotizing autoimmune myopathy (NAM) associated with a novel autoantibody against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and describe the clinical and therapeutic challenges of managing these patients and an optimal therapeutic strategy. Methods: Clinical, laboratory, EMG, and histopathologic results and response to immunomodulation are reported in 6 Australian patients with previous statin exposure and antibodies targeting HMGCR. Results: All patients presented with painless proximal weakness following statin therapy, which persisted after statin cessation. Serum creatine kinase (CK) levels ranged from 2,700 to 16,200 IU/L. EMG was consistent with a myopathic picture. Muscle biopsies revealed a pauci-immune necrotizing myopathy. Detailed graphical representation of the clinical course of these patients showed a close association with rising CK and an increase in clinical weakness signifying relapses, particularly upon weaning or ceasing steroids. All 6 patients were responsive to initial steroid therapy, with 5 relapsing upon attempts to wean steroids. Both CK and clinical strength improved with the reinstitution of immunotherapy, in particular steroids and IV immunoglobulin (IVIg). All patients required treatment with varying multiagent immunosuppressive regimens to achieve clinical remission, including prednisone (n = 6), IVIg (n = 5), plasmapheresis (n = 2), and additional therapy including methotrexate (n = 6), cyclophosphamide (n = 2), rituximab (n = 2), azathioprine (n = 1), and cyclosporine (n = 1). Conclusions: Recognition of HMGCR antibody–associated NAM is important because these patients are responsive to immunosuppression, and early multiagent therapy and a slow and cautious approach to withdrawing steroids may improve outcomes. PMID:25866831

  18. Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions

    PubMed Central

    Barrey, Eric; Mucher, Elodie; Jeansoule, Nicolas; Larcher, Thibaut; Guigand, Lydie; Herszberg, Bérénice; Chaffaux, Stéphane; Guérin, Gérard; Mata, Xavier; Benech, Philippe; Canale, Marielle; Alibert, Olivier; Maltere, Péguy; Gidrol, Xavier

    2009-01-01

    Background Several cases of myopathies have been observed in the horse Norman Cob breed. Muscle histology examinations revealed that some families suffer from a polysaccharide storage myopathy (PSSM). It is assumed that a gene expression signature related to PSSM should be observed at the transcriptional level because the glycogen storage disease could also be linked to other dysfunctions in gene regulation. Thus, the functional genomic approach could be conducted in order to provide new knowledge about the metabolic disorders related to PSSM. We propose exploring the PSSM muscle fiber metabolic disorders by measuring gene expression in relationship with the histological phenotype. Results Genotypying analysis of GYS1 mutation revealed 2 homozygous (AA) and 5 heterozygous (GA) PSSM horses. In the PSSM muscles, histological data revealed PAS positive amylase resistant abnormal polysaccharides, inflammation, necrosis, and lipomatosis and active regeneration of fibers. Ultrastructural evaluation revealed a decrease of mitochondrial number and structural disorders. Extensive accumulation of an abnormal polysaccharide displaced and partially replaced mitochondria and myofibrils. The severity of the disease was higher in the two homozygous PSSM horses. Gene expression analysis revealed 129 genes significantly modulated (p < 0.05). The following genes were up-regulated over 2 fold: IL18, CTSS, LUM, CD44, FN1, GST01. The most down-regulated genes were the following: mitochondrial tRNA, SLC2A2, PRKCα, VEGFα. Data mining analysis showed that protein synthesis, apoptosis, cellular movement, growth and proliferation were the main cellular functions significantly associated with the modulated genes (p < 0.05). Several up-regulated genes, especially IL18, revealed a severe muscular inflammation in PSSM muscles. The up-regulation of glycogen synthase kinase-3 (GSK3β) under its active form could be responsible for glycogen synthase (GYS1) inhibition and hypoxia-inducible factor

  19. Decreased skeletal muscle mitochondrial DNA in patients with statin-induced myopathy.

    PubMed

    Stringer, Henry A J; Sohi, Gurmeet K; Maguire, John A; Côté, Hélène C F

    2013-02-15

    Statins are widely used to treat hyperlipidemia and lower cardiovascular disease risk. While statins are generally well tolerated, some patients experience statin-induced myopathy (SIM). Statin treatment has been associated with mitochondrial dysfunction and mitochondrial DNA (mtDNA) depletion. In this retrospective study, skeletal muscle biopsies from patients diagnosed with SIM were studied. These were compared with biopsies from patients clinically assessed as having statin-unrelated myopathy but whose biopsy showed no or negligible pathology. For each biopsy sample, mtDNA was quantified relative to nuclear DNA (mtDNA content) by qPCR, mtDNA deletions were investigated by long-template PCR followed by gel densitometry, and mtDNA oxidative damage was quantified using a qPCR-based assay. For a subset of matched samples, mtDNA heteroplasmy and mutations were investigated by cloning/sequencing. Skeletal muscle mtDNA content was significantly lower in SIM patients (N=23, mean±SD, 2036±1146) than in comparators (N=24, 3220±1594), p=0.006. There was no difference in mtDNA deletion score or oxidative mtDNA damage between the two groups, and no evidence of increased mtDNA heteroplasmy or somatic mutations was detected. The significant difference in skeletal muscle mtDNA suggests that SIM or statin treatments are associated with depletion of skeletal muscle mtDNA or that patients with an underlying predisposition to SIM have lower mtDNA levels. If statins induce mtDNA depletion, this would likely reflect decreased mitochondria biogenesis and/or increased mitochondria autophagy. Further work is necessary to distinguish between the lower mtDNA as a predisposition to SIM or an effect of SIM or statin treatment.

  20. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment.

    PubMed

    Chatzizisis, Yiannis S; Koskinas, Konstantinos C; Misirli, Gesthimani; Vaklavas, Christos; Hatzitolios, Apostolos; Giannoglou, George D

    2010-03-01

    HMG-CoA reductase inhibitors ('statins') represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of statins, the patient population suitable for long-term statin treatment is expected to further expand. An overall positive safety and tolerability profile of statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical. The purpose of this review is to summarize the factors that increase the risk of statin-related myopathy. Data from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum and molecular mechanisms of statin-associated myopathy are discussed. We further analyse in detail the risk factors that precipitate or increase the likelihood of statin-related myopathy. Individual demographic features, genetic factors and co-morbidities that may account for the significant interindividual variability in the myopathic risk are presented. Physicochemical properties of statins have been implicated in the differential risk of currently marketed statins. Pharmacokinetic interactions with concomitant medications that interfere with statin metabolism and alter their systemic bioavailability are reviewed. Of particular clinical interest in cases of resistant dyslipidaemia is the interaction of statins with other classes of lipid-lowering agents; current data on the relative safety of available

  1. Mitochondrial Myopathy

    MedlinePlus

    ... diseases caused by damage to the mitochondria—small, energy-producing structures that serve as the cells' "power ... brain and muscles require a great deal of energy, and thus appear to be particularly damaged when ...

  2. Inflammatory Myopathies

    MedlinePlus

    ... symptoms that include proximal muscle weakness and inflammation, edema (an abnormal collection of fluids within body tissues ... A low-sodium diet may help to counter edema and cardiovascular complications. Many individuals with dermatomyositis may ...

  3. [Metabolic myopathies].

    PubMed

    Papazian, Óscar; Rivas-Chacón, Rafael

    2013-09-06

    Objetivo. Revisar las miopatias metabolicas manifestadas solamente por crisis de mialgias, calambres y rigidez musculares con dificultad para contraer los musculos afectados y el examen neurologico normal entre las crisis en niños y adolescentes. Desarrollo. Estas miopatias metabolicas se deben a deficits enzimaticos heredados en forma autosomica recesiva del metabolismo de los carbohidratos y lipidos. El resultado final es una reduccion del trifosfato de adenosina principalmente a traves de la fosforilacion oxidativa mitocondrial con disminucion de la energia disponible para la contraccion muscular. Las secundarias a trastornos del metabolismo de los carbohidratos se producen por ejercicios de alta intensidad y breves (< 10 min) y las secundarias a trastornos de los lipidos, por ejercicios de baja intensidad y prolongados (> 10 min). Los deficits enzimaticos en el primer grupo son de miofosforilasa (glucogenosis V), fosfofructocinasa muscular (glucogenosis VII), fosfoglicerato mutasa 1 (glucogenosis X) y beta enolasa (glucogenosis XIII), y en el segundo, de carnitina palmitol transferasa tipo II y de acil-CoA deshidrogenasa de cadena muy larga. Conclusiones. Las caracteristicas diferenciales de los pacientes en cada grupo y dentro de cada grupo permitiran el diagnostico clinico presuntivo inicial en la mayoria y solicitar solamente los examenes necesarios para corroborar el diagnostico. El tratamiento de las crisis consiste en hidratacion, glucosa y alcalinizacion de la orina. Las medidas preventivas son evitar el tipo de ejercicio que induce las crisis y el ayuno. No existe cura o tratamiento especifico. El pronostico es bueno con la excepcion de casos raros de insuficiencia renal aguda debido a la elevacion sanguinea de la mioglobina producto de una rabdomiolisis grave.

  4. Thyrotoxic Myopathy

    MedlinePlus

    ... Strategy Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ... Information Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ...

  5. Metabolic Myopathies

    MedlinePlus

    ... Fellows Evidence-Based Practice for Academic Researchers Responsible Data Management in Research Career Planning Treatments Patient and Caregiver ... Fellows Evidence-Based Practice for Academic Researchers Responsible Data Management in Research Career Planning Treatments Patient and Caregiver ...

  6. Mitochondrial Myopathy

    MedlinePlus

    ... mutations: Autosomal recessive means that it takes two mutant copies of a gene—one inherited from each ... disease. Autosomal dominant means it takes just one mutant copy of a gene—inherited from one parent— ...

  7. Mitochondrial Myopathies

    MedlinePlus

    ... of mitochondria. A single cell can contain both mutant mitochondria and normal mitochondria, and the balance between ... cells in her body) contain both normal and mutant mitochondria, and that some have just a few ...

  8. Fetal akinesia caused by a novel actin filament aggregate myopathy skeletal muscle actin gene (ACTA1) mutation.

    PubMed

    Stenzel, Werner; Prokop, Stefan; Kress, Wolfram; Huppmann, Stephanie; Loui, Andrea; Sarioglu, Nanette M E; Laing, Nigel G; Sparrow, John C; Heppner, Frank L; Goebel, Hans H

    2010-08-01

    We report a female newborn, diagnosed with fetal akinesia in utero, who died one hour after birth. Post-mortem muscle biopsy demonstrated actin-filament myopathy based on immunolabelling for sarcomeric actin, and large areas of filaments, without rod formation, ultrastructurally. Analysis of DNA extracted from the muscle disclosed a novel de novo heterozygous c.44G>A, GGC>GAC, 'p.Gly15Asp' mutation in the ACTA1 gene. Analysis of the location of the mutated amino-acid in the actin molecule suggests the mutation most likely causes abnormal nucleotide binding, and consequent pathological actin polymerization. This case emphasizes the association of fetal akinesia with actin-filament myopathy.

  9. Specific binding of Ulex europaeus agglutinin I lectin to sarcolemma of distal myopathy with rimmed vacuole formation.

    PubMed

    Yatabe, K; Kawai, M

    1997-08-01

    Ulex europaeus agglutinin I (UEA I) binding was studied in 83 patients with various neuromuscular disorders. UEA I labelled endomysial capillaries and endothelial cells of perimysial blood vessels in all the examined muscles. There was no UEA I binding to muscle fibres except for all (9) cases of distal myopathy with rimmed vacuole formation (DMRV), 1 of 5 cases of inclusion body myositis and 1 of 36 cases of inflammatory myopathies. The UEA I binding was completely eliminated by preincubation of UEA I solution with L-fucose. Using electron microscopy, the UEA I binding was localized to sarcolemma and intrasarco-plasmic membranous organelles other than mitochondria. Myosatellite cells were not labelled. These findings revealed the existence of fucosylated proteins or lipids in a subset of skeletal muscles suffering from DMRV. Biochemical identification of the fucosylated substance and further detailed study on subcellular localization of UEA I binding may yield important clues to the unknown pathogenesis of DMRV.

  10. A novel mutation 3090 G>A of the mitochondrial 16S ribosomal RNA associated with myopathy.

    PubMed

    Coulbault, L; Deslandes, B; Herlicoviez, D; Read, M H; Leporrier, N; Schaeffer, S; Mouadil, A; Lombès, A; Chapon, F; Jauzac, P; Allouche, S

    2007-10-26

    We describe a young woman who presented with a progressive myopathy since the age of 9. Spectrophotometric analysis of the respiratory chain in muscle tissue revealed combined and profound complex I, III, II+III, and IV deficiency ranging from 60% to 95% associated with morphological and histochemical abnormalities of the muscle. An exhaustive screening of mitochondrial transfer and ribosomal RNAs showed a novel G>A substitution at nucleotide position 3090 which was detected only in urine sediment and muscle of the patient and was not found in her mother's blood cells and urine sample. We suggest that this novel de novo mutation in the 16S ribosomal RNA, a nucleotide which is highly conserved in different species, would impair mitochondrial protein synthesis and would cause a severe myopathy.

  11. “Target” and “Sandwich” Signs in Thigh Muscles have High Diagnostic Values for Collagen VI-related Myopathies

    PubMed Central

    Fu, Jun; Zheng, Yi-Ming; Jin, Su-Qin; Yi, Jun-Fei; Liu, Xiu-Juan; Lyn, He; Wang, Zhao-Xia; Zhang, Wei; Xiao, Jiang-Xi; Yuan, Yun

    2016-01-01

    Background: Collagen VI-related myopathies are autosomal dominant and recessive hereditary myopathies, mainly including Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). Muscle magnetic resonance imaging (MRI) has been widely used to diagnosis muscular disorders. The purpose of this study was to evaluate the diagnostic value of thigh muscles MRI for collagen VI-related myopathies. Methods: Eleven patients with collagen VI gene mutation-related myopathies were enrolled in this study. MRI of the thigh muscles was performed in all patients with collagen VI gene mutation-related myopathies and in 361 patients with other neuromuscular disorders (disease controls). T1-weighted images were used to assess fatty infiltration of the muscles using a modified Mercuri's scale. We assessed the sensitivity and specificity of the MRI features of collagen VI-related myopathies. The relationship between fatty infiltration of muscles and specific collagen VI gene mutations was also investigated. Results: Eleven patients with collagen VI gene mutation-related myopathies included six UCMD patients and five BM patients. There was no significant difference between UCMD and BM patients in the fatty infiltration of each thigh muscle except sartorius (P = 0.033); therefore, we combined the UCMD and BM data. Mean fatty infiltration scores were 3.1 and 3.0 in adductor magnus and gluteus maximus, while the scores were 1.3, 1.3, and 1.5 in gracilis, adductor longus, and sartorius, respectively. A “target” sign in rectus femoris (RF) was present in seven cases, and a “sandwich” sign in vastus lateralis (VL) was present in ten cases. The “target” and “sandwich” signs had sensitivities of 63.6% and 90.9% and specificities of 97.3% and 96.9% for the diagnosis of collagen VI-related myopathies, respectively. Fatty infiltration scores were 2.0–3.0 in seven patients with mutations in the triple-helical domain, and 1.0–1.5 in three of four patients with

  12. Differential effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on the development of myopathy in young rats.

    PubMed

    Reijneveld, J C; Koot, R W; Bredman, J J; Joles, J A; Bär, P R

    1996-06-01

    HMG-CoA reductase inhibitors (statins), cholesterol-lowering drugs that have not been approved for use in children and adolescents, may cause myopathy as a side effect. We compared the effects of three statins (simva-, prava- and lovastatin) in young rats to determine whether skeletal muscle of young animals is more susceptible than that of adults. We also evaluated whether the type of statin (lipophilic versus hydrophilic) determines the degree of muscle damage. Administration via chow of simvastatin (15 mg/kg of body weight/d) and lovastatin (43-55 mg/kg of body weight/d), both lipophilic, caused stunted growth, high creatine kinase (CK) activity in plasma, and severe myopathy. Statin doses that caused damage were much lower for young rats than for adults. Pravastatin (8-55 mg/kg of body weight/d), a hydrophilic drug, caused none of these symptoms. Histologic analysis of hind paw muscles of simvastatin-and lovastatin-treated rats showed abundant signs of damage (hypercontraction, fiber necrosis) in the extensor digitorum longus, correlating with the symptoms noted above. No cellular infiltrates were seen at the onset, pointing to a noninflammatory myopathy. Pravastatin-treated rats never showed signs of myopathy. Impaired DNA synthesis may explain why muscle toxicity is seen at lower doses in young, rapidly developing rats than in adult animals. The differences in muscle damage between the statins may be attributed to differences in lipophilicity and thus in tissue selectivity. Our results can be important when considering drug therapy in young patients with inherited lipoprotein disorders.

  13. Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.

    PubMed

    Ajroud-Driss, Senda; Fecto, Faisal; Ajroud, Kaouther; Lalani, Irfan; Calvo, Sarah E; Mootha, Vamsi K; Deng, Han-Xiang; Siddique, Nailah; Tahmoush, Albert J; Heiman-Patterson, Terry D; Siddique, Teepu

    2015-01-01

    Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5% of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.

  14. Recessive C10orf2 mutations in a family with infantile-onset spinocerebellar ataxia, sensorimotor polyneuropathy, and myopathy.

    PubMed

    Park, Mi-Hyun; Woo, Hae-Mi; Hong, Young Bin; Park, Ji Hoon; Yoon, Bo Ram; Park, Jin-Mo; Yoo, Jeong Hyun; Koo, Heasoo; Chae, Jong-Hee; Chung, Ki Wha; Choi, Byung-Ok; Koo, Soo Kyung

    2014-08-01

    Recessive mutations in chromosome 10 open reading frame 2 (C10orf2) are relevant in infantile-onset spinocerebellar ataxia (IOSCA). In this study, we investigated the causative mutation in a Korean family with combined phenotypes of IOSCA, sensorimotor polyneuropathy, and myopathy. We investigated recessive mutations in a Korean family with two individuals affected by IOSCA. Causative mutations were investigated using whole exome sequencing. Electrophysiological analyses and muscle and nerve biopsies were performed, along with magnetic resonance imaging (MRI) of the brain and lower extremities. Compound heterozygous mutations c.1460C>T and c.1485-1G>A in C10orf2 were identified as causative of IOSCA. Skeletal muscle showed mitochondrial DNA (mtDNA) deletions. Both patients showed a period of normal development until 12-15 months, followed by ataxia, athetosis, hearing loss, and intellectual disability. Electrophysiological findings indicated motor and sensory polyneuropathies. Muscle biopsy revealed variations in the size and shape of myofibers with scattered, small, and angulated degenerating myofibers containing abnormal mitochondria; these observations are consistent with myopathy and may be the result of mtDNA deletions. Sural nerve biopsy revealed an axonal neuropathy. High-signal-intensity lesions in the middle cerebellar peduncles were correlated with clinical severity, and MRI of the lower legs was compatible with the hypothesis of length-dependent axonal degeneration. We identified novel compound heterozygous mutations of the C10orf2 gene as the cause of IOSCA with sensorimotor polyneuropathy and myopathy. Signs of motor neuropathy and myopathy were discovered for the first time in IOSCA patients with C10orf2 mutations. These results suggest that the clinical spectrum of IOSCA caused by C10orf2 mutations may be more variable than previously reported.

  15. A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.

    PubMed

    Fanganiello, R D; Kimonis, V E; Côrte, C C; Nitrini, R; Passos-Bueno, M R

    2011-04-01

    Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.

  16. A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene.

    PubMed

    Løseth, Sissel; Voermans, Nicol C; Torbergsen, Torberg; Lillis, Sue; Jonsrud, Christoffer; Lindal, Sigurd; Kamsteeg, Erik-Jan; Lammens, Martin; Broman, Marcus; Dekomien, Gabriele; Maddison, Paul; Muntoni, Francesco; Sewry, Caroline; Radunovic, Aleksandar; de Visser, Marianne; Straub, Volker; van Engelen, Baziel; Jungbluth, Heinz

    2013-06-01

    Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of inherited neuromuscular disorders and have been associated with a wide clinical spectrum, ranging from various congenital myopathies to the malignant hyperthermia susceptibility (MHS) trait without any associated weakness. RYR1-related myopathies are usually of early-childhood onset. Here we present 11 patients from 8 families with a late-onset axial myopathy associated with RYR1 variants. Patients presented between the third and seventh decade of life to neuromuscular centres in Norway, the Netherlands and the United Kingdom with predominant axial muscle involvement, comprising variable degrees of lumbar hyperlordosis, scapular winging and/or camptocormia. Marked myalgia was commonly associated. Serum creatine kinase levels were normal or moderately elevated. Muscle imaging showed consistent involvement of the lower paravertebral muscles and the posterior thigh. Muscle biopsy findings were often discrete, featuring variability in fibre size, increased internal nuclei and unevenness of oxidative enzyme staining, but only rarely overt cores. RYR1 sequencing revealed heterozygous missense variants, either previously associated with the MHS trait or localizing to known MHS mutational hotspots. These findings indicate that MHS-related RYR1 mutations may present later in life with prominent axial weakness but not always typical histopathological features. We propose a combined effect of RyR1 dysfunction, aging and particular vulnerability of axial muscle groups as a possible pathogenic mechanism. RYR1 is a candidate for cases with "idiopathic" camptocormia or bent spine syndrome (BSS).

