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  1. Spinal Muscular Atrophy (SMA)

    MedlinePlus

    ... Lessons? Visit KidsHealth in the Classroom What Other Parents Are Reading Your Child's Development (Birth to 3 Years) Feeding Your 1- to 3-Month-Old Feeding Your 4- to 7-Month-Old Feeding Your 8- to 12-Month-Old Feeding Your 1- to 2-Year-Old Spinal ... > For Parents > Spinal Muscular Atrophy (SMA) Print A A A ...

  2. Spinal Muscular Atrophy (SMA)

    MedlinePlus

    ... areas of society: the arts, science, law, management, teaching — you name it. Children with SMA tend to ... or speech therapy consultations • annual flu shots • support groups for those affected, spouses, parents or other caregivers • ...

  3. Spinal Muscular Atrophy (SMA)

    MedlinePlus

    ... children with SMA develop spinal deformities, such as scoliosis (sideways curvature of the spine) and kyphosis (front- ... Magnetic Resonance Imaging (MRI) Brain and Nervous System Scoliosis Contact Us Print Resources Send to a friend ...

  4. Types of SMA (Spinal Muscular Atrophy)

    MedlinePlus

    ... Trials Research Publications Support & Care For Newly Diagnosed Care Packages Information Packets Equipment Pool Living With SMA Medical Issues Palliative Breathing Orthopedics Nutrition Equipment Daily Life At School At Home Adults With SMA Play Travel Grief & Loss Community & ...

  5. Columbia SMA Project: A Randomized, Control Trial of the Effects of Exercise on Motor Function and Strength in Patients With Spinal Muscular Atrophy (SMA)

    DTIC Science & Technology

    2011-06-01

    www.CQillmbiasma.org No. 1994 ?. 2 Musc::ular Dystrophy Assoc1at1on (hUAJ Clinic Spinal Muscular Atrophy Clinical (SMA) Research Center Nan<:y E. Strauss, M.D...3 ~ COLUMBIA UNIVERSIT~ 0 ~ Muscutar Dystrophy Association (MDA) Clinic \\WI M C Spinal Muscular Atrophy Clinical {SMA) - EDICAL ENTER Research...9lu mbi~_rlli:’U~t9 0000000000 p.1 Muscular Dystrophy Association (MDA) Clinic Spinal Muscular Atrophy Clinical (SMA) Research Center Nancy E

  6. Review of Spinal Muscular Atrophy (SMA) for Prenatal and Pediatric Genetic Counselors.

    PubMed

    Carré, Amanda; Empey, Candice

    2016-02-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular condition with degeneration of the anterior horn cells in the spinal column. Five SMA subtypes exist with classification dependent upon the motor milestones achieved. Study of the SMN1 (survival motor neuron) and SMN2 genes as well as the concepts of the "2 + 0" carriers, gene conversion, de novo mutations and intragenic mutations allow for a better understanding of SMA. Detailing the carrier and diagnostic testing options further deepens the genetic counselor's knowledge of SMA. A review of care guidelines and research options is included as this information gives a patient a well-rounded view of SMA. Although SMA is most commonly associated with the SMN1 gene, a number of spinal muscular atrophies not caused by genetic changes in this gene may be included as differential diagnoses until confirmatory testing can be completed. SMA is a complex condition requiring a detailed knowledge on the genetic counselor's part in order to explain the disorder to the patient with clarity thus facilitating increased communication and decision making guidance with the patient.

  7. Isolation of cDNA clones from within the spinal muscular atrophy (SMA) disease gene region

    SciTech Connect

    McLean, M.; Roy, N.; Tamai, K.

    1994-09-01

    Spinal muscular atrophy (SMA) is a recessive neuromuscular disease characterized by death of spinal cord {alpha} motor neurons, resulting in skeletal muscle atrophy. The critical SMA disease gene region on 5q13.1 contains families of microsatellite repeat sequences which exist at multiple subloci that are dispersed over a 100 to 200 kbp region. We have detected significant linkage disequilibrium between SMA type 1, the most severe form of the disorder, and two subloci of one such microsatellite, the CATT-1 family of microsatellites. Furthermore, a recombination event in a chromosome of an individual with SMA type 1 mapping between the members of two other extended microsatellite families, including CMS-1, has been observed. Combining this with previously reported recombinants refines the critical SMA region to approximately 300 kbp. P1 artificial chromosome (PAC), YAC and cosmid clones which possess both CMS-1 alleles which bracket this recombination event, as well as CATT-1 alleles showing linkage disequilibrium with SMA, have been used to probe cDNA libraries from human and other mammalian sources in search of genes within this interval; three of these cDNAs are currently being tested as candidates for the SMA gene.

  8. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool

    PubMed Central

    Scoto, Mariacristina; Mayhew, Anna; Main, Marion; Mazzone, Elena S.; Montes, Jacqueline; de Sanctis, Roberto; Dunaway Young, Sally; Salazar, Rachel; Glanzman, Allan M.; Pasternak, Amy; Quigley, Janet; Mirek, Elizabeth; Duong, Tina; Gee, Richard; Civitello, Matthew; Tennekoon, Gihan; Pane, Marika; Pera, Maria Carmela; Bushby, Kate; Day, John; Darras, Basil T.; De Vivo, Darryl; Finkel, Richard; Mercuri, Eugenio; Muntoni, Francesco

    2017-01-01

    Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are ‘fit for purpose’. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials. PMID:28222119

  9. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool.

    PubMed

    Ramsey, Danielle; Scoto, Mariacristina; Mayhew, Anna; Main, Marion; Mazzone, Elena S; Montes, Jacqueline; de Sanctis, Roberto; Dunaway Young, Sally; Salazar, Rachel; Glanzman, Allan M; Pasternak, Amy; Quigley, Janet; Mirek, Elizabeth; Duong, Tina; Gee, Richard; Civitello, Matthew; Tennekoon, Gihan; Pane, Marika; Pera, Maria Carmela; Bushby, Kate; Day, John; Darras, Basil T; De Vivo, Darryl; Finkel, Richard; Mercuri, Eugenio; Muntoni, Francesco

    2017-01-01

    Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

  10. Molecular, genetic and stem cell-mediated therapeutic strategies for spinal muscular atrophy (SMA).

    PubMed

    Zanetta, Chiara; Riboldi, Giulietta; Nizzardo, Monica; Simone, Chiara; Faravelli, Irene; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

    2014-02-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease. It is the first genetic cause of infant mortality. It is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The most striking component is the loss of alpha motor neurons in the ventral horn of the spinal cord, resulting in progressive paralysis and eventually premature death. There is no current treatment other than supportive care, although the past decade has seen a striking advancement in understanding of both SMA genetics and molecular mechanisms. A variety of disease modifying interventions are rapidly bridging the translational gap from the laboratory to clinical trials. In this review, we would like to outline the most interesting therapeutic strategies that are currently developing, which are represented by molecular, gene and stem cell-mediated approaches for the treatment of SMA.

  11. Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity in the ∆7 SMA Mouse.

    PubMed

    McGovern, Vicki L; Massoni-Laporte, Aurélie; Wang, Xueyong; Le, Thanh T; Le, Hao T; Beattie, Christine E; Rich, Mark M; Burghes, Arthur H M

    2015-01-01

    Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of SMN2. The SMN2 copy number inversely correlates with phenotypic severity and is a modifier of disease outcome. The SMN2 gene essentially differs from SMN1 by a single nucleotide in exon 7 that modulates the incorporation of exon 7 into the final SMN transcript. The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded. However the SMN2 gene does produce some full-length SMN and the SMN2 copy number along with how much full-length SMN the SMN2 gene makes correlates with severity of the SMA phenotype. However there are a number of discordant SMA siblings that have identical haplotypes and SMN2 copy number yet one has a milder form of SMA. It has been suggested that Plastin3 (PLS3) acts as a sex specific phenotypic modifier where increased expression of PLS3 modifies the SMA phenotype in females. To test the effect of PLS3 overexpression we have over expressed full-length PLS3 in SMA mice. To ensure no disruption of functionality or post-translational processing of PLS3 we did not place a tag on the protein. PLS3 protein was expressed under the Prion promoter as we have shown previously that SMN expression under this promoter can rescue SMA mice. High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice. Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons.