  17. A de novo mutation of the MYH7 gene in a large Chinese family with autosomal dominant myopathy

    PubMed Central

    Oda, Tetsuya; Xiong, Hui; Kobayashi, Kazuhiro; Wang, Shuo; Satake, Wataru; Jiao, Hui; Yang, Yanling; Cha, Pei-Chieng; Hayashi, Yukiko K; Nishino, Ichizo; Suzuki, Yutaka; Sugano, Sumio; Wu, Xiru; Toda, Tatsushi

    2015-01-01

    Laing distal myopathy (LDM) is an autosomal dominant myopathy that is caused by mutations in the slow/beta cardiac myosin heavy-chain (MYH7) gene. It has been recently reported that LDM presents with a wide range of clinical manifestations. We herein report a large Chinese family with autosomal dominant myopathy. The affected individuals in the family presented with foot drop in early childhood, along with progressive distal and proximal limb weakness. Their characteristic symptoms include scapular winging and scoliosis in the early disease phase and impairment of ambulation in the advanced phase. Although limb-girdle muscle dystrophy (LGMD) was suspected initially, a definite diagnosis could not be reached. As such, we performed linkage analysis and detected four linkage regions, namely 1q23.2-24.1, 14q11.2-12, 15q26.2-26.3 and 17q24.3. Through subsequent whole exome sequencing, we found a de novo p.K1617del causative mutation in the MYH7 gene and diagnosed the disease as LDM. This is the first LDM case in China. Our patients have severe clinical manifestations that mimic LGMD in comparison with the patients with the same mutation reported elsewhere. PMID:27081534

  18. Critical Evaluation of the Use of Cell Cultures for Inclusion in Clinical Trials of Patients Affected by Collagen VI Myopathies

    PubMed Central

    Sabatelli, P; Palma, E; Angelin, A; Squarzoni, S; Urciuolo, A; Pellegrini, C; Tiepolo, T; Bonaldo, P; Gualandi, F; Merlini, L; Bernardi, P; Maraldi, NM

    2012-01-01

    Collagen VI myopathies (Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM), and myosclerosis myopathy) share a common pathogenesis, that is, mitochondrial dysfunction due to deregulation of the permeability transition pore (PTP). This effect was first identified in the Col6a1−/− mouse model and then in muscle cell cultures from UCMD and BM patients; the normalizing effect of cyclosporin A (CsA) confirmed the pathogenic role of PTP opening. In order to determine whether mitochondrial performance can be used as a criterion for inclusion in clinical trials and as an outcome measure of the patient response to therapy, it is mandatory to establish whether mitochondrial dysfunction is conserved in primary cell cultures from UCMD and BM patients. In this study we report evidence that mitochondrial dysfunction and the consequent increase of apoptotic rate can be detected not only, as previously reported, in muscle, but also in fibroblast cell cultures established from muscle biopsies of collagen VI-related myopathic patients. However, the mitochondrial phenotype is no longer maintained after nine passages in culture. These data demonstrate that the dire consequences of mitochondrial dysfunction are not limited to myogenic cells, and that this parameter can be used as a suitable diagnostic criterion, provided that the cell culture conditions are carefully established. J. Cell. Physiol. 227: 2927–2935, 2012. © 2011 Wiley Periodicals, Inc. PMID:21953374

  19. Critical evaluation of the use of cell cultures for inclusion in clinical trials of patients affected by collagen VI myopathies.

    PubMed

    Sabatelli, P; Palma, E; Angelin, A; Squarzoni, S; Urciuolo, A; Pellegrini, C; Tiepolo, T; Bonaldo, P; Gualandi, F; Merlini, L; Bernardi, P; Maraldi, N M

    2012-07-01

    Collagen VI myopathies (Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM), and myosclerosis myopathy) share a common pathogenesis, that is, mitochondrial dysfunction due to deregulation of the permeability transition pore (PTP). This effect was first identified in the Col6a1(-/-) mouse model and then in muscle cell cultures from UCMD and BM patients; the normalizing effect of cyclosporin A (CsA) confirmed the pathogenic role of PTP opening. In order to determine whether mitochondrial performance can be used as a criterion for inclusion in clinical trials and as an outcome measure of the patient response to therapy, it is mandatory to establish whether mitochondrial dysfunction is conserved in primary cell cultures from UCMD and BM patients. In this study we report evidence that mitochondrial dysfunction and the consequent increase of apoptotic rate can be detected not only, as previously reported, in muscle, but also in fibroblast cell cultures established from muscle biopsies of collagen VI-related myopathic patients. However, the mitochondrial phenotype is no longer maintained after nine passages in culture. These data demonstrate that the dire consequences of mitochondrial dysfunction are not limited to myogenic cells, and that this parameter can be used as a suitable diagnostic criterion, provided that the cell culture conditions are carefully established.

  20. Coxsackievirus B1-induced chronic inflammatory myopathy: differences in induction of autoantibodies to muscle and nuclear antigens by cloned myopathic and amyopathic viruses.

    PubMed

    Tam, Patricia E; Fontana, Donna R; Messner, Ronald P

    2003-09-01

    Infection of susceptible strains of mice with the myopathic Tucson strain of coxsackievirus B1 (CVB1(T)) leads to the development of chronic inflammatory myopathy (CIM). The underlying mechanism of CIM appears to be immunopathic, but it is not known whether autoimmunity is involved. The objectives of this study were to determine whether autoantibodies are produced and whether they correlate with the pathology of CIM. Mice were infected with either a myopathic (MP1.23 or MP1.24) or an amyopathic (AMP2.17) CVB1(T) cloned virus. The two myopathic (MP) viruses cause CIM, whereas the amyopathic (AMP) virus, derived from a variant of the same parent, causes the same acute disease but does not cause CIM. Antimuscle IgG was found in 51% of MP1.23-infected and 58% of MP1.24-infected mice but in just 18% of mice infected with AMP2.17 and in 10% of controls (MP vs AMP: chi(2), P < or =.006). Several staining patterns were observed, indicating that autoantibodies of multiple specificities were produced. Antinuclear antibodies were found in 57% of MP1.23-infected and 27% of MP1.24-infected mice but were rare in mice infected with AMP2.17 (0%) or in controls (4%) (MP vs AMP: chi(2), P < or =.01). Antiviral-antibody titers were higher with MP virus than with AMP virus (ANOVA, P <.001). A trend toward an association between antiviral antibody or autoantibodies and the presence or severity of clinical measures of CIM was noted but was not significant. These data suggest that the autoantibodies do not mediate muscle disease but are an independent manifestation of an immunopathic response induced by infection with MP but not AMP CVB1(T).

  1. Statin Intolerance Because of Myalgia, Myositis, Myopathy, or Myonecrosis Can in Most Cases be Safely Resolved by Vitamin D Supplementation

    PubMed Central

    Khayznikov, Maksim; Hemachrandra, Kallish; Pandit, Ramesh; Kumar, Ashwin; Wang, Ping; Glueck, Charles J

    2015-01-01

    Background: Low serum vitamin D can cause myalgia, myositis, myopathy, and myonecrosis. Statin-induced myalgia is a major and common cause of statin intolerance. Low serum vitamin D and statins, additively or synergistically, cause myalgia, myositis, myopathy, and/or myonecrosis. Statin-induced myalgia in vitamin D deficient patients can often be resolved by vitamin D supplementation, normalizing serum vitamin D levels. Aims: In 74 men and 72 women (age 59 ± 14 years) intolerant to ≥2 statins because of myalgia, myositis, myopathy, or myonecrosis and found to have low (<32 ng/mL) serum vitamin D, we prospectively assessed whether vitamin D supplementation (vitamin D2: 50,000-100,000 units/week) to normalize serum vitamin D would allow successful rechallenge therapy with statins. Materials and Methods: Follow-up evaluation on vitamin D supplementation was done on 134 patients at 6 months (median 5.3), 103 patients at 12 months (median 12.2), and 82 patients at 24 months (median 24). Results: Median entry serum vitamin D (22 ng/mL, 23 ng/mL, and 23 ng/mL) rose at 6 months, 12 months, and 24 months follow-up to 53 ng/mL, 53 ng/mL, and 55 ng/mL, respectively, (P < .0001 for all) on vitamin D therapy (50,000-100,000 units/week). On vitamin D supplementation, serum vitamin D normalized at 6 months, 12 months, and 24 months follow-up in 90%, 86%, and 91% of the patients, respectively. On rechallenge with statins while on vitamin D supplementation, median low-density lipoprotein cholesterol (LDLC) fell from the study entry (167 mg/dL, 164 mg/dL, and 158 mg/dL) to 90 mg/dL, 91 mg/dL, and 84 mg/dL, respectively, (P < .0001 for all). On follow-up at median 6 months, 12 months, and 24 months on statins and vitamin D, 88%, 91%, and 95% of the previously statin-intolerant patients, respectively, were free of myalgia, myositis, myopathy, and/or myonecrosis. Conclusions: Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis associated with low serum vitamin

  2. Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype

    PubMed Central

    2014-01-01

    Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype. Three groups were identified according to clinical severity. Group 1 (n = 5) comprises severe/lethal NM and biopsy in the first days of life. Group 2 (n = 4) includes intermediate NM and biopsy in infancy. Group 3 (n = 5) comprises typical/mild NM and biopsy in childhood or early adult life. Biopsies underwent histoenzymological, immunohistochemical and ultrastructural analysis. Fibre type distribution patterns, rod characteristics, distribution and localization were investigated. Contractile performance was studied in muscle fibre preparations isolated from seven muscle biopsies from each of the three groups. G1 showed significant myofibrillar dissociation and smallness with scattered globular rods in one third of fibres; there was no type 1 predominance. G2 presented milder sarcomeric dissociation, dispersed or clustered nemaline bodies, and type 1 predominance/uniformity. In contrast, G3 had well-delimited clusters of subsarcolemmal elongated rods and type 1 uniformity without sarcomeric alterations. In accordance with the clinical and morphological data, functional studies revealed markedly low forces in muscle bundles from G1 and a better contractile performance in muscle bundles from biopsies of patients from G2, and G3. In conclusion NEB-mutated NM patients present a wide spectrum of morphological features. It is difficult to establish firm genotype phenotype correlation. Interestingly, there was a correlation

  3. Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin.

    PubMed

    Allenbach, Yves; Drouot, Laurent; Rigolet, Aude; Charuel, Jean Luc; Jouen, Fabienne; Romero, Norma B; Maisonobe, Thierry; Dubourg, Odile; Behin, Anthony; Laforet, Pascal; Stojkovic, Tania; Eymard, Bruno; Costedoat-Chalumeau, Nathalie; Campana-Salort, Emmanuelle; Tournadre, Anne; Musset, Lucile; Bader-Meunier, Brigitte; Kone-Paut, Isabelle; Sibilia, Jean; Servais, Laurent; Fain, Olivier; Larroche, Claire; Diot, Elisabeth; Terrier, Benjamin; De Paz, Raphael; Dossier, Antoine; Menard, Dominique; Morati, Chafika; Roux, Marielle; Ferrer, Xavier; Martinet, Jeremie; Besnard, Sophie; Bellance, Remi; Cacoub, Patrice; Arnaud, Laurent; Grosbois, Bernard; Herson, Serge; Boyer, Olivier; Benveniste, Olivier

    2014-05-01

    Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 ± 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 ≤3 in 75.5%). Subacute onset (<6 mo) was noted for most of them (64.4%). Nevertheless, 3 patients (6.6%) had a slowly progressive course over more than 10 years. Except for weight loss (20%), no extramuscular sign was observed. The mean CK level was high (6941 ± 8802 IU/L) and correlated with muscle strength evaluated by manual muscle testing (r = -0.37, p = 0.03). Similarly, anti-HMGCR aAb titers were correlated with muscular strength (r = -0.31; p = 0.03) and CK level (r = 0.45; p = 0.01). Mean duration of treatment was 34.1 ± 40.8 months, and by the end of the study no patient had been able to stop treatment.This study confirms the observation and description of anti-HMGCR aAb associated with NAM. The majority of patients were statin naive and needed prolonged treatments. Some patients had a dystrophic-like presentation. Anti-HMGR aAb titers correlated with CK levels and muscle strength, suggesting their pathogenic role.

  4. Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors.

    PubMed

    Zulian, Alessandra; Tagliavini, Francesca; Rizzo, Erika; Pellegrini, Camilla; Sardone, Francesca; Zini, Nicoletta; Maraldi, Nadir Mario; Santi, Spartaco; Faldini, Cesare; Merlini, Luciano; Petronilli, Valeria; Bernardi, Paolo; Sabatelli, Patrizia

    2014-01-01

    Ullrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI (ColVI) genes, which encode an extracellular matrix protein; yet, mitochondria play a major role in disease pathogenesis through a short circuit caused by inappropriate opening of the permeability transition pore, a high-conductance channel, which causes a shortage in ATP production. We find that melanocytes do not produce ColVI yet they bind it at the cell surface, suggesting that this protein may play a trophic role and that its absence may cause lesions similar to those seen in skeletal muscle. We show that mitochondria in melanocytes of Ullrich congenital muscular dystrophy and Bethlem myopathy patients display increased size, reduced matrix density, and disrupted cristae, findings that suggest a functional impairment. In keeping with this hypothesis, mitochondria (i) underwent anomalous depolarization after inhibition of the F-ATP synthase with oligomycin, and (ii) displayed decreased respiratory reserve capacity. The non-immunosuppressive cyclophilin inhibitor NIM811 prevented mitochondrial depolarization in response to oligomycin in melanocytes from both Ullrich congenital muscular dystrophy and Bethlem myopathy patients, and partially restored the respiratory reserve of melanocytes from one Bethlem myopathy patient. These results match our recent findings on melanocytes from patients affected by Duchenne muscular dystrophy (Pellegrini et al., 2013), and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in ColVI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia.

  5. Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy.

    PubMed

    Min, Kisuk; Kwon, Oh-Sung; Smuder, Ashley J; Wiggs, Michael P; Sollanek, Kurt J; Christou, Demetra D; Yoo, Jeung-Ki; Hwang, Moon-Hyon; Szeto, Hazel H; Kavazis, Andreas N; Powers, Scott K

    2015-04-15

    Although doxorubicin (DOX) is a highly effective anti-tumour agent used to treat a variety of cancers, DOX administration is associated with significant side effects, including myopathy of both cardiac and skeletal muscles. The mechanisms responsible for DOX-mediated myopathy remain a topic of debate. We tested the hypothesis that both increased mitochondrial reactive oxygen species (ROS) emission and activation of the cysteine protease calpain are required for DOX-induced myopathy in rat cardiac and skeletal muscle. Cause and effect was determined by administering a novel mitochondrial-targeted anti-oxidant to prevent DOX-induced increases in mitochondrial ROS emission, whereas a highly-selective pharmacological inhibitor was exploited to inhibit calpain activity. Our findings reveal that mitochondria are a major site of DOX-mediated ROS production in both cardiac and skeletal muscle fibres and the prevention of DOX-induced increases in mitochondrial ROS emission protects against fibre atrophy and contractile dysfunction in both cardiac and skeletal muscles. Furthermore, our results indicate that DOX-induced increases in mitochondrial ROS emission are required to activate calpain in heart and skeletal muscles and, importantly, calpain activation is a major contributor to DOX-induced myopathy. Taken together, these findings show that increased mitochondrial ROS production and calpain activation are significant contributors to the development of DOX-induced myopathy in both cardiac and skeletal muscle fibres.

  6. Gait Characteristics in a Canine Model of X-linked Myotubular Myopathy

    PubMed Central

    Goddard, Melissa A.; Burlingame, Emily; Beggs, Alan H.; Buj-Bello, Anna; Childers, Martin K.; Marsh, Anthony P.; Kelly, Valerie E.

    2014-01-01

    X-linked myotubular myopathy (XLMTM) is a fatal pediatric disease where affected boys display profound weakness of the skeletal muscles. Possible therapies are under development but robust outcome measures in animal models are required for effective translation to human patients. We established a naturally-occuring canine model, where XLMTM dogs display clinical symptoms similar to those observed in humans. The aim of this study was to determine potential endpoints for the assessment of future treatments in this model. Video-based gait analysis was selected, as it is a well-established method of assessing limb function in neuromuscular disease and measures have been correlated to patient quality of life. XLMTM dogs (N=3) and their true littermate wild type controls (N=3) were assessed at 4–5 time points, beginning at 10 weeks and continuing through 17 weeks. Motion capture and an instrumented carpet were used separately to evaluate spatiotemporal and kinematic changes over time. XLMTM dogs walk more slowly and with shorter stride lengths than wild type dogs, and these differences became greater over time. However, there was no clear difference in angular measures between affected and unaffected dogs. These data demonstrate that spatiotemporal parameters capture functional changes in gait in an XLMTM canine model and support their utility in future therapeutic trials. PMID:25281397

  7. Dynamin GTPase Regulation is Altered by PH Domain Mutations Found in Centronuclear Myopathy Patients

    SciTech Connect

    Kenniston, J.; Lemmon, M

    2010-01-01

    The large GTPase dynamin has an important membrane scission function in receptor-mediated endocytosis and other cellular processes. Self-assembly on phosphoinositide-containing membranes stimulates dynamin GTPase activity, which is crucial for its function. Although the pleckstrin-homology (PH) domain is known to mediate phosphoinositide binding by dynamin, it remains unclear how this promotes activation. Here, we describe studies of dynamin PH domain mutations found in centronuclear myopathy (CNM) that increase dynamin's GTPase activity without altering phosphoinositide binding. CNM mutations in the PH domain C-terminal {alpha}-helix appear to cause conformational changes in dynamin that alter control of the GTP hydrolysis cycle. These mutations either 'sensitize' dynamin to lipid stimulation or elevate basal GTPase rates by promoting self-assembly and thus rendering dynamin no longer lipid responsive. We also describe a low-resolution structure of dimeric dynamin from small-angle X-ray scattering that reveals conformational changes induced by CNM mutations, and defines requirements for domain rearrangement upon dynamin self-assembly at membrane surfaces. Our data suggest that changes in the PH domain may couple lipid binding to dynamin GTPase activation at sites of vesicle invagination.

  8. Neo-epitope Peptides as Biomarkers of Disease Progression for Muscular Dystrophies and Other Myopathies

    PubMed Central

    Arvanitidis, A.; Henriksen, K.; Karsdal, M.A.; Nedergaard, A.

    2016-01-01

    For several decades, serological biomarkers of neuromuscular diseases as dystrophies, myopathies and myositis have been limited to routine clinical biochemistry panels. Gauging the pathological progression is a prerequisite for proper treatment and therefore identifying accessible, easy to monitor biomarkers that can predict the disease progression would be an important advancement. Most muscle diseases involve accelerated muscle fiber degradation, inflammation, fatty tissue substitution and/or fibrosis. All these pathological traits have been shown to give rise to serological peptide biomarkers in other tissues, underlining the potential application of existing biomarkers of such traits in muscle disorders. A significant quantity of tissue is involved in these pathological mechanisms alongside with qualitative changes in protein turnover in myofibrillar, extra-cellular matrix and immunological cell protein fractions accompanied by alterations in body fluids. We propose that protein and peptides can leak out of the afflicted muscles and can be of use in diagnosis, prediction of pathology trajectory and treatment efficacy. Proteolytic cleavage systems are especially modulated during a range of muscle pathologies, thereby giving rise to peptides that are differentially released during disease manifestation. Therefore, we believe that pathology-specific post-translational modifications like cleavages can give rise to neoepitope peptides that may represent a promising class of peptides for discovery of biomarkers pertaining to neuromuscular diseases. PMID:27854226

  9. Mechanisms of hyperhomocysteinemia induced skeletal muscle myopathy after ischemia in the CBS-/+ mouse model.

    PubMed

    Veeranki, Sudhakar; Tyagi, Suresh C

    2015-01-06

    Although hyperhomocysteinemia (HHcy) elicits lower than normal body weights and skeletal muscle weakness, the mechanisms remain unclear. Despite the fact that HHcy-mediated enhancement in ROS and consequent damage to regulators of different cellular processes is relatively well established in other organs, the nature of such events is unknown in skeletal muscles. Previously, we reported that HHcy attenuation of PGC-1α and HIF-1α levels enhanced the likelihood of muscle atrophy and declined function after ischemia. In the current study, we examined muscle levels of homocysteine (Hcy) metabolizing enzymes, anti-oxidant capacity and focused on protein modifications that might compromise PGC-1α function during ischemic angiogenesis. Although skeletal muscles express the key enzyme (MTHFR) that participates in re-methylation of Hcy into methionine, lack of trans-sulfuration enzymes (CBS and CSE) make skeletal muscles more susceptible to the HHcy-induced myopathy. Our study indicates that elevated Hcy levels in the CBS-/+ mouse skeletal muscles caused diminished anti-oxidant capacity and contributed to enhanced total protein as well as PGC-1α specific nitrotyrosylation after ischemia. Furthermore, in the presence of NO donor SNP, either homocysteine (Hcy) or its cyclized version, Hcy thiolactone, not only increased PGC-1α specific protein nitrotyrosylation but also reduced its association with PPARγ in C2C12 cells. Altogether these results suggest that HHcy exerts its myopathic effects via reduction of the PGC-1/PPARγ axis after ischemia.

  10. DNM2 mutations in a cohort of sporadic patients with centronuclear myopathy

    PubMed Central

    Abath, Osorio; Martins, Cristiane de Araújo; Carvalho, Mary; Chadi, Gerson; Seitz, Katia Werneck; Oliveira, Acary Souza Bulle; Reed, Umbertina Conti; Laporte, Jocelyn; Zanoteli, Edmar

    2015-01-01

    Centronuclear myopathy (CNM) is a rare congenital muscle disease characterized by fibers with prominent centralized nuclei in muscle biopsies. The disease is clinically heterogeneous, ranging from severe neonatal hypotonic phenotypes to adult-onset mild muscle weakness, and can have multiple modes of inheritance in association with various genes, including MTM1, DNM2, BIN1 and RYR1. Here we analyzed 18 sporadic patients with clinical and histological diagnosis of CNM and sequenced the DNM2 gene, which codes for the dynamin 2 protein. We found DNM2 missense mutations in two patients, both in exon 8, one known (p.E368K) and one novel (p.F372C), which is found in a position of presumed pathogenicity and appeared de novo. The patients had similar phenotypes characterized by neonatal signs followed by improvement and late childhood reemergence of slowly progressive generalized muscle weakness, elongated face with ptosis and ophthalmoparesis, and histology showing fibers with radiating sarcoplasmic strands (RSS). These patients were the only ones in the series to present this histological marker, which together with previous reports in the literature suggest that, when RSS are present, direct sequencing of DNM2 mutation hot spot regions should be the first step in the molecular diagnosis of CNM, even in sporadic cases. PMID:26273216

  11. Impaired Insulin/IGF Signaling in Experimental Alcohol-Related Myopathy

    PubMed Central

    Nguyen, Van Anh; Le, Tran; Tong, Ming; Silbermann, Elizabeth; Gundogan, Fusun; de la Monte, Suzanne M.

    2012-01-01

    Alcohol-related myopathy (Alc-M) is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8) or 35.5% (N = 13) ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3β. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration. PMID:23016132

  12. Developments in the Classification and Treatment of the Juvenile Idiopathic Inflammatory Myopathies

    PubMed Central

    Rider, Lisa G.; Katz, James D.; Jones, Olcay Y.

    2013-01-01

    The juvenile idiopathic inflammatory myopathies (JIIM) are rare, heterogeneous autoimmune diseases that share chronic muscle inflammation and weakness. JIIM broadly includes three major clinicopathologic groups: juvenile dermatomyositis, juvenile polymyositis, and overlap myositis. A growing spectrum of clinicopathologic groups and serologic phenotypes defined by the presence of myositis-specific or myositis-associated autoantibodies are now recognized, each with differing demographics, clinical manifestations, laboratory findings, and prognoses. With the first multi-center collaborative studies and controlled trials using standardized preliminarily validated outcome measures, the therapy of juvenile myositis has advanced. Although daily oral corticosteroids remain the backbone of treatment, disease-modifying anti-rheumatic drugs (DMARDs) are almost always used as adjunctive therapy. Methotrexate is the conventional DMARD for the initial therapy, either alone or combined with intravenous pulse methylprednisolone, and/or intravenous immunoglobulin for patients with moderate to severe disease. Cyclosporine may be added to these or serve as an alternative to methotrexate. Other drugs and biologic therapies, including mycophenolate mofetil, tacrolimus, cyclophosphamide, rituximab, and infliximab, might benefit selected patients with recalcitrant disease, unacceptable steroid toxicity, or patients with risk factors for poor prognosis. The treatment of cutaneous disease, calcinosis, and the role for rehabilitation are also discussed. PMID:24182859

  13. [Higher Brain Dysfunction in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS)].

    PubMed

    Ichikawa, Hiroo

    2016-02-01

    Stroke-like episodes are one of the cardinal features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and occur in 84-99% of the patients. The affected areas detected on neuroimaging do not have classical vascular distribution, and involve predominantly the temporal, parietal and occipital lobes. Thus, the neurological symptoms including higher brain dysfunction correlate with this topographical distribution. In association with the occipital lobe involvement, the most frequent symptom is cortical blindness. Other symptoms have been occasionally reported in case reports: visual agnosia, prosopagnosia, cortical deafness, auditory agnosia, topographical disorientation, various types of aphasia, hemispatial neglect, and so on. On the other hand, cognitive decline associated with more diffuse brain impairment rather than with focal stroke-like lesions has been postulated. This condition is also known as mitochondrial dementia. Domains of cognitive dysfunction include abstract reasoning, verbal memory, visual memory, language (naming and fluency), executive or constructive functions, attention, and visuospatial function. Cognitive functions and intellectual abilities may decline from initially minimal cognitive impairment to dementia. To date, the neuropsychological and neurologic impairment has been reported to be associated with cerebral lactic acidosis as estimated by ventricular spectroscopic lactate levels.

  14. Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy.

    PubMed

    Guinto, Jake B; Ritson, Gillian P; Taylor, J Paul; Forman, Mark S

    2007-07-01

    Frontotemporal dementia with inclusion body myopathy and Paget's disease of bone (IBMPFD) is a rare, autosomal dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions without VCP mutations. Yet, the ubiquitin-positive inclusions in IBMPFD also stain for TAR DNA binding protein, a feature that links this rare disease with the pathology associated with the majority of sporadic FTD as well as disease resulting from different genetic alterations. VCP, a member of the AAA-ATPase gene family, associates with a plethora of protein adaptors to perform a variety of cellular processes including Golgi assembly/disassembly and regulation of the ubiquitin-proteasome system. However, the mechanism whereby mutations in VCP lead to CNS, muscle, and bone disease is largely unknown. In this report, we review current literature on IBMPFD, focusing on the pathology of the disease and the biology of VCP with respect to IBMPFD.

  15. Health-Related Quality of Life (HRQoL) in Idiopathic Inflammatory Myopathy: A Systematic Review

    PubMed Central

    Regardt, Malin; Wojcik, Sophie

    2016-01-01

    Health-related quality of life (HRQoL) is a research priority in chronic diseases. We undertook a systematic review (registration #CRD42015024939) to identify, appraise and synthesize the evidence relating to HRQoL in idiopathic inflammatory myopathies (IIM). A comprehensive search was conducted in August 2015 using CINAHL, EMBase and Pubmed to identify studies reporting original data on HRQoL in IIM using generic HRQoL instruments. Characteristics of samples and results from selected studies were extracted and appraised using a standardized approach. Qualitative synthesis of the results was performed. Ten studies including a total of 654 IIM subjects were included in this systematic review. HRQoL was significantly impaired in all subsets of IIM compared with the general population. Disease activity, disease damage and chronic disease course were associated with poorer HRQoL. Insufficient or conflicting results were found in associations between clinical features, treatment, disease duration and mood or illness perception, and HRQoL in IIM. This study suggests that HRQoL is impaired in IIM. However, due to the paucity and heterogeneity of the evidence to date, robust estimates are lacking and significant knowledge gaps persist. There is a need for studies that systematically investigate the correlates and trajectory of HRQoL in IIM. PMID:27504827

  16. Characterization of hereditary inclusion body myopathy myoblasts: possible primary impairment of apoptotic events.

    PubMed

    Amsili, S; Shlomai, Z; Levitzki, R; Krause, S; Lochmuller, H; Ben-Bassat, H; Mitrani-Rosenbaum, S

    2007-11-01

    Hereditary inclusion body myopathy (HIBM) is a unique muscular disorder caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. GNE encodes a bi-functional enzyme acting in the biosynthetic pathway of sialic acid. Since the underlying myopathological mechanism leading to the disease phenotype is poorly understood, we have established human myoblasts cultures, derived from HIBM satellite cells carrying the homozygous M712T mutation, and identified cellular and molecular characteristics of these cells. HIBM and control myoblasts showed similar heterogeneous patterns of proliferation and differentiation. Upon apoptosis induction, phosphatidylserine externalization was similar in HIBM and controls. In contrast, the active forms of caspase-3 and -9 were strongly enhanced in most HIBM cultures compared to controls, while pAkt, downregulated in controls, remained high in HIBM cells. These results could indicate impaired apoptotic signaling in HIBM cells. Since satellite cells enable partial regeneration of the post-mitotic muscle tissue, these altered processes could contribute to the muscle mass loss seen in patients. The identification of survival defects in HIBM affected muscle cells could disclose new functions for GNE in muscle cells.

  17. Role of TGF-β signaling in inherited and acquired myopathies

    PubMed Central

    2011-01-01

    The transforming growth factor-beta (TGF-β) superfamily consists of a variety of cytokines expressed in many different cell types including skeletal muscle. Members of this superfamily that are of particular importance in skeletal muscle are TGF-β1, mitogen-activated protein kinases (MAPKs), and myostatin. These signaling molecules play important roles in skeletal muscle homeostasis and in a variety of inherited and acquired neuromuscular disorders. Expression of these molecules is linked to normal processes in skeletal muscle such as growth, differentiation, regeneration, and stress response. However, chronic elevation of TGF-β1, MAPKs, and myostatin is linked to various features of muscle pathology, including impaired regeneration and atrophy. In this review, we focus on the aberrant signaling of TGF-β in various disorders such as Marfan syndrome, muscular dystrophies, sarcopenia, and critical illness myopathy. We also discuss how the inhibition of several members of the TGF-β signaling pathway has been implicated in ameliorating disease phenotypes, opening up novel therapeutic avenues for a large group of neuromuscular disorders. PMID:21798096

  18. The Correlation of Muscle Biopsy Scores with the Clinical Variables in Idiopathic Inflammatory Myopathies

    PubMed Central

    Wangkaew, Suparaporn; Suwansirikul, Songkiet; Aroonrungwichian, Kantawut; Kasitanon, Nuntana; Louthrenoo, Worawit

    2016-01-01

    Objectives: To compare the muscle pathology findings among subgroups of idiopathic inflammatory myopathies (IIM) patients, and to determine the correlations of muscle biopsy scores with muscle power and creatine kinase (CK). Methods: The medical records of IIM patients consisting of the demographic data, clinical parameters and laboratory conducted were retrospectively reviewed. Their initial muscle biopsies were reviewed, and four domains were scored: inflammation, vascular, muscle, and connective tissue. Results: Ninety-five IIM patients (28 patients with idiopathic polymyositis (PM) 9 idiopathic dermatomyositis (DM), 5 DM associated with malignancy, and 53 PM/DM associated with connective tissue disease) with median (IQR: Q1, Q3) disease duration of 1.2 (0.5, 3.1) months were included. No significant differences in initial muscle pathology findings and muscle pathology score among the subgroups were found. Muscle degeneration and endomysial fibrosis scores were negatively correlated with muscle power (r=-0.23 and-0.24, respectively, p<0.05) and positively correlated with CK (r=0.27 and 0.39, respectively, p<0.01). No significant correlation was detected either inflammation or vasculitis scores with muscle power and CK levels. Conclusion: In this study, muscle biopsy cannot be used to differentiate among subgroups of IIM patients. In addition, we found only modest correlation of muscle biopsy scores with muscle power and CK. Further study is necessary to confirm our findings. PMID:28144368

  19. The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy.

    PubMed

    Janiesch, Philipp Christoph; Kim, Johnny; Mouysset, Julien; Barikbin, Roja; Lochmüller, Hanns; Cassata, Giuseppe; Krause, Sabine; Hoppe, Thorsten

    2007-04-01

    Protein degradation in eukaryotes often requires the ubiquitin-selective chaperone p97 for substrate recruitment and ubiquitin-chain assembly. However, the physiological relevance of p97, and its role in developmental processes, remain unclear. Here, we discover an unanticipated function for CDC-48/p97 in myosin assembly and myofibril organization, both in Caenorhabditis elegans and humans. The developmentally regulated assembly of a CDC-48-UFD-2-CHN-1 complex links turnover of the myosin-directed chaperone UNC-45 to functional muscle formation. Our data suggest a similarly conserved pathway regulating myosin assembly in humans. Remarkably, mutations in human p97, known to cause hereditary inclusion-body myopathy, abrogate UNC-45 degradation and result in severely disorganized myofibrils, detrimental towards sarcomeric function. These results identify a key role for CDC-48/p97 in the process of myofibre differentiation and maintenance, which is abolished during pathological conditions leading to protein aggregation and inclusion-body formation in human skeletal muscle.

  20. The evolution of capture myopathy in hooved mammals: a model for human stress cardiomyopathy?

    PubMed Central

    Blumstein, Daniel T.; Buckner, Janet; Shah, Sajan; Patel, Shane; Alfaro, Michael E.; Natterson-Horowitz, Barbara

    2015-01-01

    Background and objectives: Capture myopathy (CM) syndromes in wildlife may be a model for human stress cardiomyopathy, including Takotsubo cardiomyopathy. Emotional stress or grief may trigger heart attack-like symptoms, and occasionally, sudden death in some humans. Similarly, wildlife exposed to predatory stresses, chase, or capture occasionally results in sudden death. To better understand the nature of vulnerability to stress-induced sudden death, we studied cases of CM in hooved mammals—ungulates—and hypothesized that CM would be associated with a syndrome of longevity-related traits. Methodology: We reconstructed the evolution of CM in ungulates then determined how a set of life history traits explained variation in the likelihood that CM was reported. Results: CM is broadly reported, but not in all genera, and phylogenetic analyses suggest that it is an evolutionarily labile trait. We found that the following traits were significantly associated with reports of CM: greater brain mass, faster maximum running speed, greater minimum group size and greater maximum longevity. Conclusions and implications: CM may be an unavoidable consequence of adaptations to reduce predation risk that include increased running speed, sociality and having larger brains. Moreover, longer-lived species seem to be more likely to be susceptible to CM. Exploring variable susceptibility to CM highlights the evolutionary origins of the disorder, potential basic mechanisms that underlie vulnerability to the phenomenon, and the potential for reduction of risk through modification of life history trajectory. PMID:26198189

  1. Polysaccharide storage myopathy in the M. longissimus lumborum of showjumpers and dressage horses with back pain.

    PubMed

    Quiroz-Rothe, E; Novales, M; Aguilera-Tejero, E; Rivero, J L L

    2002-03-01

    This study was designed to investigate whether horses with clinical signs of back pain due to suspected soft tissue injuries were affected by polysaccharide storage myopathy (PSSM). Diagnosis of PSSM in muscle biopsies obtained from the M. longissimus lumborum of 5 showjumpers and 4 dressage horses with a history of back pain is reported. M. longissimus lumborum biopsies of these horses were characterised histopathologically and in 3/9 cases also by electron microscopy. Observations were compared with M. gluteus biopsies of the same horses, and with M. gluteus biopsies obtained from 6 Standardbreds with recurrent exertional rhabdomyolysis and from 6 healthy trotters. M. longissimus biopsies from horses with back pain showed pathognomonic signs of PSSM, i.e. high glycogen and/or abnormal complex amylase-resistant polysaccharide deposits. Similar features were found in M. gluteus biopsies of the same horses. Sections of horses with rhabdomyolysis had increased PAS stain when compared with healthy horses, but did not show amylase-resistant material. Qualitative observations were corroborated by quantitative histochemistry (optical densities) of sections stained with PAS and amylase PAS. This study demonstrated the presence of PSSM in the M. longissimus of showjumpers and dressage horses with back pain and indicates that epaxial muscle biopsy is an option in diagnosing back problems in horses when clinical examination and imaging techniques do not provide a precise diagnosis.

  2. Insulin sensitivity and skeletal muscle glucose transport in horses with equine polysaccharide storage myopathy.

    PubMed

    Annandale, Erin J; Valberg, Stephanie J; Mickelson, James R; Seaquist, Elizabeth R

    2004-10-01

    Equine polysaccharide storage myopathy (PSSM) is an inherited disorder characterized by the accumulation of glycogen and abnormal polysaccharide in muscle with normal glyco(geno)lytic enzyme activities. The purpose of this study was to evaluate in vivo insulin sensitivity and glucose excursion in PSSM using a euglycemic hyperinsulinemic clamp. In addition, the content of muscle glucose transporters (GLUT1 and GLUT4) and the insulin receptor was determined in muscle biopsies using Western blot analysis. The glycogen content was 1.8-fold higher, and isolated polysaccharide analyzed by iodine absorption spectra, was less branched in equine PSSM. Throughout the clamp, the affected horses required a higher rate of glucose infusion to maintain euglycemia. Although GLUT1 content was lower, the total content of GLUT4 and insulin receptor was not different in myopathic vs. control horses. PSSM therefore represents a novel disorder where enhanced insulin sensitivity and elevated glucose excursion leads to increased synthesis of muscle glycogen, which in our horses appears to be independent of augmented GLUT4 or IR quantity.

  3. Blockade of ActRIIB Signaling Triggers Muscle Fatigability and Metabolic Myopathy

    PubMed Central

    Relizani, Karima; Mouisel, Etienne; Giannesini, Benoit; Hourdé, Christophe; Patel, Ketan; Morales Gonzalez, Susanne; Jülich, Kristina; Vignaud, Alban; Piétri-Rouxel, France; Fortin, Dominique; Garcia, Luis; Blot, Stéphane; Ritvos, Olli; Bendahan, David; Ferry, Arnaud; Ventura-Clapier, Renée; Schuelke, Markus; Amthor, Helge

    2014-01-01

    Myostatin regulates skeletal muscle size via the activin receptor IIB (ActRIIB). However, its effect on muscle energy metabolism and energy-dependent muscle function remains largely unexplored. This question needs to be solved urgently since various therapies for neuromuscular diseases based on blockade of ActRIIB signaling are being developed. Here, we show in mice, that 4-month pharmacological abrogation of ActRIIB signaling by treatment with soluble ActRIIB-Fc triggers extreme muscle fatigability. This is associated with elevated serum lactate levels and a severe metabolic myopathy in the mdx mouse, an animal model of Duchenne muscular dystrophy. Blockade of ActRIIB signaling downregulates porin, a crucial ADP/ATP shuttle between cytosol and mitochondrial matrix leading to a consecutive deficiency of oxidative phosphorylation as measured by in vivo Phophorus Magnetic Resonance Spectroscopy (31P-MRS). Further, ActRIIB blockade reduces muscle capillarization, which further compounds the metabolic stress. We show that ActRIIB regulates key determinants of muscle metabolism, such as Pparβ, Pgc1α, and Pdk4 thereby optimizing different components of muscle energy metabolism. In conclusion, ActRIIB signaling endows skeletal muscle with high oxidative capacity and low fatigability. The severe metabolic side effects following ActRIIB blockade caution against deploying this strategy, at least in isolation, for treatment of neuromuscular disorders. PMID:24861054

  4. Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy*

    PubMed Central

    Lewis, Kevin M.; Ronish, Leslie A.; Ríos, Eduardo; Kang, ChulHee

    2015-01-01

    Calsequestrin 1 is the principal Ca2+ storage protein of the sarcoplasmic reticulum of skeletal muscle. Its inheritable D244G mutation causes a myopathy with vacuolar aggregates, whereas its M87T “variant” is weakly associated with malignant hyperthermia. We characterized the consequences of these mutations with studies of the human proteins in vitro. Equilibrium dialysis and turbidity measurements showed that D244G and, to a lesser extent, M87T partially lose Ca2+ binding exhibited by wild type calsequestrin 1 at high Ca2+ concentrations. D244G aggregates abruptly and abnormally, a property that fully explains the protein inclusions that characterize its phenotype. D244G crystallized in low Ca2+ concentrations lacks two Ca2+ ions normally present in wild type that weakens the hydrophobic core of Domain II. D244G crystallized in high Ca2+ concentrations regains its missing ions and Domain II order but shows a novel dimeric interaction. The M87T mutation causes a major shift of the α-helix bearing the mutated residue, significantly weakening the back-to-back interface essential for tetramerization. D244G exhibited the more severe structural and biophysical property changes, which matches the different pathophysiological impacts of these mutations. PMID:26416891

  5. Two desmin gene mutations associated with myofibrillar myopathies in Polish families.

    PubMed

    Fichna, Jakub Piotr; Karolczak, Justyna; Potulska-Chromik, Anna; Miszta, Przemyslaw; Berdynski, Mariusz; Sikorska, Agata; Filipek, Slawomir; Redowicz, Maria Jolanta; Kaminska, Anna; Zekanowski, Cezary

    2014-01-01

    Desmin is a muscle-specific intermediate filament protein which forms a network connecting the sarcomere, T tubules, sarcolemma, nuclear membrane, mitochondria and other organelles. Mutations in the gene coding for desmin (DES) cause skeletal myopathies often combined with cardiomyopathy, or isolated cardiomyopathies. The molecular pathomechanisms of the disease remain ambiguous. Here, we describe and comprehensively characterize two DES mutations found in Polish patients with a clinical diagnosis of desminopathy. The study group comprised 16 individuals representing three families. Two mutations were identified: a novel missense mutation (Q348P) and a small deletion of nine nucleotides (A357_E359del), previously described by us in the Polish population. A common ancestry of all the families bearing the A357_E359del mutation was confirmed. Both mutations were predicted to be pathogenic using a bioinformatics approach, including molecular dynamics simulations which helped to rationalize abnormal behavior at molecular level. To test the impact of the mutations on DES expression and the intracellular distribution of desmin muscle biopsies were investigated. Elevated desmin levels as well as its atypical localization in muscle fibers were observed. Additional staining for M-cadherin, α-actinin, and myosin heavy chains confirmed severe disruption of myofibrill organization. The abnormalities were more prominent in the Q348P muscle, where both small atrophic fibers as well large fibers with centrally localized nuclei were observed. We propose that the mutations affect desmin structure and cause its aberrant folding and subsequent aggregation, triggering disruption of myofibrils organization.