  12. Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity in the ∆7 SMA Mouse

    PubMed Central

    Wang, Xueyong; Le, Thanh T.; Le, Hao T.; Beattie, Christine E.; Rich, Mark M.; Burghes, Arthur H. M.

    2015-01-01

    Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of SMN2. The SMN2 copy number inversely correlates with phenotypic severity and is a modifier of disease outcome. The SMN2 gene essentially differs from SMN1 by a single nucleotide in exon 7 that modulates the incorporation of exon 7 into the final SMN transcript. The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded. However the SMN2 gene does produce some full-length SMN and the SMN2 copy number along with how much full-length SMN the SMN2 gene makes correlates with severity of the SMA phenotype. However there are a number of discordant SMA siblings that have identical haplotypes and SMN2 copy number yet one has a milder form of SMA. It has been suggested that Plastin3 (PLS3) acts as a sex specific phenotypic modifier where increased expression of PLS3 modifies the SMA phenotype in females. To test the effect of PLS3 overexpression we have over expressed full-length PLS3 in SMA mice. To ensure no disruption of functionality or post-translational processing of PLS3 we did not place a tag on the protein. PLS3 protein was expressed under the Prion promoter as we have shown previously that SMN expression under this promoter can rescue SMA mice. High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice. Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons. PMID:26134627

  13. Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA).

    PubMed

    Fayzullina, Saniya; Martin, Lee J

    2014-01-01

    Spinal Muscular Atrophy (SMA) is a hereditary childhood disease that causes paralysis by progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. The mechanisms by which lack of SMN causes SMA pathology are not known, making it very difficult to develop effective therapies. We investigated whether DNA damage is a perinatal pathological event in SMA, and whether DNA damage and cell death first occur in skeletal muscle or spinal cord of SMA mice. We used a mouse model of severe SMA to ascertain the extent of cell death and DNA damage throughout the body of prenatal and newborn mice. SMA mice at birth (postnatal day 0) exhibited internucleosomal fragmentation in genomic DNA from hindlimb skeletal muscle, but not in genomic DNA from spinal cord. SMA mice at postnatal day 5, compared with littermate controls, exhibited increased apoptotic cell death profiles in skeletal muscle, by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and electron microscopy. SMA mice had no increased cell death, no loss of choline acetyl transferase (ChAT)-positive motor neurons, and no overt pathology in the ventral horn of the spinal cord. At embryonic days 13 and 15.5, SMA mice did not exhibit statistically significant increases in cell death profiles in spinal cord or skeletal muscle. Motor neuron numbers in the ventral horn, as identified by ChAT immunoreactivity, were comparable in SMA mice and control littermates at embryonic day 15.5 and postnatal day 5. These observations demonstrate that in SMA, disease in skeletal muscle emerges before pathology in spinal cord, including loss of motor neurons. Overall, this work identifies DNA damage and cell death in skeletal muscle as therapeutic targets for SMA.

  14. SMA-EUROPE workshop report: opportunities and challenges in developing clinical trials for spinal muscular atrophy in Europe

    PubMed Central

    2013-01-01

    Spinal muscular atrophy (SMA) is the most common lethal recessive disease in childhood, and there is currently no effective treatment to halt disease progression. The translation of scientific advances into effective therapies is hampered by major roadblocks in clinical trials, including the complex regulatory environment in Europe, variations in standards of care, patient ascertainment and enrolment, a narrow therapeutic window and a lack of biomarkers of efficacy. In this context, SMA-Europe organized its first international workshop in July 2012 in Rome, gathering 34 scientists, clinicians and representatives of patient organizations to establish recommendations for improving clinical trials for SMAa. PMID:23514578

  15. Candidate Proteins, Metabolites and Transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study

    PubMed Central

    Finkel, Richard S.; Crawford, Thomas O.; Swoboda, Kathryn J.; Kaufmann, Petra; Juhasz, Peter; Li, Xiaohong; Guo, Yu; Li, Rebecca H.; Trachtenberg, Felicia; Forrest, Suzanne J.; Kobayashi, Dione T.; Chen, Karen S.; Joyce, Cynthia L.; Plasterer, Thomas

    2012-01-01

    Background Spinal Muscular Atrophy (SMA) is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1) gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets. Objective: To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches. Materials and Methods: A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2–12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS) and to a number of secondary clinical measures. Results A total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites) and 44 urine metabolites. No transcripts correlated with MHFMS. Discussion In this cross-sectional study, “BforSMA” (Biomarkers for SMA), candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm

  16. Whole transcriptome sequencing in blood provides a diagnosis of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME).

    PubMed

    Kernohan, Kristin D; Frésard, Laure; Zappala, Zachary; Hartley, Taila; Smith, Kevin S; Wagner, Justin; Xu, Hongbin; McBride, Arran; Bourque, Pierre R; Consortium, Care Rare Canada; Bennett, Steffany A L; Dyment, David A; Boycott, Kym M; Montgomery, Stephen B; Warman-Chardon, Jodi

    2017-03-02

    At least 15% of disease-causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in non-coding regions. Whole transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease relevant tissue for RNA. Here, we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation (c.458A>G;p.Tyr153Cys). Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(p<10(-16) ). Subsequent Sanger-sequencing identified the splice mutation responsible for the isoform (c.504A>C;p.Lys168Asn) and provided a molecular diagnosis of autosomal recessive spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Our findings demonstrate the utility of RNA sequencing from blood to identify splice-impacting disease mutations for non-hematological conditions, providing a diagnosis for these otherwise unsolved patients. This article is protected by copyright. All rights reserved.

  17. Learning about Spinal Muscular Atrophy

    MedlinePlus

    ... causes the disorder. Top of page NHGRI Clinical Research on Spinal Muscular Atrophy Currently, NHGRI is not conducting studies on SMA. The National Institutes of Health is conducting clinical trials identified as enrolling individuals with SMA: Quantitative Analysis of SMN1 and SMN2 Gene Based on ...

  18. Spontaneous Breathing Pattern as Respiratory Functional Outcome in Children with Spinal Muscular Atrophy (SMA)

    PubMed Central

    LoMauro, A.; Aliverti, A.; Mastella, C.; Arnoldi, M. T.; Banfi, P.; Baranello, G.

    2016-01-01

    Introduction SMA is characterised by progressive motor and respiratory muscle weakness. We aimed to verify if in SMA children 1)each form is characterized by specific ventilatory and thoraco-abdominal pattern(VTAp) during quiet breathing(QB); 2)VTAp is affected by salbutamol therapy, currently suggested as standard treatment, or by the natural history(NH) of SMA; 3)the severity of global motor impairment linearly correlates with VTAp. Materials and methods VTAp was analysed on 32 SMA type I (SMA1,the most severe form), 51 type II (SMA2,the moderate), 8 type III (SMA3,the mildest) and 20 healthy (HC) using opto-electronic plethysmography. Spirometry, cough and motor function were measured in a subgroup of patients. Results In SMA1, a normal ventilation is obtained in supine position by rapid and shallow breathing with paradoxical ribcage motion. In SMA2, ventilation is within a normal range in seated position due to an increased respiratory rate(p<0.05) with reduced tidal volume(p<0.05) secondary to a poor contribution of pulmonary ribcage(%ΔVRC,P, p<0.001). Salbutamol therapy had no effect on VTAp during QB(p>0.05) while tachypnea occurred in type I NH. A linear correlation(p<0.001) was found between motor function scales and VTAp. Conclusion A negative or reduced %ΔVRC,P, indicative of ribcage muscle weakness, is a distinctive feature of SMA1 and SMA2 since infancy. Its quantitative assessment represents a non-invasive, non-volitional index that can be obtained in all children, even uncollaborative, and provides useful information on the action of ribcage muscles that are known to be affected by the disease.Low values of motor function scales indicate impairment of motor but also of respiratory function. PMID:27820869