  6. Hereditary myopathy of the diaphragmatic muscles in Holstein-Friesian cattle.

    PubMed

    Furuoka, H; Doi, T; Nakamura, N; Inada, I; Osame, S; Matsui, T

    1995-01-01

    We describe a family line with an autosomal recessive disease of muscular dystrophy of the diaphragmatic muscles in Holstein-Friesian cattle. Histopathological examination in the present cases revealed various degenerative changes in the diaphragmatic and other thoracic muscles as follows: variation in muscle fiber diameter, fiber splitting, sarcoplasmic masses, ring fiber, vacuolar and hyalinized degeneration of muscle fibers. In addition, central core-like structures were the prominent features in the diaphragmatic muscles, occupying the center of the fiber or scattered within the fiber. These pathological alterations are consistent with the diaphragmatic myopathy previously reported in Meuse-Rhine-Yssel cattle in the Netherlands. The fibers containing core-like structures consisted of three distinct zones which could be well distinguished by NADH-tetrazolium reductase activity. This activity was absent in the innermost zone, decreased in the intermediate zone, and normal or increased in the periphery. Electron microscopically, this structure appeared to be composed of focal myofibrillar degeneration beginning with streaming or disintegration of the Z disk. We discuss here the similarity between this core-like structure and the other alternative organelles that have been reported previously, and a possible defect or storage in the cytoskeleton from the findings of the Z disk abnormalities.

  7. Animal models in idiopathic inflammatory myopathies: How to overcome a translational roadblock?

    PubMed

    Afzali, Ali Maisam; Ruck, Tobias; Wiendl, Heinz; Meuth, Sven G

    2017-03-07

    Idiopathic inflammatory myopathies (IIMs) encompass a heterogenic group of rare muscle diseases with common symptoms including muscle weakness and the presence of certain histological features. Since the pathogenesis remains unclear, therapeutic approaches in general comprise unspecific immunosuppression strategies that have been met with limited success. Therefore, a deeper understanding of the underlying pathophysiological mechanisms is critically required to assist in development of targeted therapies. Animal models have proven to be tremendously helpful in mechanistic studies and allow researchers to overcome the inevitable restrictions of human research. Although the number of different IIM models has drastically increased over the last few decades, a model that exhibits the phenotypical and histopathological hallmarks of IIM is still missing. Recent publications have shown promising results addressing different pathophysiological issues like mechanisms of onset, chronification or relapse in IIM. However, a standardization of the methodology is critically required in order to improve comparability and transferability among different groups. Here we provide an overview of the currently available IIM models including our own C-peptide based small-peptide model, critically discuss their advantages and disadvantages and give perspectives to their future use.

  8. Vitamin D Receptor Gene Polymorphisms and Haplotypes in Hungarian Patients with Idiopathic Inflammatory Myopathy

    PubMed Central

    Griger, Zoltán; Dankó, Katalin

    2015-01-01

    Idiopathic inflammatory myopathies are autoimmune diseases characterized by symmetrical proximal muscle weakness. Our aim was to identify a correlation between VDR polymorphisms or haplotypes and myositis. We studied VDR-BsmI, VDR-ApaI, VDR-TaqI, and VDR-FokI polymorphisms and haplotypes in 89 Hungarian poly-/dermatomyositis patients (69 females) and 93 controls (52 females). We did not obtain any significant differences for VDR-FokI, BsmI, ApaI, and TaqI genotypes and allele frequencies between patients with myositis and healthy individuals. There was no association of VDR polymorphisms with clinical manifestations and laboratory profiles in myositis patients. Men with myositis had a significantly different distribution of BB, Bb, and bb genotypes than female patients, control male individuals, and the entire control group. Distribution of TT, Tt, and tt genotypes was significantly different in males than in females in patient group. According to four-marker haplotype prevalence, frequencies of sixteen possible haplotypes showed significant differences between patient and control groups. The three most frequent haplotypes in patients were the fbAt, FBaT, and fbAT. Our findings may reveal that there is a significant association: Bb and Tt genotypes can be associated with myositis in the Hungarian population we studied. We underline the importance of our result in the estimated prevalence of four-marker haplotypes. PMID:25649962

  9. RyR1 deficiency in congenital myopathies disrupts excitation-contraction coupling.

    PubMed

    Zhou, Haiyan; Rokach, Ori; Feng, Lucy; Munteanu, Iulia; Mamchaoui, Kamel; Wilmshurst, Jo M; Sewry, Caroline; Manzur, Adnan Y; Pillay, Komala; Mouly, Vincent; Duchen, Michael; Jungbluth, Heinz; Treves, Susan; Muntoni, Francesco

    2013-07-01

    In skeletal muscle, excitation-contraction (EC) coupling is the process whereby the voltage-gated dihydropyridine receptor (DHPR) located on the transverse tubules activates calcium release from the sarcoplasmic reticulum by activating ryanodine receptor (RyR1) Ca(2+) channels located on the terminal cisternae. This subcellular membrane specialization is necessary for proper intracellular signaling and any alterations in its architecture may lead to neuromuscular disorders. In this study, we present evidence that patients with recessive RYR1-related congenital myopathies due to primary RyR1 deficiency also exhibit downregulation of the alfa 1 subunit of the DHPR and show disruption of the spatial organization of the EC coupling machinery. We created a cellular RyR1 knockdown model using immortalized human myoblasts transfected with RyR1 siRNA and confirm that knocking down RyR1 concomitantly downregulates not only the DHPR but also the expression of other proteins involved in EC coupling. Unexpectedly, this was paralleled by the upregulation of inositol-1,4,5-triphosphate receptors; functionally however, upregulation of the latter Ca(2+) channels did not compensate for the lack of RyR1-mediated Ca(2+) release. These results indicate that in some patients, RyR1 deficiency concomitantly alters the expression pattern of several proteins involved in calcium homeostasis and that this may influence the manifestation of these diseases.

  10. Serum enzymes as indicators of capture myopathy in mallards (Anas platyrhynchos).

    PubMed

    Dabbert, C B; Powell, K C

    1993-04-01

    Serum concentrations of the enzymes creatine kinase (CK) and aspartate aminotransferase (AST) were measured in captive and wild mallards (Anas platyrhynchos) as indicators of muscle damage. Baseline values for both enzymes were determined from six captive male mallards. During winter 1990 to 1991, six diets (including controls) representative of food available in the Mississippi alluvial valley were fed to captive female mallards housed in an outdoor aviary at the White River National Wildlife Refuge, Arkansas County, Arkansas (USA). Controlled handling of penned mallards resulted in elevated serum CK (means = 1,352 IU/liter; SD = 1,212) and AST (means = 101 IU/liter; SD = 95) concentrations consistent with myopathies. These serum enzyme elevations were not affected (P > 0.3) by dietary selenium concentrations in the six diets or by energy malnutrition suffered by birds fed soybeans. Capture of wild mallards with an entanglement type rocket net resulted in serum CK and AST concentrations (means = 12,035 and 330 IU/liter; SD = 8,125 and 171, respectively) that were higher (P < 0.001) than those reported after capture with an enveloping type rocket net. Baseline values, controlled handling values, and entanglement rocket net values for serum CK and AST all differed (P < 0.0001).

  11. Myofibrillar Myopathies: New Perspectives from Animal Models to Potential Therapeutic Approaches

    PubMed Central

    Batonnet-Pichon, Sabrina; Behin, Anthony; Cabet, Eva; Delort, Florence; Vicart, Patrick; Lilienbaum, Alain

    2017-01-01

    Myofibrillar myopathies (MFMs) are muscular disorders involving proteins that play a role in the structure, maintenance processes and protein quality control mechanisms closely related to the Z-disc in the muscular fibers. MFMs share common histological characteristics including progressive disorganization of the interfibrillar network and protein aggregation. Currently no treatment is available. In this review, we describe first clinical symptoms associated with mutations of the six genes (DES, CRYAB, MYOT, ZASP, FLNC and BAG3) primary involved in MFM and defining the origin of this pathology. As mechanisms determining the aetiology of the disease remain unclear yet, several research teams have developed animal models from invertebrates to mammalians species. Thus we describe here these different models that often recapitulate human clinical symptoms. Therefore they are very useful for deeper studies to understand early molecular and progressive mechanisms determining the pathology. Finally in the last part, we emphasize on the potential therapeutic approaches for MFM that could be conducted in the future. In conclusion, this review offers a link from patients to future therapy through the use of MFMs animal models. PMID:28269794

  12. HMGB1 expression and muscle regeneration in idiopathic inflammatory myopathies and degenerative joint diseases.

    PubMed

    Cseri, Karolina; Vincze, János; Cseri, Julianna; Fodor, János; Csernátony, Zoltán; Csernoch, László; Dankó, Katalin

    2015-06-01

    The High-Mobility Group Box 1 protein (HMGB1) is a known nuclear protein which may be released from the nucleus into the cytoplasm and the extracellular space. It is believed that the mobilized HMGB1 plays role in the autoimmune processes as an alarmin, stimulating the immune response. In addition, muscle regeneration and differentiation may also be altered in the inflammatory surroundings. Biopsy specimens derived from patients with idiopathic inflammatory myopathies (IIM) such as polymyositis or dermatomyositis were compared to muscle samples from patients undergoing surgical interventions for coxarthrosis. The biopsy and surgery specimens were used for Western blot analysis, for immunohistochemical detection of HMGB1 in histological preparations and for cell culturing to examine cell proliferation and differentiation. Our data show lower HMGB1 expression, impaired proliferation and slightly altered fusion capacity in the primary cell cultures started from IIM specimens than in cultures of coxarthrotic muscles. The ratio of regenerating muscle fibres with centralised nuclei (myotubes) is lower in the IIM samples than in the coxarthrotic ones but corticosteroid treatment shifts the ratio towards the coxarthrotic value. Our data suggest that the impaired regeneration capacity should also be considered to be behind the muscle weakness in IIM patients. The role of HMGB1 as a pathogenic signal requires further investigation.

  13. PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models

    PubMed Central

    Sabha, Nesrin; Volpatti, Jonathan R.; Gonorazky, Hernan; Davidson, Ann E.; Li, Xingli; Eltayeb, Nadine M.; Dall’Armi, Claudia; Di Paolo, Gilbert; Brooks, Susan V.; Buj-Bello, Ana; Feldman, Eva L.; Dowling, James J.

    2016-01-01

    Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets. PMID:27548528

  14. Mutations in FAM111B Cause Hereditary Fibrosing Poikiloderma with Tendon Contracture, Myopathy, and Pulmonary Fibrosis

    PubMed Central

    Mercier, Sandra; Küry, Sébastien; Shaboodien, Gasnat; Houniet, Darren T.; Khumalo, Nonhlanhla P.; Bou-Hanna, Chantal; Bodak, Nathalie; Cormier-Daire, Valérie; David, Albert; Faivre, Laurence; Figarella-Branger, Dominique; Gherardi, Romain K.; Glen, Elise; Hamel, Antoine; Laboisse, Christian; Le Caignec, Cédric; Lindenbaum, Pierre; Magot, Armelle; Munnich, Arnold; Mussini, Jean-Marie; Pillay, Komala; Rahman, Thahira; Redon, Richard; Salort-Campana, Emmanuelle; Santibanez-Koref, Mauro; Thauvin, Christel; Barbarot, Sébastien; Keavney, Bernard; Bézieau, Stéphane; Mayosi, Bongani M.

    2013-01-01

    Congenital poikiloderma is characterized by a combination of mottled pigmentation, telangiectasia, and epidermal atrophy in the first few months of life. We have previously described a South African European-descent family affected by a rare autosomal-dominant form of hereditary fibrosing poikiloderma accompanied by tendon contracture, myopathy, and pulmonary fibrosis. Here, we report the identification of causative mutations in FAM111B by whole-exome sequencing. In total, three FAM111B missense mutations were identified in five kindreds of different ethnic backgrounds. The mutation segregated with the disease in one large pedigree, and mutations were de novo in two other pedigrees. All three mutations were absent from public databases and were not observed on Sanger sequencing of 388 ethnically matched control subjects. The three single-nucleotide mutations code for amino acid changes that are clustered within a putative trypsin-like cysteine/serine peptidase domain of FAM111B. These findings provide evidence of the involvement of FAM111B in congenital poikiloderma and multisystem fibrosis. PMID:24268661

  15. Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs.

    PubMed

    Mack, David L; Poulard, Karine; Goddard, Melissa A; Latournerie, Virginie; Snyder, Jessica M; Grange, Robert W; Elverman, Matthew R; Denard, Jérôme; Veron, Philippe; Buscara, Laurine; Le Bec, Christine; Hogrel, Jean-Yves; Brezovec, Annie G; Meng, Hui; Yang, Lin; Liu, Fujun; O'Callaghan, Michael; Gopal, Nikhil; Kelly, Valerie E; Smith, Barbara K; Strande, Jennifer L; Mavilio, Fulvio; Beggs, Alan H; Mingozzi, Federico; Lawlor, Michael W; Buj-Bello, Ana; Childers, Martin K

    2017-04-05

    X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-specific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10 weeks of age, when signs of the disease are already present. A comprehensive analysis of survival, limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression, and immune response was performed over a 9-month study period. Results indicate that systemic gene therapy was well tolerated, prolonged lifespan, and corrected the skeletal musculature throughout the body in a dose-dependent manner, defining an efficacious dose in this large-animal model of the disease. These results support the development of gene therapy clinical trials for XLMTM.

  16. Pathogenic mitochondrial mt-tRNAAla variants are uniquely associated with isolated myopathy

    PubMed Central

    Lehmann, Diana; Schubert, Kathrin; Joshi, Pushpa R; Hardy, Steven A; Tuppen, Helen A L; Baty, Karen; Blakely, Emma L; Bamberg, Christian; Zierz, Stephan; Deschauer, Marcus; Taylor, Robert W

    2015-01-01

    Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNAAla variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNAAla levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNAAla variants. Previously described mt-tRNAAla mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene. PMID:25873012

  17. Impaired insulin/IGF signaling in experimental alcohol-related myopathy.

    PubMed

    Nguyen, Van Anh; Le, Tran; Tong, Ming; Silbermann, Elizabeth; Gundogan, Fusun; de la Monte, Suzanne M

    2012-08-01

    Alcohol-related myopathy (Alc-M) is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8) or 35.5% (N = 13) ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3β. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration.

  18. Absence of keratin 19 in mice causes skeletal myopathy with mitochondrial and sarcolemmal reorganization.

    PubMed

    Stone, Michele R; O'Neill, Andrea; Lovering, Richard M; Strong, John; Resneck, Wendy G; Reed, Patrick W; Toivola, Diana M; Ursitti, Jeanine A; Omary, M Bishr; Bloch, Robert J

    2007-11-15

    Intermediate filaments, composed of desmin and of keratins, play important roles in linking contractile elements to each other and to the sarcolemma in striated muscle. We examined the contractile properties and morphology of fast-twitch skeletal muscle from mice lacking keratin 19. Tibialis anterior muscles of keratin-19-null mice showed a small but significant decrease in mean fiber diameter and in the specific force of tetanic contraction, as well as increased plasma creatine kinase levels. Costameres at the sarcolemma of keratin-19-null muscle, visualized with antibodies against spectrin or dystrophin, were disrupted and the sarcolemma was separated from adjacent myofibrils by a large gap in which mitochondria accumulated. The costameric dystrophin-dystroglycan complex, which co-purified with gamma-actin, keratin 8 and keratin 19 from striated muscles of wild-type mice, co-purified with gamma-actin but not keratin 8 in the mutant. Our results suggest that keratin 19 in fast-twitch skeletal muscle helps organize costameres and links them to the contractile apparatus, and that the absence of keratin 19 disrupts these structures, resulting in loss of contractile force, altered distribution of mitochondria and mild myopathy. This is the first demonstration of a mammalian phenotype associated with a genetic perturbation of keratin 19.

  19. Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy.

    PubMed

    Lehmann, Diana; Schubert, Kathrin; Joshi, Pushpa R; Hardy, Steven A; Tuppen, Helen A L; Baty, Karen; Blakely, Emma L; Bamberg, Christian; Zierz, Stephan; Deschauer, Marcus; Taylor, Robert W

    2015-12-01

    Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA(Ala) variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNA(Ala) levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNA(Ala) variants. Previously described mt-tRNA(Ala) mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene.

  20. Acute Pancreatitis and Pregnancy

    MedlinePlus

    ... Pancreatitis Acute Pancreatitis and Pregnancy Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is defined as ... pancreatitis in pregnancy. Reasons for Acute Pancreatitis and Pregnancy While acute pancreatitis is responsible for almost 1 ...

  1. Serum enolase: a non-destructive biomarker of white skeletal myopathy during pancreas disease (PD) in Atlantic salmon Salmo salar L.

    PubMed

    Braceland, M; McLoughlin, M F; Tinsley, J; Wallace, C; Cockerill, D; McLaughlin, M; Eckersall, P D

    2015-09-01

    Diseases which cause skeletal muscle myopathy are some of the most economically damaging diseases in Atlantic salmon, Salmo salar L., aquaculture. Despite this, there are limited means of assessing fish health non-destructively. Previous investigation of the serum proteome of Atlantic salmon, Salmo salar L., during pancreas disease (PD) has identified proteins in serum that have potential as biomarkers of the disease. Amongst these proteins, the enzyme enolase was selected as the most viable for use as a biomarker of muscle myopathy associated with PD. Western blot and immunoassay (ELISA) validated enolase as a biomarker for PD, whilst immunohistochemistry identified white muscle as the source of enolase. Enolase was shown to be a specific marker for white muscle myopathy in salmon, rising in serum concentration significantly correlating with pathological damage to the tissue.

  2. Acute digital ischemia: A rare presentation of antisynthetase syndrome

    PubMed Central

    Chan, Jin Ei; Palakodeti, Sandeep; Koster, Matthew J.

    2017-01-01

    Antisynthetase syndrome (ASS) is recognized as a subgroup of idiopathic inflammatory myopathies (IIMs). It is associated with autoantibodies directed against aminoacyl-transfer ribonucleic acid (tRNA) synthetase enzymes. We report the first case of anti-PL-7/anti-SSA 52kD ASS presenting as acute digital ischemia, an association not described previously. Occlusive vasculopathy is a rare but serious manifestation that can be seen at presentation in patients with ASS and may herald the onset of severe interstitial lung disease (ILD). Comprehensive evaluation should be performed to confirm the presence of subclinical myositis. Extensive myositis-specific antibody testing is strongly recommended even if initial screening autoimmune serologies are unrevealing. PMID:28293456

  3. Acute digital ischemia: A rare presentation of antisynthetase syndrome.

    PubMed

    Chan, Jin Ei; Palakodeti, Sandeep; Koster, Matthew J

    2017-03-01

    Antisynthetase syndrome (ASS) is recognized as a subgroup of idiopathic inflammatory myopathies (IIMs). It is associated with autoantibodies directed against aminoacyl-transfer ribonucleic acid (tRNA) synthetase enzymes. We report the first case of anti-PL-7/anti-SSA 52kD ASS presenting as acute digital ischemia, an association not described previously. Occlusive vasculopathy is a rare but serious manifestation that can be seen at presentation in patients with ASS and may herald the onset of severe interstitial lung disease (ILD). Comprehensive evaluation should be performed to confirm the presence of subclinical myositis. Extensive myositis-specific antibody testing is strongly recommended even if initial screening autoimmune serologies are unrevealing.