  19. Spinal muscular atrophy

    PubMed Central

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic

  20. The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype.

    PubMed

    Hosseinibarkooie, Seyyedmohsen; Peters, Miriam; Torres-Benito, Laura; Rastetter, Raphael H; Hupperich, Kristina; Hoffmann, Andrea; Mendoza-Ferreira, Natalia; Kaczmarek, Anna; Janzen, Eva; Milbradt, Janine; Lamkemeyer, Tobias; Rigo, Frank; Bennett, C Frank; Guschlbauer, Christoph; Büschges, Ansgar; Hammerschmidt, Matthias; Riessland, Markus; Kye, Min Jeong; Clemen, Christoph S; Wirth, Brunhilde

    2016-09-01

    Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only ∼10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and -bundling protein, fully protects against SMA in SMN1-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression-a situation resembling the human condition in asymptomatic SMN1-deleted individuals-rescues survival (from 14 to >250 days) and motoric abilities in a severe SMA mouse model. Because PLS3 knockout in yeast impairs endocytosis, we hypothesized that disturbed endocytosis might be a key cellular mechanism underlying impaired neurotransmission and neuromuscular junction maintenance in SMA. Indeed, SMN deficit dramatically reduced endocytosis, which was restored to normal levels by PLS3 overexpression. Upon low-frequency electro-stimulation, endocytotic FM1-43 (SynaptoGreen) uptake in the presynaptic terminal of neuromuscular junctions was restored to control levels in SMA-PLS3 mice. Moreover, proteomics and biochemical analysis revealed CORO1C, another F-actin binding protein, whose direct binding to PLS3 is dependent on calcium. Similar to PLS3 overexpression, CORO1C overexpression restored fluid-phase endocytosis in SMN-knockdown cells by elevating F-actin amounts and rescued the axonal truncation and branching phenotype in Smn-depleted zebrafish. Our findings emphasize the power of genetic modifiers to unravel the cellular pathomechanisms underlying SMA and the power of combinatorial therapy based on splice correction of SMN2 and endocytosis improvement to efficiently treat SMA.

  1. A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA)

    PubMed Central

    Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

    2015-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA. PMID:26258776

  2. A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA).

    PubMed

    Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

    2015-08-06

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.

  3. Refined physical map of the Spinal Muscular Atrophy gene (SMA) region at 5q13 based on YAC and cosmid contiguous arrays

    SciTech Connect

    Roy, N.; Yaraghi, Z.; McLean, M.D.

    1995-04-10

    The gene for the autosomal recessive neurodegenerative disorder spinal muscular atrophy has been mapped to a region of 5q13 flanked proximally by CMS-1 and distally by D5S557. We present a 2-Mb yeast artificial chromosome (YAC) contig constructed from three libraries encompassing the D5S435/D5S629/CMS-1-SMA-D5S557/D5S112 interval. The D5S629/CMS-1-SMA-D5S557 interval is unusual insofar as chromosome 5-specific repetitive sequences are present and many of the simple tandem repeats (STR) are located at multiple loci that are unstable in our YAC clones. A long-range restriction map that demonstrates the SMA-containing interval to be 550 kb is presented. Moreover, a 210-kb cosmid array from both a YAC-specific and a chromosome 5-specific cosmid library encompassing the multilocus STRs CATT-1, CMS-1, D5F149, D5F150, and D5F153 has been assembled. We have recently reported strong linkage disequilibrium with Type I SMA for two of these STRs, indicating that the gene is located in close proximity to or within our cosmid clone array. 39 refs., 5 figs., 2 tabs.

  4. High resolution physical mapping of the spinal muscular atrophy (SMA) region utilizing YAC, PAC, and cosmid clones

    SciTech Connect

    Roy, N.; Yaraghi, Z.; Besner, A.

    1994-09-01

    The childhood SMAs are a group of autosomal recessive disorders characterized by anterior horn cells degeneration resulting in muscular wasting and weakness. All three types have been mapped to a 1.4 Mb region of 5q13.1 flanked centromerically by D5S435 and telomerically by D5S557. Several groups including our own have generated YAC contigs of the region documenting deletion, duplications and repetitive sequences. We have generated a higher resolution contiguous array of cosmid clones encompassing the region containing the microsatellites (MSRs) CATT-1 and CMS-1. These MSRs exist in multiple copies, termed subloci, which are present in a variable number among chromosomes. We have mapped four of the CATT-1 subloci, two of that we have shown to be in linkage disequilibrium with SMA, to a 100 kb interval within our cosmid array. The lack of a representation of all the CMS-1 subloci in our YAC and cosmid clones, in addition to the instability of these MSRs within the YAC clones, has rendered mapping problematic. Due to the reported stability of P1 artificial chromosomes (PAC), we have also constructed a contiguous array of 11 PAC clones spanning this critical interval. The unequivocal orientation of the contig along 5q13 has been confirmed by analysis with 4 genetic markers, 4 single copy probes and 3 STSs. Preliminary analysis has shown greater retention of MSR alleles in the PACs, suggesting their greater stability when compared to YACs. Mapping of cosmid and PAC clones derived from different individuals has allowed us to map the multiple CMS-1 and CATT-1 subloci along 5q13. We have identified a recombination event indicating that the SMA gene lies telomeric to one CMS sublocus. Placement of this sublocus in our physical map has enabled further refinement of the critical SMA region from previous estimates of 700 kb to an approximate 300 kb interval flanked by the markers CMS and D5S557.

  5. Bone and Spinal Muscular Atrophy.

    PubMed

    Vai, Silvia; Bianchi, Maria Luisa; Moroni, Isabella; Mastella, Chiara; Broggi, Francesca; Morandi, Lucia; Arnoldi, Maria Teresa; Bussolino, Chiara; Baranello, Giovanni

    2015-10-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease, leading to progressive denervation atrophy in the involved skeletal muscles. Bone status has been poorly studied. We assessed bone metabolism, bone mineral density (BMD) and fractures in 30 children (age range 15-171 months) affected by SMA types 2 and 3. Eighteen children (60%) had higher than normal levels of CTx (bone resorption marker); 25-OH vitamin D was in the lower range of normal (below 20 ng/ml in 9 children and below 12 ng/ml in 2). Lumbar spine BMAD (bone mineral apparent density) Z-score was below -1.5 in 50% of children. According to clinical records, four children had sustained four peripheral fractures; on spine X-rays, we observed 9 previously undiagnosed vertebral fractures in 7 children. There was a significant inverse regression between PTH and 25-OH D levels, and a significant regression between BMC and BMAD values and the scores of motor-functional tests. Even if this study could not establish the pathogenesis of bone derangements in SMA, its main findings - reduced bone density, low 25OH vitamin D levels, increased bone resorption markers and asymptomatic vertebral fractures also in very young patients - strongly suggest that even young subjects affected by SMA should be considered at risk of osteopenia and even osteoporosis and fractures.

  6. Very severe spinal muscular atrophy (Type 0).

    PubMed

    Al Dakhoul, Suleiman

    2017-01-01

    This case report describes a rare phenotype of very severe spinal muscular atrophy (SMA) in a newborn who presented with reduced fetal movements in utero and significant respiratory distress at birth. The patient was homozygously deleted for exon 7 and exon 8 of the survival motor neuron gene 1. Very severe SMA should be considered in the differential diagnosis of respiratory distress at birth, and more research should be dedicated to investigate the genetic determinants of its widely variable phenotypes.

  7. Very severe spinal muscular atrophy (Type 0)

    PubMed Central

    Al Dakhoul, Suleiman

    2017-01-01

    This case report describes a rare phenotype of very severe spinal muscular atrophy (SMA) in a newborn who presented with reduced fetal movements in utero and significant respiratory distress at birth. The patient was homozygously deleted for exon 7 and exon 8 of the survival motor neuron gene 1. Very severe SMA should be considered in the differential diagnosis of respiratory distress at birth, and more research should be dedicated to investigate the genetic determinants of its widely variable phenotypes. PMID:28182029

  8. Bed Rest Muscular Atrophy

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.