  4. Low Vitamin D Levels and Genetic Polymorphism in the Vitamin D Receptor are Associated with Increased Risk of Statin-Induced Myopathy.

    PubMed

    Ovesjö, Marie-Louise; Skilving, Ilona; Bergman, Peter; Rane, Anders; Ekström, Lena; Björkhem-Bergman, Linda

    2016-03-01

    The main aim of this study was to test the hypothesis whether 25-hydroxyvitamin D (25OHD) levels <50 nmol/L at baseline could predict statin-induced myopathy during the course of treatment. In addition, we analysed the association between a genetic polymorphism in the vitamin D receptor (VDR) and the risk of statin-induced myopathy. We used serum samples from a prospective, observational study in statin-treated patients in Sweden who were thoroughly followed with interviews and questionnaires regarding muscular symptoms (n = 127). In this cohort, 16 developed muscular symptoms and 111 had no muscular symptoms associated with statin treatment during the first year of follow-up. Patients with 25OHD levels <50 nmol/L before starting on statin treatment had four times higher risk of developing muscular symptoms compared with individuals having 25OHD levels >50 nmol/L (RR 4.2; 95% CI 1.7-10.2; p < 0.01). The mean levels of 25OHD at baseline were 50 ± 4 nmol/L among patients developing myopathy and 60 ± 2 nmol/L among patients without myopathy (p < 0.01). Individuals homozygous for the C allele in the VDR polymorphism TaqI (rs731236) had a four times higher risk of developing muscular symptoms; (RR 4.37, 95% CI 1.9-10.1, p < 0.01). In conclusion, 25OHD levels <50 nmol/L might be a useful marker to predict muscular adverse events during statin treatment. In addition, the finding that the VDR polymorphism TaqI was associated with myopathy may indicate a causal relationship between vitamin D function and myopathy, but larger studies are needed before firm conclusions can be drawn.

  5. Protein Structure-Function Relationship at Work: Learning from Myopathy Mutations of the Slow Skeletal Muscle Isoform of Troponin T

    PubMed Central

    Mondal, Anupom; Jin, J.-P.

    2016-01-01

    Troponin T (TnT) is the sarcomeric thin filament anchoring subunit of the troponin complex in striated muscles. A nonsense mutation in exon 11 of the slow skeletal muscle isoform of TnT (ssTnT) gene (TNNT1) was found in the Amish populations in Pennsylvania and Ohio. This single nucleotide substitution causes a truncation of the ssTnT protein at Glu180 and the loss of the C-terminal tropomyosin (Tm)-binding site 2. As a consequence, it abolishes the myofilament integration of ssTnT and the loss of function causes an autosomal recessive nemaline myopathy (NM). More TNNT1 mutations have recently been reported in non-Amish ethnic groups with similar recessive NM phenotypes. A nonsense mutation in exon 9 truncates ssTnT at Ser108, deleting Tm-binding site 2 and a part of the middle region Tm-binding site 1. Two splicing site mutations result in truncation of ssTnT at Leu203 or deletion of the exon 14-encoded C-terminal end segment. Another splicing mutation causes an internal deletion of the 39 amino acids encoded by exon 8, partially damaging Tm-binding site 1. The three splicing mutations of TNNT1 all preserve the high affinity Tm-binding site 2 but still present recessive NM phenotypes. The molecular mechanisms for these mutations to cause myopathy provide interesting models to study and understand the structure-function relationship of TnT. This focused review summarizes the current knowledge of TnT isoform regulation, structure-function relationship of TnT and how various ssTnT mutations cause recessive NM, in order to promote in depth studies for further understanding the pathogenesis and pathophysiology of TNNT1 myopathies toward the development of effective treatments. PMID:27790152

  6. Spatial influence on breast muscle morphological structure, myofiber size, and gene expression associated with the wooden breast myopathy in broilers.

    PubMed

    Clark, D L; Velleman, S G

    2016-12-01

    The wooden breast (WB) myopathy is identified by the palpation of a rigid pectoralis major (p. major) muscle and is characterized as a fibrotic, necrotic p. major disorder in broilers. The objective of the current study was to determine spatial morphological and gene expression differences at 4 locations within WB affected muscle from different genetic lines. Morphology was evaluated in 2 broiler lines expressing the WB myopathy (Lines A and B) and a line without WB (Line C) at 3 ventral locations and one anterodorsal location in the p. major muscle. In WB affected muscle of Line A, fibrosis was greatest in the anterior locations of WB affected muscle. In Line B muscle, fibrosis was greatest in the anteroventral region and minimal in the anterodorsal or posterior regions. Average p. major myofiber diameter was 30% larger in Lines A and B compared to Line C. However, in Line A there were no differences between the percentage of large fibers (diameter >70 μm) in unaffected and WB affected muscles at any sampling region. The percentage of small fibers (diameter <10 μm), likely small regenerating fibers, and expression of myogenic determination factor 1 (MYOD1) and myogenin were increased in Line A WB affected muscle compared to unaffected muscle. In Line B, the percentage of small fibers and MYOD1 expression in WB affected muscle was not different from unaffected muscle. Connective tissue organization within WB affected muscle was also different in Lines A and B, which may be attributed to decorin, a proteoglycan that mediates collagen crosslinking, growth factor signaling, and cell growth. Decorin expression was increased at all locations within Line A. However, in Line B decorin was increased only in the fibrotic regions of the p. major. The compiled results provide evidence that the WB myopathy is not uniform throughout the entire p. major muscle and the anterior end of the p. major muscle was more affected by the condition.

  7. [Acute pancreatitis].

    PubMed

    Hecker, M; Mayer, K; Askevold, I; Collet, P; Weigand, M A; Krombach, G A; Padberg, W; Hecker, A

    2014-03-01

    Acute pancreatitis is a potentially fatal disease with individually differing expression of systemic involvement. For this reason early diagnosis with subsequent risk stratification is essential in the clinical management of this frequent gastroenterological disorder. Severe forms of acute pancreatitis occur in approximately 20 % of cases often requiring intensive care monitoring and interdisciplinary therapeutic approaches. In the acute phase adequate fluid replacement and sufficient analgesic therapy is of major therapeutic importance. Concerning the administration of antibiotics and the nutritional support of patients with acute pancreatitis a change in paradigms could be observed in recent years. Furthermore, endoscopic, radiological or surgical interventions can be necessary depending on the severity of the disease and potential complications.

  8. Bronchitis - acute

    MedlinePlus

    ... to breathe. Other symptoms of bronchitis are a cough and coughing up mucus. Acute means the symptoms ... diagnosed with chronic bronchitis, you must have a cough with mucus on most days for at least ...

  9. Acute Bronchitis

    MedlinePlus

    ... bronchitis? Acute bronchitis is inflammation of your bronchial tree. The bronchial tree consists of tubes that carry air into your ... weeks or months. This happens because the bronchial tree takes a while to heal. A lasting cough ...

  10. [Occurrence of chloroquine-induced myopathy after low-dose treatment of rheumatoid arthritis for seven years].

    PubMed

    Haberl, A; Fischer, P; Pongratz, D; Sieb, J P

    2005-05-01

    The myotoxicity of chloroquine and hydroxychloroquine has been known for decades. Limb-girdle weakness due to a vacuolar myopathy may occur occasionally in a dose-dependent manner during the first 24 months on chloroquine. However, we report on a case in which muscular weakness developed after a daily intake of 250 chloroquine phosphate (= 155 mg chloroquine base) for a period of 7 years. Even after long-term and apparently well-tolerated chloroquine treatment, the occurrence of severe side-effects is possible.

  11. X-linked Myotubular Myopathy in a Family with Two Infant Siblings: A Case with MTM1 Mutation

    PubMed Central

    Jeon, Ji Hyun; Namgung, Ran; Park, Min Soo; Park, Kook In; Lee, Jin Sung; Kim, Se Hoon

    2011-01-01

    X-linked myotubular myopathy (XLMTM) is a rare congenital muscle disorder, caused by mutations in the MTM1 gene. Affected male infants present severe hypotonia, and generalized muscle weakness, and the disorder is most often complicated by respiratory failure. Herein, we describe a family with 2 infants with XLMTM which was diagnosed by gene analysis and muscle biopsy. In both cases, histological findings of muscle showed severely hypoplastic muscle fibers with centrally placed nuclei. From the family gene analysis, the Arg486STOP mutation in the MTM1 gene was confirmed. PMID:21488203

  12. Clinical and Electron Microscopic Findings in Two Patients with Mitochondrial Myopathy Associated with Episodic Hyper-creatine Kinase-emia.

    PubMed

    Nozuma, Satoshi; Okamoto, Yuji; Higuchi, Itsuro; Yuan, Junhui; Hashiguchi, Akihiro; Sakiyama, Yusuke; Yoshimura, Akiko; Higuchi, Yujiro; Takashima, Hiroshi

    2015-01-01

    Mitochondrial myopathy with episodic hyper-creatine kinase (CK)-emia (MIMECK) is a new disease entity characterized by episodic or persistent muscle weakness and elevated CK levels. We herein report two cases of MIMECK with the findings of histopathological studies. Histopathological examinations revealed strongly succinate dehydrogenase-reactive vessels. Electron microscopy showed abnormal mitochondria in the vessels and proliferating and vacuolated mitochondria under the sarcolemma. Both patients exhibited recurrent severe myalgia, weakness and increased CK levels. L-arginine treatment significantly ameliorated their muscle symptoms. These findings indicate that mitochondrial angiopathy plays an important role in the pathophysiology of MIMECK. L-arginine may be a potential therapeutic agent for this disorder.

  13. Activation of the Keap1/Nrf2 stress response pathway in autophagic vacuolar myopathies.

    PubMed

    Duleh, Steve; Wang, Xianhong; Komirenko, Allison; Margeta, Marta

    2016-10-31

    Nrf2 (nuclear factor [erythroid-derived 2]-like 2; the transcriptional master regulator of the antioxidant stress response) is regulated through interaction with its cytoplasmic inhibitor Keap1 (Kelch-like ECH-associated protein 1), which under basal conditions targets Nrf2 for proteasomal degradation. Sequestosome 1 (SQSTM1)/p62-a multifunctional adapter protein that accumulates following autophagy inhibition and can serve as a diagnostic marker for human autophagic vacuolar myopathies (AVMs)-was recently shown to compete with Nrf2 for Keap1 binding, resulting in activation of the Nrf2 pathway. In this study, we used 55 human muscle biopsies divided into five groups [normal control, hydroxychloroquine- or colchicine-treated non-AVM control, hydroxychloroquine- or colchicine-induced toxic AVM, polymyositis, and inclusion body myositis (IBM)] to evaluate whether Keap1-SQSTM1 interaction led to increased Nrf2 signaling in human AVMs. In toxic AVMs and IBM, but not in control muscle groups or polymyositis, Keap1 antibody labeled sarcoplasmic protein aggregates that can be used as an alternate diagnostic marker for both AVM types; these Keap1-positive aggregates were co-labeled with the antibody against SQSTM1 but not with the antibody against autophagosome marker LC3 (microtubule-associated protein 1 light chain 3). In human AVM muscle, sequestration of Keap1 into the SQSTM1-positive protein aggregates was accompanied by an increase in mRNA and protein levels of Nrf2 target genes; similarly, treatment of differentiated C2C12 myotubes with autophagy inhibitor chloroquine led to an increase in the nuclear Nrf2 protein level and an increase in expression of the Nrf2-regulated genes. Taken together, our findings demonstrate that Nrf2 signaling is upregulated in autophagic muscle disorders and raise the possibility that autophagy disruption in skeletal muscle leads to dysregulation of cellular redox homeostasis.

  14. Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation

    PubMed Central

    Yaou, Rabah Ben; Navarro, Claire; Quijano-Roy, Susana; Bertrand, Anne T; Massart, Catherine; De Sandre-Giovannoli, Annachiara; Cadiñanos, Juan; Mamchaoui, Kamel; Butler-Browne, Gillian; Estournet, Brigitte; Richard, Pascale; Barois, Annie; Lévy, Nicolas; Bonne, Gisèle

    2011-01-01

    Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome. Phenotype severity is correlated with the residual enzyme activity of ZMPSTE24 and accumulation of prelamin A. We had previously demonstrated that a complete loss of function in ZMPSTE24 was lethal in the neonatal period, whereas compound heterozygous mutations including one PTC and one missense mutation were associated with type B mandibuloacral dysplasia. In this study, we report a 30-year longitudinal clinical survey of a patient harboring a novel severe and complex phenotype, combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion. A unique homozygous missense ZMPSTE24 mutation (c.281T>C, p.Leu94Pro) was identified and predicted to produce two possible ZMPSTE24 conformations, leading to a partial loss of function. Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts. These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure. This is the first report of MAD presenting with confirmed myopathic abnormalities associated with ZMPSTE24 defects, extending the clinical spectrum of ZMPSTE24 gene mutations. Moreover, our results suggest that defective prelamin A processing affects muscle regeneration and development, thus providing new insights into the disease mechanism of prelamin A-defective associated syndromes in general. PMID:21267004

  15. A TALEN-Exon Skipping Design for a Bethlem Myopathy Model in Zebrafish

    PubMed Central

    Elipot, Yannick; Bretaud, Sandrine; Arnould, Sylvain; Duchateau, Philippe; Ruggiero, Florence; Joly, Jean-Stéphane; Sohm, Frédéric

    2015-01-01

    Presently, human collagen VI-related diseases such as Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) remain incurable, emphasizing the need to unravel their etiology and improve their treatments. In UCMD, symptom onset occurs early, and both diseases aggravate with ageing. In zebrafish fry, morpholinos reproduced early UCMD and BM symptoms but did not allow to study the late phenotype. Here, we produced the first zebrafish line with the human mutation frequently found in collagen VI-related disorders such as UCMD and BM. We used a transcription activator-like effector nuclease (TALEN) to design the col6a1ama605003-line with a mutation within an essential splice donor site, in intron 14 of the col6a1 gene, which provoke an in-frame skipping of exon 14 in the processed mRNA. This mutation at a splice donor site is the first example of a template-independent modification of splicing induced in zebrafish using a targetable nuclease. This technique is readily expandable to other organisms and can be instrumental in other disease studies. Histological and ultrastructural analyzes of homozygous and heterozygous mutant fry and 3 months post-fertilization (mpf) fish revealed co-dominantly inherited abnormal myofibers with disorganized myofibrils, enlarged sarcoplasmic reticulum, altered mitochondria and misaligned sarcomeres. Locomotion analyzes showed hypoxia-response behavior in 9 mpf col6a1 mutant unseen in 3 mpf fish. These symptoms worsened with ageing as described in patients with collagen VI deficiency. Thus, the col6a1ama605003-line is the first adult zebrafish model of collagen VI-related diseases; it will be instrumental both for basic research and drug discovery assays focusing on this type of disorders. PMID:26221953

  16. Bridging integrator 1 (Bin1) deficiency in zebrafish results in centronuclear myopathy

    PubMed Central

    Smith, Laura L.; Gupta, Vandana A.; Beggs, Alan H.

    2014-01-01

    Autosomal recessive centronuclear myopathy (CNM2), caused by mutations in bridging integrator 1 (BIN1), is a mildly progressive neuromuscular disorder characterized by abnormally centralized myonuclei and muscle weakness. BIN1 is important for membrane sensing and remodeling in vitro in different cell types. However, to fully understand the biological roles of BIN1 in vivo and to answer critical questions concerning the muscle-specific function of BIN1 in vertebrates, robust small animal models are required. In this study, we create and characterize a novel zebrafish model of CNM2 using antisense morpholinos. Immunofluorescence and histopathological analyses of Bin1-deficient zebrafish skeletal muscle reveal structural defects commonly reported in human CNM2 biopsies. Live imaging of zebrafish embryos shows defective calcium release in bin1 morphants, linking the presence of abnormal triads to impairments in intracellular signaling. RNA-mediated rescue assays demonstrate that knockdown of zebrafish bin1 can reliably examine the pathogenicity of novel BIN1 mutations in vivo. Finally, our results strongly suggest that the phosphoinositide-binding domain of BIN1, present only in skeletal muscle isoforms, may be more critical for muscle maturation and maintenance than for early muscle development. Overall, our data support that BIN1 plays an important role in membrane tubulation and may promote skeletal muscle weakness in CNM2 by disrupting machinery necessary for excitation–contraction coupling in vertebrate organisms. The reproducible phenotype of Bin1-deficient zebrafish, together with the generalized advantages of the teleost system, makes this model readily adaptable to high-throughput screening strategies and may be used to identify therapies for CNM2 and related neuromuscular diseases. PMID:24549043

  17. Differential Effects of Myopathy-Associated Caveolin-3 Mutants on Growth Factor Signaling

    PubMed Central

    Brauers, Eva; Dreier, Agnes; Roos, Andreas; Wormland, Berthold; Weis, Joachim; Krüttgen, Alexander

    2010-01-01

    Caveolin-3 is an important scaffold protein of cholesterol-rich caveolae. Mutations of caveolin-3 cause hereditary myopathies that comprise remarkably different pathologies. Growth factor signaling plays an important role in muscle physiology; it is influenced by caveolins and cholesterol-rich rafts and might thus be affected by caveolin-3 dysfunction. Prompted by the observation of a marked chronic peripheral neuropathy in a patient suffering from rippling muscle disease due to the R26Q caveolin-3 mutation and because TrkA is expressed by neuronal cells and skeletal muscle fibers, we performed a detailed comparative study on the effect of pathogenic caveolin-3 mutants on the signaling and trafficking of the TrkA nerve growth factor receptor and, for comparison, of the epidermal growth factor receptor. We found that the R26Q mutant slightly and the P28L strongly reduced nerve growth factor signaling in TrkA-transfected cells. Surface biotinylation experiments revealed that the R26Q caveolin-3 mutation markedly reduced the internalization of TrkA, whereas the P28L did not. Moreover, P28L expression led to increased, whereas R26Q expression decreased, epidermal growth factor signaling. Taken together, we found differential effects of the R26Q and P28L caveolin-3 mutants on growth factor signaling. Our findings are of clinical interest because they might help explain the remarkable differences in the degree of muscle lesions caused by caveolin-3 mutations and also the co-occurrence of peripheral neuropathy in the R26Q caveolinopathy case presented. PMID:20472890

  18. Coenzyme Q(10) and selenium in statin-associated myopathy treatment.

    PubMed

    Fedacko, Jan; Pella, Daniel; Fedackova, Petra; Hänninen, Osmo; Tuomainen, Petri; Jarcuska, Peter; Lopuchovsky, Tomas; Jedlickova, Lucia; Merkovska, Lucia; Littarru, Gian Paolo

    2013-02-01

    The objective of this study was to evaluate the possible benefits of coenzyme Q10 and selenium supplementation administered to patients with statin-associated myopathy (SAM). Sixty eligible patients entered the pilot study. Laboratory examination (CoQ10, selenium, creatin kinase) and intensity of SAM (visual scale) were performed at baseline, after 1 month, and at the end of study at month 3. Plasma levels of CoQ10 increased from 0.81 ± 0.39 to 3.31 ± 1.72 μmol/L in the active group of patients treated by CoQ10, compared with the placebo (p = 0.001). Also, the symptoms of SAM significantly improved in the active group (p < 0.001): the intensity of muscle pain decreased from 6.7 ± 1.72 to 3.2 ± 2.1 (p < 0.01, -53.4 ± 28.2%); muscle weakness decreased from 7.0 ± 1.63 to 2.8 ± 2.34 (p < 0.01, -60 ± 24.0%); muscle cramps decreased from 5.33 ± 2.06 to 1.86 ± 2.42, p < 0.01, -65 ± 28%); tiredness decreased from the initial 6.7 ± 1.34 to 1.2 ± 1.32 (p < 0.01, -82 ± 22%). We did not observe any significant changes in the placebo group. In conclusion, supplementation of statin-treated patients with CoQ10 resulted in a decrease in the symptoms of SAM, both in absolute numbers and intensity. Additional selenium supplementation was not associated with any statistically significant decrease of SAM. However, it is not possible to draw any definite conclusions, even though this study was carried out in double-blind fashion, because it involved a small number of patients.

  19. A Randomized Trial of Coenzyme Q10 in Patients with Statin Myopathy: Rationale and Study Design

    PubMed Central

    Parker, Beth A.; Gregory, Sara M.; Lorson, Lindsay; Polk, Donna; White, C. Michael; Thompson, Paul D.

    2013-01-01

    Background Statins are the most commonly prescribed and effective medications for reducing low-density lipoprotein levels. Some patients experience myopathic symptoms during statin treatment. The etiology is not known, but depletion of mevalonate pathway metabolites, including coenzyme Q10 (CoQ10), has been suggested. CoQ10 supplementation has been recommended to patients who experience myalgic symptoms despite a lack of conclusive evidence supporting its utility. Objective The Co-Enzyme Q10 in Statin Myopathy study is designed to examine the effect of CoQ10 supplementation on the extent and intensity of muscle pain during treatment with simvastatin. Methods We will recruit patients with a documented history of myalgia during statin treatment. The presence of statin-related myalgia will be confirmed in a crossover run-in trial during which presence and absence of symptoms will be documented during statin and placebo treatment, respectively. Individuals with myalgic symptoms while on statin but not placebo will be randomized to receive simvastatin 20 mg daily plus either 600 mg daily of CoQ10 or placebo. Muscle pain intensity will be documented during weekly phone calls using the Brief Pain Inventory (Short Form) (BPI-SF). Treatment will continue for 8 weeks or until muscle symptoms are reported continuously for one week or become intolerable, and then subjects will crossover to the alternative treatment (CoQ10 or placebo). Results This study is an ongoing clinical trial. Conclusions This study will determine the utility of CoQ10 for reducing pain intensity in myalgic patients and will provide guidance for clinicians treating patients with hypercholesterolemia who are intolerant to statins. PMID:23725917

  20. Isolated inclusion body myopathy caused by a multisystem proteinopathy–linked hnRNPA1 mutation

    PubMed Central

    Izumi, Rumiko; Warita, Hitoshi; Niihori, Tetsuya; Takahashi, Toshiaki; Tateyama, Maki; Suzuki, Naoki; Nishiyama, Ayumi; Shirota, Matsuyuki; Funayama, Ryo; Nakayama, Keiko; Mitsuhashi, Satomi; Nishino, Ichizo; Aoki, Yoko

    2015-01-01

    Objective: To identify the genetic cause of isolated inclusion body myopathy (IBM) with autosomal dominant inheritance in 2 families. Methods: Genetic investigations were performed using whole-exome and Sanger sequencing of the heterogeneous nuclear ribonucleoprotein A1 gene (hnRNPA1). The clinical and pathologic features of patients in the 2 families were evaluated with neurologic examinations, muscle imaging, and muscle biopsy. Results: We identified a missense p.D314N mutation in hnRNPA1, which is also known to cause familial amyotrophic lateral sclerosis, in 2 families with IBM. The affected individuals developed muscle weakness in their 40s, which slowly progressed toward a limb-girdle pattern. Further evaluation of the affected individuals revealed no apparent motor neuron dysfunction, cognitive impairment, or bone abnormality. The muscle pathology was compatible with IBM, lacking apparent neurogenic change and inflammation. Multiple immunohistochemical analyses revealed the cytoplasmic aggregation of hnRNPA1 in close association with autophagosomes and myonuclei. Furthermore, the aberrant accumulation was characterized by coaggregation with ubiquitin, sequestome-1/p62, valosin-containing protein/p97, and a variety of RNA-binding proteins (RBPs). Conclusions: The present study expands the clinical phenotype of hnRNPA1-linked multisystem proteinopathy. Mutations in hnRNPA1, and possibly hnRNPA2B1, will be responsible for isolated IBM with a pure muscular phenotype. Although the mechanisms underlying the selective skeletal muscle involvement remain to be elucidated, the immunohistochemical results suggest a broad sequestration of RBPs by the mutated hnRNPA1. PMID:27066560

  1. Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy

    PubMed Central

    Gimenes, A.C.; Bravo, D.M.; Nápolis, L.M.; Mello, M.T.; Oliveira, A.S.B.; Neder, J.A.; Nery, L.E.

    2015-01-01

    Exercise intolerance due to impaired oxidative metabolism is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still uncertain whether L-carnitine supplementation is beneficial for patients with MM. The aim of our study was to investigate the effects of L-carnitine on exercise performance in MM. Twelve MM subjects (mean age±SD=35.4±10.8 years) with chronic progressive external ophthalmoplegia (CPEO) were first compared to 10 healthy controls (mean age±SD=29±7.8 years) before they were randomly assigned to receive L-carnitine supplementation (3 g/daily) or placebo in a double-blind crossover design. Clinical status, body composition, respiratory function tests, peripheral muscle strength (isokinetic and isometric torque) and cardiopulmonary exercise tests (incremental to peak exercise and at 70% of maximal), constant work rate (CWR) exercise test, to the limit of tolerance [Tlim]) were assessed after 2 months of L-carnitine/placebo administration. Patients with MM presented with lower mean height, total body weight, fat-free mass, and peripheral muscle strength compared to controls in the pre-test evaluation. After L-carnitine supplementation, the patients with MM significantly improved their Tlim (14±1.9 vs 11±1.4 min) and oxygen consumption (V˙O2) at CWR exercise, both at isotime (1151±115 vs 1049±104 mL/min) and at Tlim (1223±114 vs 1060±108 mL/min). These results indicate that L-carnitine supplementation may improve aerobic capacity and exercise tolerance during high-intensity CWRs in MM patients with CPEO. PMID:25714882

  2. Expression of the intermediate filament protein synemin in myofibrillar myopathies and other muscle diseases.

    PubMed

    Olivé, Montse; Goldfarb, Lev; Dagvadorj, Ayush; Sambuughin, Nyamkhishig; Paulin, Denise; Li, Zhenlin; Goudeau, Bertrand; Vicart, Patrick; Ferrer, Isidro

    2003-07-01

    Synemin is a member of the intermediate protein superfamily. Previous studies in avian and rodent skeletal and cardiac muscles have demonstrated that synemin localises at the Z-band, where it associates with desmin and alpha-actinin. In the present study, the distribution of synemin was examined using immunohistochemistry in muscle biopsy specimens from patients suffering from myofibrillar myopathy (MM, n=6), dermatomyositis (DM, n=3), inclusion body myositis (IBM, n=5), oculopharyngeal muscular dystrophy (OPD, n=3) and denervation atrophy (DA, n=3), to investigate the possible participation of this protein in the pathogenesis of various muscular diseases. Of patients affected by MM, two showed the presence of mutations in the desmin gene; none had mutations in the alphaB-crystallin gene; and no mutations were identified in synemin or syncoilin genes of three patients. Synemin immunohistochemistry disclosed a faint staining corresponding to the Z-bands in the cytoplasm of control muscle fibres; in contrast, focal aggregates of synemin were seen in patients with MM. Increased synemin immunoreactivity was identified diffusely or in the subsarcolemmal space of scattered fibres in patients with DM, and in vacuolated fibres of patients with IBM and OPD. Strong synemin immunoreactivity was observed in target formations and atrophic fibres of patients with denervating disorders, as well as in atrophic fibres, regardless of their origin, in all patients studied. Synemin co-localised with desmin, as seen on consecutive serial sections immunostained with anti-synemin or anti-desmin antibodies. These observations demonstrate abnormal accumulations containing both synemin and desmin in muscle fibres in patients with MM, IBM, DM, OPD and DA. Considering the important role of synemin as one of intermediate filaments of skeletal and cardiac muscle, its destruction and accumulation in the intracellular debris suggest that synemin may participate in the pathogenesis of these

  3. Reliability of the Adult Myopathy Assessment Tool in Individuals with Myositis

    PubMed Central

    Harris-Love, Michael O.; Joe, Galen; Davenport, Todd E.; Koziol, Deloris; Rose, Kristen Abbett; Shrader, Joseph A.; Vasconcelos, Olavo M.; McElroy, Beverly; Dalakas, Marinos C.

    2015-01-01

    Objective The Adult Myopathy Assessment Tool (AMAT) is a 13-item performance-based battery developed to assess functional status and muscle endurance. The purpose of this study was to determine the intrarater and interrater reliability of the AMAT in adults with myosits. Methods Nineteen raters (13 physical therapists and 6 physicians) scored videotaped recordings of patients with myositis performing the AMAT for a total of 114 tests and 1,482 item observations per session. Raters rescored the AMAT test and item observations during a follow up session (19 ±6 days between scoring sessions). All raters completed a single, self-directed, electronic training module prior to the initial scoring session. Results Intrarater and interrater reliability correlation coefficients were .94 or greater for the AMAT Functional Subscale, Endurance Subscale, and Total score (all p < 0.02 for Ho:ρ ≤ 0.75). All AMAT items had satisfactory intrarater agreement (Kappa statistics with Fleiss-Cohen weights, Kw = .57-1.00). Interrater agreement was acceptable for each AMAT item (K = .56-.89) except the sit up (K = .16). The standard error of measurement and 95% confidence interval range for the AMAT Total scores did not exceed 2 points across all observations (AMAT Total score range = 0-45). Conclusions The AMAT is a reliable, domain-specific assessment of functional status and muscle endurance for adult subjects with myositis. Results of this study suggest that physicians and physical therapists may reliably score the AMAT following a single training session. The AMAT Functional Subscale, Endurance Subscale, and Total score exhibit interrater and intrarater reliability suitable for clinical and research use. PMID:25201624

  4. COLQ variant associated with Devon Rex and Sphynx feline hereditary myopathy.

    PubMed

    Gandolfi, Barbara; Grahn, Robert A; Creighton, Erica K; Williams, D Colette; Dickinson, Peter J; Sturges, Beverly K; Guo, Ling T; Shelton, G Diane; Leegwater, Peter A J; Longeri, Maria; Malik, Richard; Lyons, Leslie A

    2015-12-01

    Some Devon Rex and Sphynx cats have a variably progressive myopathy characterized by appendicular and axial muscle weakness, megaesophagus, pharyngeal weakness and fatigability with exercise. Muscle biopsies from affected cats demonstrated variable pathological changes ranging from dystrophic features to minimal abnormalities. Affected cats have exacerbation of weakness following anticholinesterase dosing, a clue that there is an underlying congenital myasthenic syndrome (CMS). A genome-wide association study and whole-genome sequencing suggested a causal variant for this entity was a c.1190G>A variant causing a cysteine to tyrosine substitution (p.Cys397Tyr) within the C-terminal domain of collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). Alpha-dystroglycan expression, which is associated with COLQ anchorage at the motor end-plate, has been shown to be deficient in affected cats. Eighteen affected cats were identified by genotyping, including cats from the original clinical descriptions in 1993 and subsequent publications. Eight Devon Rex and one Sphynx not associated with the study were identified as carriers, suggesting an allele frequency of ~2.0% in Devon Rex. Over 350 tested cats from other breeds did not have the variant. Characteristic clinical features and variant presence in all affected cats suggest a model for COLQ CMS. The association between the COLQ variant and this CMS affords clinicians the opportunity to confirm diagnosis via genetic testing and permits owners and breeders to identify carriers in the population. Moreover, accurate diagnosis increases available therapeutic options for affected cats based on an understanding of the pathophysiology and experience from human CMS associated with COLQ variants.

  5. Severe insulin-resistant diabetes mellitus in patients with congenital muscle fiber type disproportion myopathy.

    PubMed

    Vestergaard, H; Klein, H H; Hansen, T; Müller, J; Skovby, F; Bjørbaek, C; Røder, M E; Pedersen, O

    1995-04-01

    Congenital muscle fiber type disproportion myopathy (CFTDM) is a chronic, nonprogressive muscle disorder characterized by universal muscle hypotrophy and growth retardation. Histomorphometric examination of muscle shows a preponderance of smaller than normal type 1 fibers and overall fiber size heterogeneity. Concomitant endocrine dysfunctions have not been described. We report the findings of altered insulin secretion and insulin action in two brothers affected with CFTDM and glucose intolerance as well as in their nonconsanguineous glucose-tolerant parents. Results are compared with those of six normoglycemic control subjects. All study participants underwent an oral glucose tolerance test to estimate insulin secretion. The oldest boy and his parents volunteered for studies of whole-body insulin sensitivity consisting of a 4-h euglycemic hyperinsulinemic clamp in combination with indirect calorimetry. Insulin receptor function and glycogen synthase (GS) activity and expression were examined in biopsies of vastus lateralis muscle. Despite a 45-90-fold increase in both fasting and postprandial serum insulin levels, both CFTDM patients had diabetes mellitus. Clamp studies revealed that the oldest boy had severe insulin resistance of both liver and peripheral tissues. The impaired insulin-stimulated glucose disposal to peripheral tissues was primarily due to reduced nonoxidative glucose metabolism. These changes were paralleled by reduced basal values of muscle GS total activity, allosterical activation of GS by glucose-6-phosphate, GS protein, and GS mRNA. The father expressed a lesser degree of insulin resistance, and studies of muscle insulin receptor function showed a severe impairment of receptor kinase activity. In conclusion, CFTDM is a novel form of severe hyperinsulinemia and insulin resistance. Whether insulin resistance is causally related to the muscle disorder awaits to be clarified.

  6. Immunoglobulin Gene Polymorphisms are Susceptibility Factors for Clinical and Autoantibody Subgroups of the Idiopathic Inflammatory Myopathies

    PubMed Central

    O’Hanlon, Terrance P.; Rider, Lisa G.; Schiffenbauer, Adam; Targoff, Ira N.; Malley, Karen; Pandey, Janardan P.; Miller, Frederick W.

    2009-01-01

    Objective To investigate possible associations of GM and KM markers in European Americans (EA) and African Americans (AA) with adult and juvenile forms of the idiopathic inflammatory myopathies (IIM). Methods We performed serologic analyses of polymorphic determinants associated with immunoglobulin gamma heavy (GM) and kappa light chains (KM) in large populations of EA (n=514: 297 adults and 217 juveniles) and AA IIM patients (n=109: 73 adults and 50 juveniles) representing the major clinicopathologic and autoantibody groups. Results For EA dermatomyositis (DM) patients, the GM 3 23 5,13 phenotype was a risk factor for both adults (OR=2.2; Pc=0.020) and juveniles (OR=2.2; Pc=0.0013). Of interest, the GM 13 allotype was a risk factor for juvenile DM (JDM) for both EA (OR=3.9; Pc<0.0001) and AA (OR=4.8; Pc=0.033). However, the GM 1,3,17 5,13,21 phenotype was a risk factor for JDM in EA but not in AA. Among the IIM autoantibody groups, GM 3 23 5,13 was a risk factor for EA adults with anti-Jo-1 autoantibodies (OR=3.4; Pc=0.0031), while the GM 3 allotype was protective for adults with anti-threonyl tRNA synthetase or anti-RNP autoantibodies (OR=0.1; Pc=0.047 and OR=0.2; Pc=0.034, respectively). In contrast, GM 6 was a risk factor for AA adults with anti-SRP autoantibodies (OR=7.5; Pc=0.041). Conclusions These data suggest that polymorphic alleles of GM and KM loci are differentially associated with IIM subgroups defined by age, ethnicity, clinical features and autoantibodies, and expand the list of immune response genes possibly important in the pathogenesis of myositis. PMID:18821675

  7. Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy.

    PubMed

    Gimenes, A C; Bravo, D M; Nápolis, L M; Mello, M T; Oliveira, A S B; Neder, J A; Nery, L E

    2015-04-01

    Exercise intolerance due to impaired oxidative metabolism is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still uncertain whether L-carnitine supplementation is beneficial for patients with MM. The aim of our study was to investigate the effects of L-carnitine on exercise performance in MM. Twelve MM subjects (mean age±SD=35.4±10.8 years) with chronic progressive external ophthalmoplegia (CPEO) were first compared to 10 healthy controls (mean age±SD=29±7.8 years) before they were randomly assigned to receive L-carnitine supplementation (3 g/daily) or placebo in a double-blind crossover design. Clinical status, body composition, respiratory function tests, peripheral muscle strength (isokinetic and isometric torque) and cardiopulmonary exercise tests (incremental to peak exercise and at 70% of maximal), constant work rate (CWR) exercise test, to the limit of tolerance [Tlim]) were assessed after 2 months of L-carnitine/placebo administration. Patients with MM presented with lower mean height, total body weight, fat-free mass, and peripheral muscle strength compared to controls in the pre-test evaluation. After L-carnitine supplementation, the patients with MM significantly improved their Tlim (14±1.9 vs 11±1.4 min) and oxygen consumption ( V ˙ O 2 ) at CWR exercise, both at isotime (1151±115 vs 1049±104 mL/min) and at Tlim (1223±114 vs 1060±108 mL/min). These results indicate that L-carnitine supplementation may improve aerobic capacity and exercise tolerance during high-intensity CWRs in MM patients with CPEO.

  8. Myopathy induced by HMG-CoA reductase inhibitors in rabbits: a pathological, electrophysiological, and biochemical study.

    PubMed

    Nakahara, K; Kuriyama, M; Sonoda, Y; Yoshidome, H; Nakagawa, H; Fujiyama, J; Higuchi, I; Osame, M

    1998-09-01

    A combination of electrophysiological, pathological, and biochemical studies were performed in myopathy induced by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Simvastatin (a lipophilic inhibitor) or pravastatin (a hydrophilic inhibitor) were administered by gavage to rabbits. In Group I (simvastatin-treated group, 50 mg/kg/day for 4 weeks), four rabbits showed muscle necrosis and high serum creatine kinase (CK) levels, and all six rabbits showed electrical myotonia. In Group II (pravastatin-treated group, 100 mg/kg/day for 4 weeks), no rabbit showed either condition. In Group III (pravastatin-treated group, 200 mg/kg/day for 3 weeks plus 300 mg/kg/day for 3 weeks), one rabbit showed muscle necrosis and high serum CK level and two rabbits showed electrical myotonia. The pathological findings were muscle fiber necrosis and degeneration with increased acid phosphatase activity by light microscopy, autophagic vacuoles and mitochondrial swelling, and disruption and hypercontraction of myofibrils by electron microscopy. Ubiquinone content decreased in skeletal muscle by 22 to 36% in Group I, by 18 to 52% in Group II, and by 49 to 72% in Group III. However, mitochondrial enzyme activities of respiratory chain were normal in all groups. These results indicate that myopathy was not induced by a secondary dysfunction of mitochondrial respiration due to low ubiquinone levels.

  9. Activation of the Unfolded Protein Response in Sporadic Inclusion Body Myositis But Not in Hereditary GNE Inclusion Body Myopathy

    PubMed Central

    Nogalska, Anna; D’Agostino, Carla; Engel, W. King; Cacciottolo, Mafalda; Asada, Shinichi; Mori, Kazutoshi; Askanas, Valerie

    2015-01-01

    Muscle fibers in patients with sporadic inclusion-body myositis (s-IBM), the most common age-associated myopathy, are characterized by autophagic vacuoles and accumulation of ubiquitinated and congophilic multiprotein aggregates that contain amyloid-β and phosphorylated tau. Muscle fibers of autosomal-recessive hereditary inclusion-body myopathy due to the GNE mutation (GNE-h-IBM) display similar pathologic features, except with less pronounced congophilia. Accumulation of unfolded/misfolded proteins inside the ER lumen leads to ER stress, which elicits the unfolded protein response (UPR) as a protective mechanism. Here we demonstrate for the first time that UPR is activated in s-IBM muscle biopsies, since there was a) increased ATF4 protein and increased mRNA of its target CHOP, b) cleavage of the ATF6 and increased mRNA of its target GRP78, and c) an increase of the spliced form of XBP-1 and increased mRNA of EDEM, target of heterodimer of cleaved ATF6 and spliced XBP-1. In contrast, we did not find similar evidence of the UPR induction in GNE-h-IBM patient muscle, suggesting that different intracellular mechanisms might lead to the similar pathological phenotypes. Interestingly, cultured GNE-h-IBM muscle fibers had a robust UPR response to experimental ER stress stimuli, suggesting that the GNE mutation per se is not responsible for the lack of UPR in GNE-h-IBM biopsied muscle. PMID:25978849

  10. Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems.

    PubMed

    Walmsley, Gemma L; Blot, Stéphane; Venner, Kerrie; Sewry, Caroline; Laporte, Jocelyn; Blondelle, Jordan; Barthélémy, Inès; Maurer, Marie; Blanchard-Gutton, Nicolas; Pilot-Storck, Fanny; Tiret, Laurent; Piercy, Richard J

    2017-02-01

    Mutations in HACD1/PTPLA cause recessive congenital myopathies in humans and dogs. Hydroxyacyl-coA dehydratases are required for elongation of very long chain fatty acids, and HACD1 has a role in early myogenesis, but the functions of this striated muscle-specific enzyme in more differentiated skeletal muscle remain unknown. Canine HACD1 deficiency is histopathologically classified as a centronuclear myopathy (CNM). We investigated the hypothesis that muscle from HACD1-deficient dogs has membrane abnormalities in common with CNMs with different genetic causes. We found progressive changes in tubuloreticular and sarcolemmal membranes and mislocalized triads and mitochondria in skeletal muscle from animals deficient in HACD1. Furthermore, comparable membranous abnormalities in cultured HACD1-deficient myotubes provide additional evidence that these defects are a primary consequence of altered HACD1 expression. Our novel findings, including T-tubule dilatation and disorganization, associated with defects in this additional CNM-associated gene provide a definitive pathophysiologic link with these disorders, confirm that dogs deficient in HACD1 are relevant models, and strengthen the evidence for a unifying pathogenesis in CNMs via defective membrane trafficking and excitation-contraction coupling in muscle. These results build on previous work by determining further functional roles of HACD1 in muscle and provide new insight into the pathology and pathogenetic mechanisms of HACD1 CNM. Consequently, alterations in membrane properties associated with HACD1 mutations should be investigated in humans with related phenotypes.