    2000-01-01

    A major debilitating response from prolonged bed rest (BR) is muscle atrophy, defined as a "decrease in size of a part of tissue after full development has been attained: a wasting away of tissue as from disuse, old age, injury or disease". Part of the complicated mechanism for the dizziness, increased body instability, and exaggerated gait in patients who arise immediately after BR may be a result of not only foot pain, but also of muscular atrophy and associated reduction in lower limb strength. Also, there seems to be a close association between muscle atrophy and bone atrophy. A discussion of many facets of the total BR homeostatic syndrome has been published. The old adage that use determines form which promotes function of bone (Wolff's law) also applies to those people exposed to prolonged BR (without exercise training) in whom muscle atrophy is a consistent finding. An extreme case involved a 16-year-old boy who was ordered to bed by his mother in 1932: after 50 years in bed he had "a lily-white frame with limbs as thin as the legs of a ladder-back chair". These findings emphasize the close relationship between muscle atrophy and bone atrophy. In addition to loss of muscle mass during deconditioning, there is a significant loss of muscle strength and a decrease in protein synthesis. Because the decreases in force (strength) are proportionately greater than those in fiber size or muscle cross-sectional area, other contributory factors must be involved; muscle fiber dehydration may be important.

  9. Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, that Prolongs the Median Survival Time of Δ7 SMA KO Mouse Model of Spinal Muscular Atrophy.

    PubMed

    Chen, Po C; Gaisina, Irina N; El-Khodor, Bassem F; Ramboz, Sylvie; Makhortova, Nina R; Rubin, Lee L; Kozikowski, Alan P

    2012-01-18

    The discovery of upregulated glycogen synthase kinase-3 (GSK-3) in various pathological conditions has led to the development of a host of chemically diverse small molecule GSK-3 inhibitors, such as BIP-135. GSK-3 inhibition emerged as an alternative therapeutic target for treating spinal muscular atrophy (SMA) when a number of GSK-3 inhibitors were shown to elevate survival motor neuron (SMN) levels in vitro and to rescue motor neurons when their intrinsic SMN level was diminished by SMN-specific short hairpin RNA (shRNA). Despite their cellular potency, the in vivo efficacy of GSK-3 inhibitors has yet to be evaluated in an animal model of SMA. Herein, we disclose that a potent and reasonably selective GSK-3 inhibitor, namely BIP-135, was tested in a transgenic Δ7 SMA KO mouse model of SMA, and found to prolong the median survival of these animals. In addition, this compound was shown to elevate the SMN protein level in SMA patient-derived fibroblast cells as determined by western blot, and was neuroprotective in a cell-based, SMA-related model of oxidative stress-induced neurodegeneration.

  10. Spinal Muscular Atrophy

    PubMed Central

    Kolb, Stephen J.; Kissel, John T.

    2015-01-01

    Incidence The incidence of SMA is 1:11,000 live births [1]. Prevalence The prevalence of the carrier state is approximately 1 in 54 [1]. Severity The clinical severity of SMA correlates inversely with SMN2 gene copy number and varies from an extreme weakness and paraplegia of infancy to a mild proximal weakness of adulthood. Natural History The natural history of SMA is complex and variable. For this reason, clinical subgroups have been defined based upon best motor function attainment during development. Type 1 SMA infants never sit independently. Type 2 SMA children sit at some point during their childhood, but never walk independently. And Type 3 SMA children and adults are able to walk independently at some point in their childhood. PMID:26515624

  11. [Upper limb functional assessment scale for children with Duchenne muscular dystrophy and Spinal muscular atrophy].

    PubMed

    Escobar, Raúl G; Lucero, Nayadet; Solares, Carmen; Espinoza, Victoria; Moscoso, Odalie; Olguín, Polín; Muñoz, Karin T; Rosas, Ricardo

    2017-02-01

    Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA) causes significant disability and progressive functional impairment. Readily available instruments that assess functionality, especially in advanced stages of the disease, are required to monitor the progress of the disease and the impact of therapeutic interventions.

  12. Spinal muscular atrophy

    MedlinePlus

    ... type II have less severe symptoms during early infancy, but they become weaker with time. SMA type ... MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood, and Adolescence . 2nd ed. Philadelphia, PA: Elsevier; ...

  13. Modeling Spinal Muscular Atrophy in Drosophila

    PubMed Central

    Mukherjee, Ashim; Kankel, Mark W.; Sen, Anindya; Sridhar, Vasanthi; Fulga, Tudor A.; Hart, Anne C.; Van Vactor, David; Artavanis-Tsakonas, Spyros

    2008-01-01

    Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets. PMID:18791638

  14. Defects in Motoneuron-Astrocyte Interactions in Spinal Muscular Atrophy.

    PubMed

    Zhou, Chunyi; Feng, Zhihua; Ko, Chien-Ping

    2016-02-24

    Spinal muscular atrophy (SMA) is a motoneuron disease caused by loss or mutation in Survival of Motor Neuron 1 (SMN1) gene. Recent studies have shown that selective restoration of SMN protein in astrocytes partially alleviates pathology in an SMA mouse model, suggesting important roles for astrocytes in SMA. Addressing these underlying mechanisms may provide new therapeutic avenues to fight SMA. Using primary cultures of pure motoneurons or astrocytes from SMNΔ7 (SMA) and wild-type (WT) mice, as well as their mixed and matched cocultures, we characterized the contributions of motoneurons, astrocytes, and their interactions to synapse loss in SMA. In pure motoneuron cultures, SMA motoneurons exhibited normal survival but intrinsic defects in synapse formation and synaptic transmission. In pure astrocyte cultures, SMA astrocytes exhibited defects in calcium homeostasis. In motoneuron-astrocyte contact cocultures, synapse formation and synaptic transmission were significantly reduced when either motoneurons, astrocytes or both were from SMA mice compared with those in WT motoneurons cocultured with WT astrocytes. The reduced synaptic activity is unlikely due to changes in motoneuron excitability. This disruption in synapse formation and synaptic transmission by SMN deficiency was not detected in motoneuron-astrocyte noncontact cocultures. Additionally, we observed a downregulation of Ephrin B2 in SMA astrocytes. These findings suggest that there are both cell autonomous and non-cell-autonomous defects in SMA motoneurons and astrocytes. Defects in contact interactions between SMA motoneurons and astrocytes impair synaptogenesis seen in SMA pathology, possibly due to the disruption of the Ephrin B2 pathway.

  15. Defining new borders of the spinal muscular atrophy (SMA) candidate region by two new microsatellites and isolation of cDNAs

    SciTech Connect

    Wirth, B.; Schoenling, J.; Dadze, A.

    1994-09-01

    A high number of cosmids and phages were identified that contained di-, tri-, and tetranucleotide repeats. These clones were isolated from STSs that map to the SMA region as well as from three cosmid and one phage library that had been prepared from YACs which span the SMA candidate interval. We developed two new microsatellites, A31 (D5S823) and 95/23, which enabled us to define new borders of the SMA region and to reduce it to approximately 700 kb. Physically, the marker A31 maps to the overlapping region of the YACs y116, y55 and y122 at about 550 kb distal to the locus D5S435. A recombination in one SMA type I family places A31 proximal to the SMA gene. The multicopy microsatellite, 95/23, developed from a cosmid including the STS y97U revealed in a consanguine SMA type I family different alleles, while all proximal markers were heterozygous. This suggests a location of 95/23 distal to the SMA gene. Furthermore, we tested 157 German SMA families (100 SMA type I, 50 SMA type II and 20 SMA type III) for linkage disequilibrium with the marker AG1-CA which reveals no recombination with the SMA gene. We found in SMA type I families strong allelic association between the 100 bp allele and the SMA gene. In 7 families we got deletions within the AG1-CA microsatellite. On the way to isolate the SMA gene, we hybridized whole cosmid and YAC inserts to cDNA libraries of spinal cord, brain and muscle. Seven cDNAs were initially identified and cDNA walking was used to begin the isolation of whole transcribed sequences.