  11. Comparison of histopathologic criteria and skeletal muscle fixation techniques for the diagnosis of polysaccharide storage myopathy in horses.

    PubMed

    Firshman, A M; Valberg, S J; Bender, J B; Annandale, E J; Hayden, D W

    2006-05-01

    The purpose of the study reported here was to determine the effect of three methods of fixation of skeletal muscle biopsy specimens on the histopathologic appearance of muscle sections and to determine criteria that were most consistently associated with a diagnosis of polysaccharide storage myopathy (PSSM) in horses. Surgically excised semimembranosus muscle biopsy specimens were obtained from nine horses previously diagnosed with PSSM and from 15 control horses. Portions of each specimen were fixed in formalin, frozen immediately, and chilled for 24 hours prior to freezing. Sections stained with hematoxylin and eosin (HE), periodic acid-Schiff (PAS), and amylase-PAS were scored for histopathologic criteria by three investigators blinded to the sample origin. The presence of amylase-resistant, abnormal polysaccharide was found to be the most sensitive and specific diagnostic indicator for PSSM, and was readily detected regardless of the fixation technique or investigator. Other less-specific features associated with PSSM included atrophy and cytoplasmic and subsarcolemmal vacuoles; however, their histologic scores varied among fixation technique and investigators. Scores for subsarcolemmal and cytoplasmic amylase-sensitive glycogen in horses with PSSM were similar to those for control horses and varied among fixation techniques. In conclusion, PSSM is most accurately diagnosed in muscle biopsy specimens on the basis of appearance of amylase-resistant, abnormal polysaccharide, not amylase-sensitive glycogen, regardless of fixation technique. In general, frozen sections appeared to be better suited for studying myopathies because many histopathologic features of skeletal muscle were obscured by formalin fixation.

  12. A GYS1 gene mutation is highly associated with polysaccharide storage myopathy in Cob Normand draught horses.

    PubMed

    Herszberg, B; McCue, M E; Larcher, T; Mata, X; Vaiman, A; Chaffaux, S; Chérel, Y; Valberg, S J; Mickelson, J R; Guérin, G

    2009-02-01

    Glycogen storage diseases or glycogenoses are inherited diseases caused by abnormalities of enzymes that regulate the synthesis or degradation of glycogen. Deleterious mutations in many genes of the glyco(geno)lytic or the glycogenesis pathways can potentially cause a glycogenosis, and currently mutations in fourteen different genes are known to cause animal or human glycogenoses, resulting in myopathies and/or hepatic disorders. The genetic bases of two forms of glycogenosis are currently known in horses. A fatal neonatal polysystemic type IV glycogenosis, inherited recessively in affected Quarter Horse foals, is due to a mutation in the glycogen branching enzyme gene (GBE1). A second type of glycogenosis, termed polysaccharide storage myopathy (PSSM), is observed in adult Quarter Horses and other breeds. A severe form of PSSM also occurs in draught horses. A mutation in the skeletal muscle glycogen synthase gene (GYS1) was recently reported to be highly associated with PSSM in Quarter Horses and Belgian draught horses. This GYS1 point mutation appears to cause a gain-of-function of the enzyme and to result in the accumulation of a glycogen-like, less-branched polysaccharide in skeletal muscle. It is inherited as a dominant trait. The aim of this work was to test for possible associations between genetic polymorphisms in four candidate genes of the glycogen pathway or the GYS1 mutation in Cob Normand draught horses diagnosed with PSSM by muscle biopsy.

  13. A Premature Stop Codon in MYO18B is Associated with Severe Nemaline Myopathy with Cardiomyopathy

    PubMed Central

    Malfatti, Edoardo; Böhm, Johann; Lacène, Emmanuelle; Beuvin, Maud; Guy Brochier; Romero, Norma B.; Laporte, Jocelyn

    2015-01-01

    Abstract Background: Nemaline myopathies (NM) are rare and severe muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Although ten genes have been implicated in the etiology of NM, an important number of patients remain without a molecular diagnosis. Objective: Here we describe the clinical and histopathological features of a sporadic case presenting with severe NM and cardiomyopathy. Using exome sequencing, we aimed to identify the causative gene. Results: We identified a homozygous nonsense mutation in the last exon of MYO18B, leading to a truncated protein lacking the most C-terminal part. MYO18B codes for an unconventional myosin protein and it is mainly expressed in skeletal and cardiac muscles, two tissues severely affected in the patient. We showed that the mutation does not impact on mRNA stability. Immunostaining and Western blot confirmed the absence of the full-length protein. Conclusion: We propose MYO18B as a novel gene associated with nemaline myopathy and cardiomyopathy. PMID:27858739

  14. A novel COL12A1 variant expands the clinical picture of congenital myopathies with extracellular matrix defects

    PubMed Central

    Punetha, Jaya; Kesari, Akanchha; Hoffman, Eric P.; Gos, Monika; Kamińska, Anna; Kostera-Pruszczyk, Anna; Hausmanowa-Petrusewicz, Irena; Hu, Ying; Zou, Yaqun; Bönnemann, Carsten G.; Jędrzejowska, Maria

    2017-01-01

    Introduction Mutations in the COL12A1 gene have been described in a milder Bethlem-like myopathy in 6 patients from 3 families (dominant missense), and in a severe congenital form with failure to attain ambulation in 2 patients in a single pedigree (recessive loss-of-function). Methods We describe an 8-year old girl of Polish origin who presented with profound hypotonia and joint hyperlaxity at birth after a pregnancy complicated by oligohydramnios and intrauterine growth retardation. Results We identified a novel, potentially pathogenic heterozygous missense COL12A1 c.8329G>C (p.Gly2777Arg) variant using a targeted sequencing panel. Patient fibroblast studies confirmed intracellular retention of the COL12A1 protein, consistent with a dominant-negative mutation. Conclusions As our patient showed a more intermediate phenotype, this case expands the phenotypic spectrum for COL12A1 disorders. So far, COL12A1 disorders seem to cover much of the severity range of an Ehlers-Danlos/Bethlem-like myopathy overlap syndrome associated with both connective tissue abnormalities and muscle weakness. PMID:27348394

  15. Hereditary inclusion-body myopathy with sparing of the quadriceps: the many tiles of an incomplete puzzle.

    PubMed

    Broccolini, A; Gidaro, T; Morosetti, R; Sancricca, C; Mirabella, M

    2011-10-01

    The hereditary inclusion-body myopathies encompass several syndromes with autosomal recessive or dominant inheritance. Despite a different clinical presentation they all have a progressive course leading to severe disability and share similar pathologic findings at the muscle biopsy. Quadriceps-sparing autosomal recessive hereditary inclusion-body myopathy (h-IBM) is the commonest form and is tied to mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been clarified how mutations of the GNE gene impair muscle homeostasis. Although several lines of evidence argue in favor of an abnormal sialylation of muscle glycoproteins playing a key role in h-IBM pathogenesis, others studies have demonstrated new functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h-IBM and the main clues available to date concerning the possible pathogenic mechanisms of this disorder. Understanding the molecular mechanism underlying h-IBM pathology is a fundamental requisite to plan a future attempt to therapy.

  16. Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype

    PubMed Central

    Vasli, Nasim; Laugel, Vincent; Böhm, Johann; Lannes, Béatrice; Biancalana, Valérie; Laporte, Jocelyn

    2012-01-01

    Mutations impacting on the splicing of pre-mRNA are one important cause of genetically inherited diseases. However, detection of splice mutations, that are mainly due to intronic variations, and characterization of their effects are usually not performed as a first approach during genetic diagnosis. X-linked recessive myotubular myopathy is a severe congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. Here, we screened a male patient showing an unusually mild phenotype without respiratory distress by western blot with specific myotubularin antibodies and detected a strong reduction of the protein level.The disease was subsequently linked to a hemizygous point mutation affecting the acceptor splice site of exon 8 of MTM1, proven by protein, transcript and genomic DNA analysis. Detailed analysis of the MTM1 mRNA by RT-PCR, sequencing and quantitative PCR revealed multiple abnormal transcripts with retention of a truncated exon 8, and neighboring exons 7 and 9 but exclusion of several other exons, suggesting a complex effect of this mutation on the splicing of non-adjacent exons. We conclude that the analysis of RNA by RT-PCR and sequencing is an important step to characterize the precise impact of detected splice variants. It is likely that complex splice aberrations due to a single mutation also account for unsolved cases in other diseases. PMID:22258523

  17. Proximal myopathy with focal depletion of mitochondria and megaconial congenital muscular dystrophy are allelic conditions caused by mutations in CHKB.

    PubMed

    Brady, L; Giri, M; Provias, J; Hoffman, E; Tarnopolsky, M

    2016-02-01

    We recently evaluated two of the original three patients (siblings) diagnosed with Proximal Myopathy with Focal Depletion of Mitochondria. The condition was named for the distinctive pattern of enlarged mitochondria around the periphery of muscle fibres with a complete absence in the middle. These siblings, aged 37 and 40, are cognitively normal with mild non-progressive muscle weakness and a susceptibility to rhabdomyolysis. Both were shown to be compound heterozygotes for novel mutations (c.263C>T + c.950T>A) in CHKB, the gene currently associated with Megaconial Congenital Muscular Dystrophy. Individuals with this condition have early-onset muscle weakness and profound intellectual disability but share the same unique pattern on muscle biopsy as was noted in Proximal Myopathy with Focal Depletion of Mitochondria; focal depletion of mitochondria was surrounded by abnormally large "megaconial" mitochondria. Thus the phenotypic spectrum of CHKB mutations ranges from a congenital muscular dystrophy with intellectual disability to a later-onset non-progressive muscular weakness with normal cognition.

  18. Increased amyloid β-peptide uptake in skeletal muscle is induced by hyposialylation and may account for apoptosis in GNE myopathy

    PubMed Central

    Bosch-Morató, Mònica; Iriondo, Cinta; Guivernau, Biuse; Valls-Comamala, Victòria; Vidal, Noemí; Olivé, Montse; Querfurth, Henry; Muñoz, Francisco J.

    2016-01-01

    GNE myopathy is an autosomal recessive muscular disorder of young adults characterized by progressive skeletal muscle weakness and wasting. It is caused by a mutation in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, which encodes a key enzyme in sialic acid biosynthesis. The mutated hypofunctional GNE is associated with intracellular accumulation of amyloid β-peptide (Aβ) in patient muscles through as yet unknown mechanisms. We found here for the first time that an experimental reduction in sialic acid favors Aβ1-42 endocytosis in C2C12 myotubes, which is dependent on clathrin and heparan sulfate proteoglycan. Accordingly, Aβ1-42 internalization in myoblasts from a GNE myopathy patient was enhanced. Next, we investigated signal changes triggered by Aβ1-42 that may underlie toxicity. We observed that p-Akt levels are reduced in step with an increase in apoptotic markers in GNE myopathy myoblasts compared to control myoblasts. The same results were experimentally obtained when Aβ1-42 was overexpressed in myotubes. Hence, we propose a novel disease mechanism whereby hyposialylation favors Aβ1-42 internalization and the subsequent apoptosis in myotubes and in skeletal muscle from GNE myopathy patients. PMID:26968811

  19. Effect of simvastatin on cholesterol metabolism in C2C12 myotubes and HepG2 cells, and consequences for statin-induced myopathy.

    PubMed

    Mullen, Peter James; Lüscher, Barbara; Scharnagl, Hubert; Krähenbühl, Stephan; Brecht, Karin

    2010-04-15

    The mechanism of statin-induced skeletal muscle myopathy is poorly understood. We investigated how simvastatin affects cholesterol metabolism, ubiquinone levels, and the prenylation and N-linked glycosylation of proteins in C2C12 myotubes. We used liver HepG2 cells for comparison, as their responses to statins are well-characterized in terms of their cholesterol metabolism (in contrast to muscle cells), and statins are well-tolerated in the liver. Differences between the two cell lines could indicate the mechanism behind statin-induced myopathy. Simvastatin reduced de novo cholesterol production in C2C12 myotubes by 95% after 18h treatment. The reduction was 82% in the HepG2 cells. Total cholesterol pools, however, remained constant in both cell lines. Simvastatin treatment similarly did not affect total ubiquinone levels in the myotubes, unlike in HepG2 cells (22% reduction in CoQ10). Statin treatment reduced levels of Ras and Rap1 prenylation in both cell lines, whereas N-linked glycosylation was only affected in C2C12 myotubes (21% reduction in rate). From these observations, we conclude that total cholesterol and ubiquinone levels are unlikely to be involved in statin-mediated myopathy, but reductions in protein prenylation and especially N-linked glycosylation may play a role. This first comparison of the responses to simvastatin between liver and skeletal muscle cell lines may be important for future research directions concerning statin-induced myopathy.

  20. Selected case from the Arkadi M. Rywlin International Pathology Slide Series: Mitochondrial myopathy presenting with chronic progressive external ophthalmoplegia (CPEO): a case report.

    PubMed

    Bisceglia, Michele; Crociani, Paola; Fogli, Danilo; Centola, Antonio; Galliani, Carlos A; Pasquinelli, Gianandrea

    2014-11-01

    A 43-year-old female patient diagnosed with chronic progressive external ophthalmoplegia (CPEO) because of mitochondrial myopathy documented by muscle biopsy is presented. The chief complaints were represented by blepharoptosis and ophthalmoplegia. The muscle biopsy was evaluated by histology, using the appropriate histochemical and histoenzimological stains. Ragged red fibers with Gomori trichrome stain were seen, which showed cytochrome c oxydase deficiency and abnormal succinate dehydrogenase staining in around 20% of muscle fibres. Electron microscopy was also performed which demonstrated abnormal, hyperplastic, pleomorphic, and hypertrophic mitochondria, characterized by paracrystalline inclusions arranged in parallel rows ("parking-lot" inclusions), consisting of rectangular arrays of mitochondrial membranes in a linear or grid-like pattern. In conclusion, mitochondrial myopathy was definitely diagnosed. Although molecular analysis, which was subsequently carried out, failed to reveal mutations in the mitochondrial DNA or in selected nuclear genes, the pathologic diagnosis was not changed. The differential diagnosis of CPEO with other forms of ocular myopathies as well as the possible association of CPEO with systemic syndromes is discussed. Ophtalmologists and medical internists should always suspect CPEO when dealing with patients affected by ocular myopathy, either in its pure form or in association with other myopathic or systemic signs.

  1. Severe protein aggregate myopathy in a knockout mouse model points to an essential role of cofilin2 in sarcomeric actin exchange and muscle maintenance.

    PubMed

    Gurniak, Christine B; Chevessier, Frédéric; Jokwitz, Melanie; Jönsson, Friederike; Perlas, Emerald; Richter, Hendrik; Matern, Gabi; Boyl, Pietro Pilo; Chaponnier, Christine; Fürst, Dieter; Schröder, Rolf; Witke, Walter

    2014-01-01

    Mutations in the human actin depolymerizing factor cofilin2 result in an autosomal dominant form of nemaline myopathy. Here, we report on the targeted ablation of murine cofilin2, which leads to a severe skeletal muscle specific phenotype within the first two weeks after birth. Apart from skeletal muscle, cofilin2 is also expressed in heart and CNS, however the pathology was restricted to skeletal muscle. The two close family members of cofilin2 - ADF and cofilin1 - were co-expressed in muscle, but unable to compensate for the loss of cofilin2. While primary myofibril assembly and muscle development were unaffected in cofilin2 mutant mice, progressive muscle degeneration was observed between postnatal days 3 and 7. Muscle pathology was characterized by sarcoplasmic protein aggregates, fiber size disproportion, mitochondrial abnormalities and internal nuclei. The observed muscle pathology differed from nemaline myopathy, but showed combined features of actin-associated myopathy and myofibrillar myopathy. In cofilin2 mutant mice, the postnatal expression pattern and turnover of sarcomeric α-actin isoforms were altered. Levels of smooth muscle α-actin were increased and remained high in developing muscles, suggesting that cofilin2 plays a crucial role during the exchange of α-actin isoforms during the early postnatal remodeling of the sarcomere.

  2. Physical rehabilitation for critical illness myopathy and neuropathy: an abridged version of Cochrane Systematic Review.

    PubMed

    Mehrholz, J; Pohl, M; Kugler, J; Burridge, J; Mückel, S; Elsner, B

    2015-10-01

    Intensive care unit (ICU) acquired or generalised weakness due to critical illness myopathy (CIM) and polyneuropathy (CIP) are major causes of chronically impaired motor function that can affect activities of daily living and quality of life. Physical rehabilitation of those affected might help to improve activities of daily living. Our primary objective was to assess the effects of physical rehabilitation therapies and interventions for people with CIP and CIM in improving activities of daily living such as walking, bathing, dressing and eating. Secondary objectives were to assess effects on muscle strength and quality of life, and to assess adverse effects of physical rehabilitation. On 16 July 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register and on 14 July 2014 we searched CENTRAL, MEDLINE, EMBASE and CINAHL Plus. In July 2014, we searched the Physiotherapy Evidence Database (PEDro) and three trials registries for ongoing trials and further data about included studies with no language restrictions. We also handsearched relevant conference proceedings and screened reference lists to identify further trials. We planned to include randomised controlled trials (RCTs), quasi-RCTs and randomised controlled cross-over trials of any rehabilitation intervention in people with acquired weakness syndrome due to CIP/CIM. We would have extracted data, assessed the risk of bias and classified the quality of evidence for outcomes in duplicate, according to the standard procedures of The Cochrane Collaboration. Outcome data collection would have been for activities of daily living (for example, mobility, walking, transfers and self care). Secondary outcomes included muscle strength, quality of life and adverse events. The search strategy retrieved 3587 references. After examination of titles and abstracts, we retrieved the full text of 24 potentially relevant studies. None of these studies met the inclusion criteria of our review. No data were

  3. Comparative skeletal muscle histopathologic and ultrastructural features in two forms of polysaccharide storage myopathy in horses.

    PubMed

    McCue, M E; Armién, A G; Lucio, M; Mickelson, J R; Valberg, S J

    2009-11-01

    Polysaccharide storage myopathy (PSSM) has been found in more than 35 different horse breeds through identification of abnormal storage of polysaccharide in muscle biopsies. A dominant mutation in the glycogen synthase 1 gene (GYS1) accounts for a substantial proportion of PSSM cases in at least 17 breeds, including Quarter Horses, but some horses diagnosed with PSSM by muscle histopathologic analysis are negative for the mutation. We hypothesized that a second distinct form of glycogen storage disease exists in GYS1-negative horses with PSSM. The objectives of this study were to compare the histopathologic features, ultrastructure of polysaccharide, signalment, history, and presenting complaints of GYS1-negative Quarter Horses and related breeds with PSSM to those of GYS1-positive horses with PSSM. The total histopathologic score in frozen sections of skeletal muscle stained with hematoxylin and eosin, periodic acid Schiff (PAS) and amylase-PAS stains from 53 GYS1-negative horses did not differ from that of 52 GYS1-positive horses. Abnormal polysaccharide was fine granular or homogenous in appearance (49/53; 92%), often amylase-sensitive (28/53; 53%), more commonly located under the sarcolemma, and consisting of beta glycogen particles in GYS1-negative horses. However, in GYS1-positive horses, abnormal polysaccharide was usually coarse granular (50/52; 96%), amylase-resistant (51/52; 98%), more commonly cytoplasmic, and consisting of beta glycogen particles or, in some myofibers, filamentous material surrounded by beta glycogen particles. Retrospective analysis found that GYS1-negative horses (n = 43) were younger at presentation (4.9 +/- 0.6 years vs. 6.7 +/- 0.3 years for GYS1-positive horses) and were more likely to be intact males than GYS1-positive horses (n = 160). We concluded that 2 forms of PSSM exist and often have distinctive abnormal polysaccharide. However, because evaluation of the histologic appearance of polysaccharide can be subjective and

  4. Blood glucose clearance after feeding and exercise in polysaccharide storage myopathy.

    PubMed

    De La Corte, F D; Valberg, S J; Mickelson, J R; Hower-Moritz, M

    1999-07-01

    Polysaccharide storage myopathy (PSSM) in Quarter Horses (QH) and QH crosses is a glycogen storage disorder in which blood glucose clearance and insulin sensitivity, following an i.v. or oral glucose challenge, are enhanced. Exercise is known also to enhance glucose uptake into skeletal muscle in many animal species. Therefore, the purpose of this study was to compare the effect of exercise on glucose clearance in PSSM and control horses when an oral carbohydrate meal (8 Mcal sweet feed) was fed following either 12 h fasting alone (NEX protocol) or following fasting and a standard exercise protocol (EX protocol). In the NEX protocol, horses fasted 12 h and then were fed 8 megacalories (Mcal) of sweet feed (2.3 kg). In the EX protocol, horses were fed sweet feed 2 h after an exercise test (SET). Blood glucose was analysed for < 480 min after feeding. Muscle biopsies were taken before and after the EX protocol. With the NEX protocol, the mean of all blood glucose and insulin concentrations were significantly lower in fed-PSSM horses than controls (P < 0.013). The EX protocol in control horses caused a less pronounced percentage change in glucose concentration from baseline following feeding compared to the NEX protocol (mean peak EX 26.5% vs. NEX 70.2%, respectively) (P < 0.0003). In PSSM horses, the EX protocol also resulted in a lower percent change in glucose concentration following feeding compared to the NEX protocol (44.7 vs. 67.5%, respectively) (P = 0.021). The magnitude of the difference in percentage change of blood glucose concentration with the EX protocol was less in PSSM than that seen for controls (mean peak PSSM-EX 44.7% vs. 26.5% for controls, respectively) (P < 0.006). No significant differences in the insulin:glucose ratios were found for control horses between NEX and EX. In PSSM horses, the insulin:glucose ratio was significantly increased in the EX vs. NEX. In conclusion, exercise in normal horses results in enhanced glucose clearance following

  5. Acute Pancreatitis

    PubMed Central

    Geokas, Michael C.