  16. Spinal Muscular Atrophy: Current Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Kiselyov, Alex S.; Gurney, Mark E.

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord. SMA is caused by deletion and/or mutation of the survival motor neuron gene (SMN1) on chromosome 5q13. There are variable numbers of copies of a second, related gene named SMN2 located in the proximity to SMN1. Both genes encode the same protein (Smn). Loss of SMN1 and incorrect splicing of SMN2 affect cellular levels of Smn triggering death of motor neurons. The severity of SMA is directly related to the normal number of copies of SMN2 carried by the patient. A considerable effort has been dedicated to identifying modalities including both biological and small molecule agents that increase SMN2 promoter activity to upregulate gene transcription and produce increased quantities of full-length Smn protein. This review summarizes recent progress in the area and suggests potential target product profile for an SMA therapeutic.

  17. Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

    PubMed Central

    El Mendili, Mohamed-Mounir; Lenglet, Timothée; Stojkovic, Tanya; Behin, Anthony; Guimarães-Costa, Raquel; Salachas, François; Meininger, Vincent; Bruneteau, Gaelle; Le Forestier, Nadine; Laforêt, Pascal; Lehéricy, Stéphane; Benali, Habib; Pradat, Pierre-François

    2016-01-01

    Purpose The mechanisms underlying the topography of motor deficits in spinal muscular atrophy (SMA) remain unknown. We investigated the profile of spinal cord atrophy (SCA) in SMN1-linked SMA, and its correlation with the topography of muscle weakness. Materials and Methods Eighteen SMN1-linked SMA patients type III/V and 18 age/gender-matched healthy volunteers were included. Patients were scored on manual muscle testing and functional scales. Spinal cord was imaged using 3T MRI system. Radial distance (RD) and cord cross-sectional area (CSA) measurements in SMA patients were compared to those in controls and correlated with strength and disability scores. Results CSA measurements revealed a significant cord atrophy gradient mainly located between C3 and C6 vertebral levels with a SCA rate ranging from 5.4% to 23% in SMA patients compared to controls. RD was significantly lower in SMA patients compared to controls in the anterior-posterior direction with a maximum along C4 and C5 vertebral levels (p-values < 10−5). There were no correlations between atrophy measurements, strength and disability scores. Conclusions Spinal cord atrophy in adult SMN1-linked SMA predominates in the segments innervating the proximal muscles. Additional factors such as neuromuscular junction or intrinsic skeletal muscle defects may play a role in more complex mechanisms underlying weakness in these patients. PMID:27089520

  18. Hybrids monosomal for human chromosome 5 reveal the presence of a spinal muscular atrophy (SMA) carrier with two SMN1 copies on one chromosome.

    PubMed

    Mailman, M D; Hemingway, T; Darsey, R L; Glasure, C E; Huang, Y; Chadwick, R B; Heinz, J W; Papp, A C; Snyder, P J; Sedra, M S; Schafer, R W; Abuelo, D N; Reich, E W; Theil, K S; Burghes, A H; de la Chapelle, A; Prior, T W

    2001-02-01

    We have analyzed the survival motor neuron gene (SMN1) dosage in 100 parents of children with homozygous SMN1 deletions. Of these parents, 96 (96%) demonstrated the expected one-copy SMN1 carrier genotype. However, four parents (4%) were observed to have a normal two-copy SMN1 dosage. The presence of two intact SMN1 genes in the parent of an affected child indicates either the occurrence of a de novo mutation event or a situation in which one chromosome has two copies of SMN1, whereas the other is null. We have separated individual chromosomes from two of these parents with two-copy SMN1 dosage by somatic cell hybridization and have employed a modified quantitative dosage assay to provide direct evidence that one parent is a two-copy/ zero-copy SMN1 carrier, whereas the other parent had an affected child as the result of a de novo mutation. These findings are important for assessing the recurrence risk of parents of children with spinal muscular atrophy and for providing accurate family counseling.

  19. RASCH ANALYSIS OF CLINICAL OUTCOME MEASURES IN SPINAL MUSCULAR ATROPHY

    PubMed Central

    CANO, STEFAN J.; MAYHEW, ANNA; GLANZMAN, ALLAN M.; KROSSCHELL, KRISTIN J.; SWOBODA, KATHRYN J.; MAIN, MARION; STEFFENSEN, BIRGIT F.; BÉRARD, CAROLE; GIRARDOT, FRANÇOISE; PAYAN, CHRISTINE A.M.; MERCURI, EUGENIO; MAZZONE, ELENA; ELSHEIKH, BAKRI; FLORENCE, JULAINE; HYNAN, LINDA S.; IANNACCONE, SUSAN T.; NELSON, LESLIE L.; PANDYA, SHREE; ROSE, MICHAEL; SCOTT, CHARLES; SADJADI, REZA; YORE, MACKENSIE A.; JOYCE, CYNTHIA; KISSEL, JOHN T.

    2015-01-01

    Introduction Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). Methods Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. Results Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. Conclusions The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges. PMID:23836324

  20. Descriptive epidemiology of spinal muscular atrophy type I in Estonia.

    PubMed

    Vaidla, Eve; Talvik, Inga; Kulla, Andres; Kahre, Tiina; Hamarik, Malle; Napa, Aita; Metsvaht, Tuuli; Piirsoo, Andres; Talvik, Tiina

    2006-01-01

    Spinal muscular atrophy is the second most frequent autosomal-recessive disorder in Europeans. There are no published epidemiological data on SMA in Estonia and other Baltic countries. The aim of this study was to estimate the incidence of SMA I in Estonia. All patients with SMA I diagnosed between January 1994 and December 2003 were included in the study. The diagnosis was established on the basis of neurological evaluation, ENMG findings, molecular studies and muscle biopsy. PCR and restriction enzyme analysis was used to detect the homozygous deletion of the SMN1 gene. A total of 9 cases of SMA I were identified during this 10-year period. The incidence of SMA I in Estonia is 1 in 14,400 live births, which is similar to the result from Hungary but lower than average incidence in the world. Only one of the patients was female. Typical SMN1 gene deletion was found in all cases.

  1. Genetic inhibition of JNK3 ameliorates spinal muscular atrophy

    PubMed Central

    Genabai, Naresh K.; Ahmad, Saif; Zhang, Zhanying; Jiang, Xiaoting; Gabaldon, Cynthia A.; Gangwani, Laxman

    2015-01-01

    Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecular mechanism underlying neurodegeneration in SMA is unknown. No treatment is available to prevent neurodegeneration and reduce the burden of illness in SMA. We report that the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required for neuron degeneration caused by SMN deficiency. JNK3 deficiency reduces degeneration of cultured neurons caused by low levels of SMN. Genetic inhibition of JNK pathway in vivo by Jnk3 knockout results in amelioration of SMA phenotype. JNK3 deficiency prevents the loss of spinal cord motor neurons, reduces muscle degeneration, improves muscle fiber thickness and muscle growth, improves motor function and overall growth and increases lifespan of mice with SMA that shows a systemic rescue of phenotype by a SMN-independent mechanism. JNK3 represents a potential (non-SMN) therapeutic target for the treatment of SMA. PMID:26423457

  2. Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy

    PubMed Central

    Deguise, Marc-Olivier; Boyer, Justin G.; McFall, Emily R.; Yazdani, Armin; De Repentigny, Yves; Kothary, Rashmi

    2016-01-01

    Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths. Previous studies have focused on deciphering disease pathogenesis in motor neurons. However, a systematic evaluation of atrophy pathways in muscles is lacking. Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice. Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn2B/− mice but not in the more severe Smn−/−; SMN2 mice. Expression of FoxO transcription factors, which regulate both proteasomal and autophagosomal degradation, is elevated in Smn2B/− muscle. Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy. Cardiac muscle also exhibits differential induction of atrophy between Smn2B/− and Smn−/−; SMN2 mice, albeit in the opposite direction to that of skeletal muscle. Altogether, our work highlights the importance of cautious analysis of different mouse models of SMA as distinct patterns of atrophy induction are at play depending on disease severity. We also revealed that one of the beneficial impacts of trichostatin A on SMA model mice is via attenuation of muscle atrophy through reduction of FoxO expression to normal levels. PMID:27349908

  3. Chronic spinal muscular atrophy of facioscapulohumeral type.

    PubMed Central

    Furukawa, T; Toyokura, Y

    1976-01-01

    Chronic spinal muscular atrophy of FSH type affecting a mother and her son and daughter is reported. The relevant literature is reviewed and the relation between this conditon and Kugelberg-Welander (K-W) disease is discussed. Chronic spinal muscular atrophy of FSH type is considered to be a different entity from the eponymous K-W disease. Each type of muscular dystrophy, e.g. limb-girdle, FSH, distal, ocular, or oculopharyngeal type, has its counterpart of nuclear origin. A classification of the chronic spinal muscular atrophies is suggested following the classification of muscular dystrophy. Images PMID:957378

  4. Establishing a standardized therapeutic testing protocol for spinal muscular atrophy.

    PubMed

    Tsai, Li-Kai; Tsai, Ming-Shung; Lin, Tzer-Bin; Hwu, Wuh-Liang; Li, Hung

    2006-11-01

    Several mice models have been created for spinal muscular atrophy (SMA); however, there is still no standard preclinical testing system for the disease. We previously generated type III-specific SMA model mice, which might be suitable for use as a preclinical therapeutic testing system for SMA. To establish such a system and test its applicability, we first created a testing protocol and then applied it as a means to investigate the use of valproic acid (VPA) as a possible treatment for SMA. These SMA mice revealed tail/ear/foot deformity, muscle atrophy, poorer motor performances, smaller compound muscle action potential and lower spinal motoneuron density at the age of 9 to 12 months in comparison with age-matched wild-type littermate mice. In addition, VPA attenuates motoneuron death, increases spinal SMN protein level and partially normalizes motor function in SMA mice. These results suggest that the testing protocol developed here is well suited for use as a standardized preclinical therapeutic testing system for SMA.

  5. Aquatic Therapy for a Child with Type III Spinal Muscular Atrophy: A Case Report

    ERIC Educational Resources Information Center

    Salem, Yasser; Gropack, Stacy Jaffee

    2010-01-01

    Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of alpha motor neurons. This case report describes an aquatic therapy program and the outcomes for a 3-year-old girl with type III SMA. Motor skills were examined using the 88-item Gross Motor Function Measure (GMFM), the Peabody Developmental Motor Scales…

  6. Disease mechanisms and therapeutic approaches in spinal muscular atrophy.

    PubMed

    Tisdale, Sarah; Pellizzoni, Livio

    2015-06-10

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease.

  7. Spinal muscular atrophy: Factors that modulate motor neurone vulnerability.

    PubMed

    Tu, Wen-Yo; Simpson, Julie E; Highley, J Robin; Heath, Paul R

    2017-02-02

    Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets.

  8. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies

    SciTech Connect

    Melki, J.; Lefebvre, S.; Burglen, L.; Burlet, P.; Clermont, O.; Reboullet, S.; Benichou, B.; Zeviani, M. ); Millasseau, P. ); Le Paslier, D. )

    1994-06-03

    Spinal muscular atrophies (SMAs) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood spinal muscular atrophies are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a yeast artificial chromosome contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in nine unrelated SMA patients. Moreover, deletions were strongly suggested in at least 18 percent of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of spinal muscular atrophy. 25 refs., 5 figs.

  9. Optimization of Spinal Muscular Atrophy subject's muscle activity during gait

    NASA Astrophysics Data System (ADS)

    Umat, Gazlia; Rambely, Azmin Sham

    2014-06-01

    Spinal Muscular Atrophy (SMA) is a hereditary disease related muscle nerve disorder caused by degeneration of the anterior cells of the spinal cord. SMA is divided into four types according to the degree of seriousness. SMA patients show different gait with normal people. Therefore, this study focused on the effects of SMA patient muscle actions and the difference that exists between SMA subjects and normal subjects. Therefore, the electromyography (EMG) test will be used to track the behavior of muscle during walking and optimization methods are used to get the muscle stress that is capable of doing the work while walking. Involved objective function is non-linear function of the quadratic and cubic functions. The study concludes with a comparison of the objective function using the force that sought to use the moment of previous studies and the objective function using the data obtained from EMG. The results shows that the same muscles, peroneus longus and bisepsfemoris, were used during walking activity by SMA subjects and control subjects. Muscle stress force best solution achieved from part D in simulation carried out.

  10. Resistance Strength Training Exercise in Children with Spinal Muscular Atrophy

    PubMed Central

    Lewelt, Aga; Krosschell, Kristin J.; Stoddard, Gregory J.; Weng, Cindy; Xue, Mei; Marcus, Robin L.; Gappmaier, Eduard; Viollet, Louis; Johnson, Barbara A.; White, Andrea T.; Viazzo-Trussell, Donata; Lopes, Philippe; Lane, Robert H.; Carey, John C.; Swoboda, Kathryn J.

    2015-01-01

    Introduction Preliminary evidence in adults with spinal muscular atrophy (SMA) and in SMA animal models suggests exercise has potential benefits in improving or stabilizing muscle strength and motor function. Methods We evaluated feasibility, safety, and effects on strength and motor function of a home-based, supervised progressive resistance strength training exercise program in children with SMA types II and III. Up to 14 bilateral proximal muscles were exercised 3 times weekly for 12 weeks. Results Nine children with SMA, aged 10.4±3.8 years, completed the resistance training exercise program. Ninety percent of visits occurred per protocol. Training sessions were pain-free (99.8%), and no study-related adverse events occurred. Trends in improved strength and motor function were observed. Conclusions A 12-week supervised, home-based, 3 days/week progressive resistance training exercise program is feasible, safe, and well tolerated in children with SMA. These findings can inform future studies of exercise in SMA. PMID:25597614

  11. Moving towards treatments for spinal muscular atrophy: hopes and limits.

    PubMed

    Wirth, Brunhilde; Barkats, Martine; Martinat, Cecile; Sendtner, Michael; Gillingwater, Thomas H

    2015-09-01

    Spinal muscular atrophy (SMA), one of the most frequent and devastating genetic disorders causing neuromuscular degeneration, has reached the forefront of clinical translation. The quite unique genetic situation of SMA patients, who lack functional SMN1 but carry the misspliced SMN2 copy gene, creates the possibility of correcting SMN2 splicing by antisense oligonucleotides or drugs. Both strategies showed impressive results in pre-clinical trials and are now in Phase II-III clinical trials. SMN gene therapy approaches using AAV9-SMN vectors are also highly promising and have entered a Phase I clinical trial. However, careful analysis of SMA animal models and patients has revealed some limitations that need to be taken very seriously, including: i) a limited time-window for successful therapy delivery, making neonatal screening of SMA mandatory; ii) multi-organ impairment, requiring systemic delivery of therapies; and iii) a potential need for combined therapies that both increase SMN levels and target pathways that preserve/rescue motor neuron function over the lifespan. Meeting these challenges will likely be crucial to cure SMA, instead of only ameliorating symptoms, particularly in its most severe form. This review discusses therapies currently in clinical trials, the hopes for SMA therapy, and the potential limitations of these new approaches.

  12. Spatial cognition in young children with spinal muscular atrophy.

    PubMed

    Rivière, James; Lécuyer, Roger

    2002-01-01

    Success in visuospatial tasks has often been demonstrated in teenagers with spinal muscular atrophy (SMA). However, what has been tested in these studies, with the Wechsler Intelligence Scale for Children-Revised (Wechsler, 1974) performance scale, does not deal with the spatial capacities that co-occur with the advent of self-produced locomotion. Indeed, various studies have shown that occurrence of locomotion in infancy is correlated with the development of visuospatial cognitive competencies, suggesting that locomotor experience might play a central role in spatial development, especially in the realm of manual search for hidden objects. It is thus of interest to assess spatial search skills in SMA young children suffering total deprivation of locomotor experience. Twelve Type-2 SMA children with a mean age of 30 months were compared with controls with respect to their spatial search skills in a memory-for-locations task. In this search task, hiding containers were rotated 180 degrees before search was permitted. The performance obtained with the SMA group did not differ from that obtained in the healthy control group. SMA patients searched correctly for a hidden object in the 3-choice search task. Locomotor impairment does not appear to be a key risk factor for dramatic slowing down or deviation in the development of spatial search skills, as assumed by some authors. Further research is needed to identify the alternative pathways to normal spatial development that are used by SMA young children.