    1972-01-01

    For many decades two types of acute pancreatitis have been recognized: the edematous or interstitial and the hemorrhagic or necrotic. In most cases acute pancreatitis is associated with alcoholism or biliary tract disease. Elevated serum or urinary α-amylase is the most important finding in diagnosis. The presence of methemalbumin in serum and in peritoneal or pleural fluid supports the diagnosis of the hemorrhagic form of the disease in patients with a history and enzyme studies suggestive of pancreatitis. There is no characteristic clinical picture in acute pancreatitis, and its complications are legion. Pancreatic pseudocyst is probably the most common and pancreatic abscess is the most serious complication. The pathogenetic principle is autodigestion, but the precise sequence of biochemical events is unclear, especially the mode of trypsinogen activation and the role of lysosomal hydrolases. A host of metabolic derangements have been identified in acute pancreatitis, involving lipid, glucose, calcium and magnesium metabolism and changes of the blood clotting mechanism, to name but a few. Medical treatment includes intestinal decompression, analgesics, correction of hypovolemia and other supportive and protective measures. Surgical exploration is advisable in selected cases, when the diagnosis is in doubt, and is considered imperative in the presence of certain complications, especially pancreatic abscess. PMID:4559467

  6. Substantial deficiency of free sialic acid in muscles of patients with GNE myopathy and in a mouse model

    PubMed Central

    Chan, Yiumo Michael; Lee, Paul; Jungles, Steve; Morris, Gabrielle; Cadaoas, Jaclyn; Skrinar, Alison; Vellard, Michel; Kakkis, Emil

    2017-01-01

    GNE myopathy (GNEM), also known as hereditary inclusion body myopathy (HIBM), is a late- onset, progressive myopathy caused by mutations in the GNE gene encoding the enzyme responsible for the first regulated step in the biosynthesis of sialic acid (SA). The disease is characterized by distal muscle weakness in both the lower and upper extremities, with the quadriceps muscle relatively spared until the late stages of disease. To explore the role of SA synthesis in the disease, we conducted a comprehensive and systematic analysis of both free and total SA levels in a large cohort of GNEM patients and a mouse model. A sensitive LC/MS/MS assay was developed to quantify SA in serum and muscle homogenates. Mean serum free SA level was 0.166 μg/mL in patients and 18% lower (p<0.001) than that of age-matched control samples (0.203 μg/mL). In biopsies obtained from patients, mean free SA levels of different muscles ranged from 0.046–0.075 μg/μmol Cr and were markedly lower by 72–85% (p<0.001) than free SA from normal controls. Free SA was shown to constitute a small fraction (3–7%) of the total SA pool in muscle tissue. Differences in mean total SA levels in muscle from patients compared with normal controls were less distinct and more variable between different muscles, suggesting a small subset of sialylation targets could be responsible for the pathogenesis of GNEM. Normal quadriceps had significantly lower levels of free SA (reduced by 39%) and total SA (reduced by 53%) compared to normal gastrocnemius. A lower SA requirement for quadriceps may be linked to the reported quadriceps sparing in GNEM. Analysis of SA levels in GneM743T/M743T mutant mice corroborated the human study results. These results show that serum and muscle free SA is severely reduced in GNEM, which is consistent with the biochemical defect in SA synthesis associated with GNE mutations. These results therefore support the approach of reversing SA depletion as a potential treatment for GNEM

  7. Acute Vestibulopathy

    PubMed Central

    Cha, Yoon-Hee

    2011-01-01

    The presentation of acute vertigo may represent both a common benign disorder or a life threatening but rare one. Familiarity with the common peripheral vestibular disorders will allow the clinician to rapidly “rule-in” a benign disorder and recognize when further testing is required. Key features of vertigo required to make an accurate diagnosis are duration, chronicity, associated symptoms, and triggers. Bedside tests that are critical to the diagnosis of acute vertigo include the Dix-Hallpike maneuver and canalith repositioning manuever, occlusive ophthalmoscopy, and the head impulse test. The goal of this review is to provide the clinician with the clinical and pathophysiologic background of the most common disorders that present with vertigo to develop a logical differential diagnosis and management plan. PMID:23983835

  8. Acute Blindness.

    PubMed

    Meekins, Jessica M

    2015-09-01

    Sudden loss of vision is an ophthalmic emergency with numerous possible causes. Abnormalities may occur at any point within the complex vision pathway, from retina to optic nerve to the visual center in the occipital lobe. This article reviews specific prechiasm (retina and optic nerve) and cerebral cortical diseases that lead to acute blindness. Information regarding specific etiologies, pathophysiology, diagnosis, treatment, and prognosis for vision is discussed.

  9. Mucosal necrosis of the small intestine in myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome.

    PubMed

    Fukuyama, Keita; Ishikawa, Yasuhide; Ogino, Tetsuro; Inoue, Hidenobu; Yamaoka, Ryoya; Hirose, Tetsuro; Nishihira, Tomohiko

    2012-11-07

    This report presents a case of massive mucosal necrosis of the small intestine in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which particularly affects the brain, nervous system and muscles. A 45-year-old Japanese female, with an established diagnosis of MELAS, presented with vomiting. Computed tomography showed portomesenteric venous gas and pneumatosis intestinalis. She underwent a resection of the small intestine. A microscopic study showed necrosis of the mucosa and vacuolar degeneration of smooth muscle cells in the arterial wall. Immunohistochemistry showed anti-mitochondrial antibody to be highly expressed in the crypts adjacent the necrotic mucosa. The microscopic and immunohistochemical findings suggested the presence of a large number of abnormal mitochondria in MELAS to be closely linked to mucosal necrosis of the small intestine.

  10. Sagging Eye Syndrome or Nemaline Rod Myopathy? Divergence Insufficiency with Levator Dehiscence as an Overlapping Symptom between Two Diagnoses.

    PubMed

    Cheung, Stephanie S L; Ghadiali, Larissa K; Brannagan Iii, Thomas H; Moonis, Gul; Faust, Phyllis L; Odel, Jeffrey G

    2017-01-01

    A 78-year-old woman complained of gradual, painless onset of horizontal binocular diplopia associated with progressive axial weakness. Physical examination revealed esotropia that was greater at distance than at near vision, bilateral levator dehiscence, and normal abducting saccadic speeds. Given the age of the patient and compatible clinical findings, the diagnosis of Sagging Eye Syndrome (SES) was made. However, further work-up with a muscle biopsy suggested Sporadic Late-Onset Nemaline Myopathy (SLONM) as the cause of her progressive muscle weakness. Although rare, external ophthalmoplegia has been described in the literature as a presenting symptom in SLONM. To elucidate the pathological mechanism for the patient's diplopia, an MRI of the orbits was performed, which revealed findings consistent with SES. This case aims to highlight the importance of integrating clinical findings during the diagnostic process and serves as a reminder that diplopia can be a common symptom for an uncommon diagnosis.

  11. Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or ‘classical’ congenital myopathy

    PubMed Central

    Zaharieva, Irina T.; Thor, Michael G.; Oates, Emily C.; van Karnebeek, Clara; Hendson, Glenda; Blom, Eveline; Witting, Nanna; Rasmussen, Magnhild; Gabbett, Michael T.; Ravenscroft, Gianina; Sframeli, Maria; Suetterlin, Karen; Sarkozy, Anna; D’Argenzio, Luigi; Hartley, Louise; Matthews, Emma; Pitt, Matthew; Vissing, John; Ballegaard, Martin; Krarup, Christian; Slørdahl, Andreas; Halvorsen, Hanne; Ye, Xin Cynthia; Zhang, Lin-Hua; Løkken, Nicoline; Werlauff, Ulla; Abdelsayed, Mena; Davis, Mark R.; Feng, Lucy; Phadke, Rahul; Sewry, Caroline A.; Morgan, Jennifer E.; Laing, Nigel G.; Vallance, Hilary; Ruben, Peter; Hanna, Michael G.; Lewis, Suzanne; Kamsteeg, Erik-Jan; Männikkö, Roope

    2016-01-01

    See Cannon (doi:10.1093/brain/awv400) for a scientific commentary on this article. Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro

  12. Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation.

    PubMed

    McCue, M E; Valberg, S J; Jackson, M; Borgia, L; Lucio, M; Mickelson, J R

    2009-01-01

    In this study we examined a family of Quarter Horses with Polysaccharide Storage Myopathy (PSSM) with a dominant mutation in the skeletal muscle glycogen synthase (GYS1) gene. A subset of horses within this family had a more severe and occasionally fatal PSSM phenotype. The purpose of this study was to identify a modifying gene(s) for the severe clinical phenotype. A genetic association analysis was used to identify RYR1 as a candidate modifying gene. A rare, known equine RYR1 mutation, associated with malignant hyperthermia (MH), was found to segregate in this GYS1 PSSM family. Retrospective analysis of patient records (n=179) demonstrated that horses with both the GYS1 and RYR1 mutations had a more severe clinical phenotype than horses with the GYS1 mutation alone. A treadmill trial (n=8) showed that serum creatine kinase activity was higher and exercise intolerance greater in horses with both mutations compared to the GYS1 mutation alone.

  13. Sagging Eye Syndrome or Nemaline Rod Myopathy? Divergence Insufficiency with Levator Dehiscence as an Overlapping Symptom between Two Diagnoses

    PubMed Central

    Ghadiali, Larissa K.; Brannagan III, Thomas H.; Moonis, Gul; Faust, Phyllis L.; Odel, Jeffrey G.

    2017-01-01

    A 78-year-old woman complained of gradual, painless onset of horizontal binocular diplopia associated with progressive axial weakness. Physical examination revealed esotropia that was greater at distance than at near vision, bilateral levator dehiscence, and normal abducting saccadic speeds. Given the age of the patient and compatible clinical findings, the diagnosis of Sagging Eye Syndrome (SES) was made. However, further work-up with a muscle biopsy suggested Sporadic Late-Onset Nemaline Myopathy (SLONM) as the cause of her progressive muscle weakness. Although rare, external ophthalmoplegia has been described in the literature as a presenting symptom in SLONM. To elucidate the pathological mechanism for the patient's diplopia, an MRI of the orbits was performed, which revealed findings consistent with SES. This case aims to highlight the importance of integrating clinical findings during the diagnostic process and serves as a reminder that diplopia can be a common symptom for an uncommon diagnosis. PMID:28182120

  14. Microduplication 10q24.31 in a Spanish girl with scoliosis and myopathy: the critical role of LBX.

    PubMed

    Fernández-Jaén, Alberto; Suela, Javier; Fernández-Mayoralas, Daniel Martín; Fernández-Perrone, Ana Laura; Wotton, Karl R; Dietrich, Susanne; Castellanos, Maria del Carmen; Cigudosa, Juan C; Calleja-Pérez, Beatriz; López-Martín, Sara

    2014-08-01

    LBX1 plays a cardinal role in neuronal and muscular development in animal models. Its function in humans is unknown; it has been reported as a candidate gene for idiopathic scoliosis. Our goal is to document the first clinical case of a microduplication at 10q24.31 (chr10:102927883-103053612, hg19), affecting exclusively LBX1. The patient, a 12-year-old girl, showed attention problems, dyspraxia, idiopathic congenital scoliosis, and marked hypotrophy of paravertebral muscles. Her paternal aunt had a severe and progressive myopathy with a genetic study that revealed the same duplication. We propose to consider genetic studies, particularly of LBX1, in patients with scoliosis and/or hypotrophy-hypoplasia of paravertebral muscles of unknown etiology.

  15. Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies

    NASA Technical Reports Server (NTRS)

    Vissing, J.; Vissing, S. F.; MacLean, D. A.; Saltin, B.; Quistorff, B.; Haller, R. G.; Blomqvist, C. G. (Principal Investigator)

    1998-01-01

    Muscle acidosis has been implicated as a major determinant of reflex sympathetic activation during exercise. To test this hypothesis we studied sympathetic exercise responses in metabolic myopathies in which muscle acidosis is impaired or augmented during exercise. As an index of reflex sympathetic activation to muscle, microneurographic measurements of muscle sympathetic nerve activity (MSNA) were obtained from the peroneal nerve. MSNA was measured during static handgrip exercise at 30% of maximal voluntary contraction force to exhaustion in patients in whom exercise-induced muscle acidosis is absent (seven myophosphorylase deficient patients; MD [McArdle's disease], and one patient with muscle phosphofructokinase deficiency [PFKD]), augmented (one patient with mitochondrial myopathy [MM]), or normal (five healthy controls). Muscle pH was monitored by 31P-magnetic resonance spectroscopy during handgrip exercise in the five control subjects, four MD patients, and the MM and PFKD patients. With handgrip to exhaustion, the increase in MSNA over baseline (bursts per minute [bpm] and total activity [%]) was not impaired in patients with MD (17+/-2 bpm, 124+/-42%) or PFKD (65 bpm, 307%), and was not enhanced in the MM patient (24 bpm, 131%) compared with controls (17+/-4 bpm, 115+/-17%). Post-handgrip ischemia studied in one McArdle patient, caused sustained elevation of MSNA above basal suggesting a chemoreflex activation of MSNA. Handgrip exercise elicited an enhanced drop in muscle pH of 0.51 U in the MM patient compared with the decrease in controls of 0.13+/-0.02 U. In contrast, muscle pH increased with exercise in MD by 0.12+/-0.05 U and in PFKD by 0.01 U. In conclusion, patients with glycogenolytic, glycolytic, and oxidative phosphorylation defects show normal muscle sympathetic nerve responses to static exercise. These findings indicate that muscle acidosis is not a prerequisite for sympathetic activation in exercise.

  16. Mutations in contactin-1, a neural adhesion and neuromuscular junction protein, cause a familial form of lethal congenital myopathy.

    PubMed

    Compton, Alison G; Albrecht, Douglas E; Seto, Jane T; Cooper, Sandra T; Ilkovski, Biljana; Jones, Kristi J; Challis, Daniel; Mowat, David; Ranscht, Barbara; Bahlo, Melanie; Froehner, Stanley C; North, Kathryn N

    2008-12-01

    We have previously reported a group of patients with congenital onset weakness associated with a deficiency of members of the syntrophin-alpha-dystrobrevin subcomplex and have demonstrated that loss of syntrophin and dystrobrevin from the sarcolemma of skeletal muscle can also be associated with denervation. Here, we have further studied four individuals from a consanguineous Egyptian family with a lethal congenital myopathy inherited in an autosomal-recessive fashion and characterized by a secondary loss of beta2-syntrophin and alpha-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. We performed homozygosity mapping and candidate gene analysis and identified a mutation that segregates with disease within CNTN1, the gene encoding for the neural immunoglobulin family adhesion molecule, contactin-1. Contactin-1 transcripts were markedly decreased on gene-expression arrays of muscle from affected family members compared to controls. We demonstrate that contactin-1 is expressed at the neuromuscular junction (NMJ) in mice and man in addition to the previously documented expression in the central and peripheral nervous system. In patients with secondary dystroglycanopathies, we show that contactin-1 is abnormally localized to the sarcolemma instead of exclusively at the NMJ. The cntn1 null mouse presents with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family. We propose that loss of contactin-1 from the NMJ impairs communication or adhesion between nerve and muscle resulting in the severe myopathic phenotype. This disorder is part of the continuum in the clinical spectrum of congenital myopathies and congenital myasthenic syndromes.

  17. Distinct muscle apoptotic pathways are activated in muscles with different fiber types a rat model of critical illness myopathy

    PubMed Central

    Barnes, Benjamin T.; Confides, Amy L.; Rich, Mark M.; Dupont-Versteegden, Esther E.

    2015-01-01

    Critical illness myopathy (CIM) is associated with severe muscle atrophy and fatigue in affected patients. Apoptotic signaling is involved in atrophy and is elevated in muscles from patients with CIM. In this study we investigated underlying mechanisms of apoptosis-related pathways in muscles with different fiber type composition in a rat model of CIM using denervation and glucocorticoid administration (denervation and steroid-induced myopathy, DSIM). Soleus and tibialis anterior (TA) muscles showed severe muscle atrophy (40–60% of control muscle weight) and significant apoptosis in interstitial as well as myofiber nuclei that was similar between the two muscles with DSIM. Caspase-3 and −8 activities, but not caspase-9 and −12, were elevated in TA and not in soleus muscle, while the caspase-independent proteins endonuclease G (EndoG) and apoptosis inducing factor (AIF) were not changed in abundance nor differentially localized in either muscle. Anti-apoptotic proteins HSP70, −27, and apoptosis repressor with a caspase recruitment domain (ARC) were elevated in soleus compared to TA muscle and ARC was significantly decreased with induction of DSIM in soleus. Results indicate that apoptosis is a significant process associated with DSIM in both soleus and TA muscles, and that apoptosis-associated processes are differentially regulated in muscles of different function and fiber type undergoing atrophy due to DSIM. We conclude that interventions combating apoptosis with CIM may need to be directed towards inhibiting caspase-dependent as well as -independent mechanisms to be able to affect muscles of all fiber types. PMID:25740800

  18. Distinct muscle apoptotic pathways are activated in muscles with different fiber types in a rat model of critical illness myopathy.

    PubMed

    Barnes, Benjamin T; Confides, Amy L; Rich, Mark M; Dupont-Versteegden, Esther E

    2015-06-01

    Critical illness myopathy (CIM) is associated with severe muscle atrophy and fatigue in affected patients. Apoptotic signaling is involved in atrophy and is elevated in muscles from patients with CIM. In this study we investigated underlying mechanisms of apoptosis-related pathways in muscles with different fiber type composition in a rat model of CIM using denervation and glucocorticoid administration (denervation and steroid-induced myopathy, DSIM). Soleus and tibialis anterior (TA) muscles showed severe muscle atrophy (40-60% of control muscle weight) and significant apoptosis in interstitial as well as myofiber nuclei that was similar between the two muscles with DSIM. Caspase-3 and -8 activities, but not caspase-9 and -12, were elevated in TA and not in soleus muscle, while the caspase-independent proteins endonuclease G (EndoG) and apoptosis inducing factor (AIF) were not changed in abundance nor differentially localized in either muscle. Anti-apoptotic proteins HSP70, -27, and apoptosis repressor with a caspase recruitment domain (ARC) were elevated in soleus compared to TA muscle and ARC was significantly decreased with induction of DSIM in soleus. Results indicate that apoptosis is a significant process associated with DSIM in both soleus and TA muscles, and that apoptosis-associated processes are differentially regulated in muscles of different function and fiber type undergoing atrophy due to DSIM. We conclude that interventions combating apoptosis with CIM may need to be directed towards inhibiting caspase-dependent as well as -independent mechanisms to be able to affect muscles of all fiber types.

  19. Statin-associated rhabdomyolysis with acute renal failure complicated by intradialytic NSTEMI: a review of lipid management considerations.

    PubMed

    Kar, Subrata; Chockalingam, Anand

    2013-01-01

    Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are associated with myopathy, myalgias, myositis, and rhabdomyolysis. Rhabdoymyolysis is a rare complication and may cause acute renal failure, which may be fatal. In such cases, alternative therapies should be considered. In this review, we attempted to elucidate the lipid management options in patients with rhabdomyolysis and coronary artery disease. We also describe a case report of a patient who developed rhabdomyolysis from dual antilipid therapy followed by acute renal failure and non-ST elevation myocardial infarction. Such a complex case has not been reported in the literature, and lipid management options may include