  13. Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I

    PubMed Central

    Harding, Brian N.; Kariya, Shingo; Monani, Umrao R.; Chung, Wendy K.; Benton, Maryjane; Yum, Sabrina W.; Tennekoon, Gihan; Finkel, Richard S.

    2014-01-01

    Neuropathological findings within the CNS and PNS in patients with spinal muscular atrophy type I (SMA-I) were examined in relation to genetic, clinical and electrophysiological features. Five infants representing the full clinical spectrum of SMAI were examined clinically for compound motor action potential amplitude and SMN2 gene copy number; morphologic analyses of postmortem CNS, neuromuscular junction and muscle tissue samples were performed and SMN protein was assessed in muscle samples. The 2 clinically most severely affected patients had a single copy of the SMN2 gene; in addition to anterior horn cells, dorsal root ganglia and thalamus, neuronal degeneration in them was widespread in cerebral cortex, basal ganglia, pigmented nuclei, brainstem and cerebellum. Two typical SMA-I patients and a milder case each had 2 copies of the SMN2 gene and more restricted neuropathological abnormalities. Maturation of acetylcholine receptor subunits was delayed and the neuromuscular junctions were abnormally formed in the SMA-1 patients. Thus, the neuropathological findings in human SMA-I are similar to many findings in animal models; factors other than SMN2 copy number modify disease severity. We present a pathophysiologic model for SMA-I as a protein deficiency disease affecting a neuronal network with variable clinical thresholds. Because new treatment strategies improve survival of infants with SMA-I, a better understanding of these factors will guide future treatments. PMID:25470343

  14. [A case of spinal muscular atrophy type 0 in Japan].

    PubMed

    Okamoto, Kentaro; Saito, Kayoko; Sato, Takatoshi; Ishigaki, Keiko; Funatsuka, Makoto; Osawa, Makiko

    2012-09-01

    The patient was a 2-month-old female infant born at 41 weeks and 2 days of gestation presenting multiple arthrogryposis, severe muscle hypotonia and respiratory distress with difficulty in feeding. She suffered from repeated complications with aspiration pneumonia. On admission to our hospital, she exhibited fasciculation and absence of deep tendon reflexes. Examination of the motor nerve conduction velocity (MCV) revealed no muscle contraction. Deletions of the SMN and NAIP genes were noted. Based on severe clinical course and disease development in utero, she was given a diagnosis of spinal muscular atrophy (SMA) type 0 (very severe type). Arthrogryposis and disappearance of MCV are exclusion criteria for SMA. However, the clinical course of the infant was very severe and included such exclusion items. Consequently, when an infant presents muscle hypotonia and respiratory distress, SMA must be considered as one of the differential diagnoses, even though arthrogryposis is an exclusion criterion for SMA. We discuss this case in relation to the few extant reports on SMA type 0 in Japanese infants in the literature.

  15. Spinal Muscular Atrophy Type I: Is It Ethical to Standardize Supportive Care Intervention in Clinical Trials?

    PubMed Central

    Finkel, Richard S.; Bishop, Kathie M.; Nelson, Robert M.

    2016-01-01

    The natural history of spinal muscular atrophy type I (SMA-I) has changed as improved medical support has become available. With investigational drugs for spinal muscular atrophy now in clinical trials, efficient trial design focuses on enrolling recently diagnosed infants, providing best available supportive care, and minimizing subject variation. The quandary has arisen whether it is ethically appropriate to specify a predefined level of nutritional and/or ventilation support for spinal muscular atrophy type I subjects while participating in these studies. We conducted a survey at 2 spinal muscular atrophy investigator meetings involving physician investigators, clinical evaluators, and study coordinators from North America, Europe, and Asia-Pacific. Each group endorsed the concept that having a predefined degree of nutritional and ventilation support was warranted in this context. We discuss how autonomy, beneficence/non-maleficence, noncoercion, social benefit, and equipoise can be maintained when a predefined level of supportive care is proposed, for participation in a clinical trial. PMID:27760875

  16. Placental Development in a Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Van Granigen Caesar, Gerialisa; Dale, Jeffrey M.; Osman, Erkan Y.; Garcia, Michael L.; Lorson, Christian L.; Schulz, Laura C.

    2016-01-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder, leading to fatal loss of motor neurons. It is caused by loss of function of the SMN gene, which is expressed throughout the body, and there is increasing evidence of dysfunction in non-neuronal tissues. Birthweight is one of most powerful prognostic factors for infants born with SMA, and intrauterine growth restriction is common. In the SMNΔ7 mouse model of SMA, pups with the disease lived 25% longer when their mothers were fed a higher fat, “breeder” diet. The placenta is responsible for transport of nutrients from mother to fetus, and is a major determinant of fetal growth. Thus, the present study tested the hypothesis that placental development is impaired in SMNΔ7 conceptuses. Detailed morphological characterization revealed no defects in SMNΔ7 placental development, and expression of key transcription factors regulating mouse placental development was unaffected. The intrauterine growth restriction observed in SMA infants likely does not result from impaired placental development. PMID:26748185

  17. Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

    PubMed Central

    Ripolone, Michela; Ronchi, Dario; Violano, Raffaella; Vallejo, Dionis; Fagiolari, Gigliola; Barca, Emanuele; Lucchini, Valeria; Colombo, Irene; Villa, Luisa; Berardinelli, Angela; Balottin, Umberto; Morandi, Lucia; Mora, Marina; Bordoni, Andreina; Fortunato, Francesco; Corti, Stefania; Parisi, Daniela; Toscano, Antonio; Sciacco, Monica; DiMauro, Salvatore; Comi, Giacomo P.; Moggio, Maurizio

    2016-01-01

    IMPORTANCE The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively). OBJECTIVE To investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA. DESIGN, SETTING, AND PARTICIPANTS We studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca’ Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015. EXPOSURES We used histochemical, biochemical, and molecular techniques to examine the muscle samples. MAIN OUTCOMES AND MEASURES Respiratory chain activity and mitochondrial content. RESULTS Results of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P < .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P < .05). We linked these alterations to downregulation of peroxisome proliferator–activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets

  18. [Fractures in spinal muscular atrophy].

    PubMed

    Febrer, Anna; Vigo, Meritxell; Rodríguez, Natalia; Medina, Julita; Colomer, Jaume; Nascimento, Andrés

    2013-09-01

    Objetivo. Determinar la frecuencia de fracturas en pacientes con atrofia muscular espinal, mecanismo de produccion, edad de aparicion y repercusion funcional. Pacientes y metodos. Se estudian 65 pacientes con atrofia muscular espinal. Se recogen las fracturas diagnosticadas mediante radiografia y se analizan los siguientes parametros: tipo de atrofia muscular espinal, marcha, edad en el momento de la fractura, mecanismo de produccion, localizacion, tratamiento aplicado y repercusion funcional. Resultados. Presentaron fracturas 13 pacientes (20%), con un total de 20 (cuatro presentaron dos o mas fracturas). La edad media fue de 6,35 años. La localizacion fue en su mayoria en el femur y el mecanismo de produccion, en 12 casos por caidas y en 8 por traumatismo menor. No detectamos ninguna fractura vertebral. Todas se trataron de manera conservadora. El unico paciente ambulante que presento una fractura dejo de caminar despues de la inmovilizacion. Conclusiones. La existencia de fracturas en estos pacientes interfiere en su calidad de vida y en el nivel funcional. Es importante la prevencion de las mismas en el manejo del paciente y vigilando la correcta postura en la silla de ruedas con sistemas de sujecion Deberian emprenderse mas estudios sobre la perdida de densidad mineral osea en estos pacientes y su posible relacion con las fracturas.

  19. Evidence of reduced frequency of spinal muscular atrophy type I in the Cuban population.

    PubMed

    Zaldívar, T; Montejo, Y; Acevedo, A M; Guerra, R; Vargas, J; Garofalo, N; Alvarez, R; Alvarez, M A; Hardiman, O

    2005-08-23

    The authors reviewed all cases of type I spinal muscular atrophy (SMA) in Cuba over a 6-year period. The incidence of SMA type I was 3.53 per 100,000 livebirths. When the population was classified according to self-reported ethnicity, the incidence was eight per 100,000 for whites; 0.89 per 100,000 for blacks, and 0.96 per 100,000 for those of mixed ethnicity. Type 1 SMA may occur less frequently in individuals of African ancestry.

  20. Neuronal involvement in muscular atrophy.

    PubMed

    Cisterna, Bruno A; Cardozo, Christopher; Sáez, Juan C

    2014-01-01

    The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor-related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression.

  1. The zinc finger protein ZPR1 is a potential modifier of spinal muscular atrophy

    PubMed Central

    Ahmad, Saif; Wang, Yi; Shaik, Gouse M.; Burghes, Arthur H.; Gangwani, Laxman

    2012-01-01

    Spinal muscular atrophy (SMA) is caused by mutation of the Survival Motor Neurons 1 (SMN1) gene and is characterized by degeneration of spinal motor neurons. The severity of SMA is primarily influenced by the copy number of the SMN2 gene. Additional modifier genes that lie outside the SMA locus exist and one gene that could modify SMA is the Zinc Finger Protein (ZPR1) gene. To test the significance of ZPR1 downregulation in SMA, we examined the effect of reduced ZPR1 expression in mice with mild and severe SMA. We report that the reduced ZPR1 expression causes increase in the loss of motor neurons, hypermyelination in phrenic nerves, increase in respiratory distress and disease severity and reduces the lifespan of SMA mice. The deficiency of SMN-containing sub-nuclear bodies correlates with the severity of SMA. ZPR1 is required for the accumulation of SMN in sub-nuclear bodies. Further, we report that ZPR1 overexpression increases levels of SMN and promotes accumulation of SMN in sub-nuclear bodies in SMA patient fibroblasts. ZPR1 stimulates neurite growth and rescues axonal growth defects in SMN-deficient spinal cord neurons from SMA mice. These data suggest that the severity of disease correlates negatively with ZPR1 levels and ZPR1 may be a protective modifier of SMA. PMID:22422766

  2. Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy.

    PubMed

    Corti, Stefania; Nizzardo, Monica; Simone, Chiara; Falcone, Marianna; Nardini, Martina; Ronchi, Dario; Donadoni, Chiara; Salani, Sabrina; Riboldi, Giulietta; Magri, Francesca; Menozzi, Giorgia; Bonaglia, Clara; Rizzo, Federica; Bresolin, Nereo; Comi, Giacomo P

    2012-12-19

    Spinal muscular atrophy (SMA) is among the most common genetic neurological diseases that cause infant mortality. Induced pluripotent stem cells (iPSCs) generated from skin fibroblasts from SMA patients and genetically corrected have been proposed to be useful for autologous cell therapy. We generated iPSCs from SMA patients (SMA-iPSCs) using nonviral, nonintegrating episomal vectors and used a targeted gene correction approach based on single-stranded oligonucleotides to convert the survival motor neuron 2 (SMN2) gene into an SMN1-like gene. Corrected iPSC lines contained no exogenous sequences. Motor neurons formed by differentiation of uncorrected SMA-iPSCs reproduced disease-specific features. These features were ameliorated in motor neurons derived from genetically corrected SMA-iPSCs. The different gene splicing profile in SMA-iPSC motor neurons was rescued after genetic correction. The transplantation of corrected motor neurons derived from SMA-iPSCs into an SMA mouse model extended the life span of the animals and improved the disease phenotype. These results suggest that generating genetically corrected SMA-iPSCs and differentiating them into motor neurons may provide a source of motor neurons for therapeutic transplantation for SMA.

  3. Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

    PubMed Central

    Wishart, Thomas M.; Mutsaers, Chantal A.; Riessland, Markus; Reimer, Michell M.; Hunter, Gillian; Hannam, Marie L.; Eaton, Samantha L.; Fuller, Heidi R.; Roche, Sarah L.; Somers, Eilidh; Morse, Robert; Young, Philip J.; Lamont, Douglas J.; Hammerschmidt, Matthias; Joshi, Anagha; Hohenstein, Peter; Morris, Glenn E.; Parson, Simon H.; Skehel, Paul A.; Becker, Thomas; Robinson, Iain M.; Becker, Catherina G.; Wirth, Brunhilde; Gillingwater, Thomas H.

    2014-01-01

    The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of Uba1 mRNA splicing was observed in the spinal cords of SMA mice exhibiting disease symptoms. Pharmacological or genetic suppression of UBA1 was sufficient to recapitulate an SMA-like neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. Dysregulation of UBA1 and subsequent ubiquitination pathways led to β-catenin accumulation, and pharmacological inhibition of β-catenin robustly ameliorated neuromuscular pathology in zebrafish, Drosophila, and mouse models of SMA. UBA1-associated disruption of β-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of β-catenin in these animals failed to prevent systemic pathology in peripheral tissues and organs, indicating fundamental molecular differences between neuromuscular and systemic SMA pathology. Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent β-catenin signaling, highlighting ubiquitin homeostasis and β-catenin as potential therapeutic targets for SMA. PMID:24590288

  4. [The construction of urine-derived cell lines from patients with spinal muscular atrophy].

    PubMed

    Wanjin, Chen; Qijie, Zhang; Jin, He; Xiang, Lin; Ning, Wang

    2014-11-01

    Spinal muscular atrophy (SMA) is a common neurodegenerative disease in childhood and infancy, clinically characterized by progressive and symmetric muscular weakness and atrophy. Few effective therapies are available now, and SMA is one of the most common genetic causes of infantile mortality. SMA patient-derived cells are beneficial in basic research on this disease, but the most common model cell, fibroblasts can only be obtained through invasive procedures such as muscle or skin biopsy, which are unwelcome to patients and their families. In this study, fresh urine from SMA patients and healthy controls was collected and centrifuged, and the urine sediment was cultured in vitro. The growth characteristics of urine-derived cells were observed, and the survival of motor neuron (SMN) gene, and the amount and localization of SMN protein in different urine cell lines were investigated. In total, 25 urine cell lines from 11 SMA patients and 14 healthy controls were established. These urine-derived cells expand robustly in vitro with stable cell morphological characteristics. The urine cell lines derived from patients carry the SMN1 gene defect and express a low level of SMN protein, while the intracellular localization of SMN protein is normal. Urine-derived cell culture technology is simple, non-invasive and highly reproducible, a way of obtaining and storing rare cell samples from SMA patients with which to study the pathogenesis of SMA.

  5. Perceptions of Equine Assisted Activities and Therapies by Parents and Children with Spinal Muscular Atrophy

    PubMed Central

    Lemke, Danielle; Rothwell, Erin; Newcomb, Tara M.; Swoboda, Kathryn J.

    2014-01-01

    Purpose To identify the physical and psychosocial effects of equine assisted activities and therapies (EAAT) on children with Spinal Muscular Atrophy (SMA) from the perspective of the child and their parents. Methods The families of all eligible children with SMA, who reported participation in EAAT, from a western metropolitan academic center were contacted and invited to participate. This study implemented qualitative, semi-structured interviews of children with SMA and their parents. Results Three themes emerged from the qualitative content analysis: physical/psychosocial benefits; relationship development with the horses, instructors, and children; and barriers to continued EAAT engagement. Conclusions The data suggest the overall EAAT experience was a source of enjoyment, self-confidence, and normalcy for the children with SMA. The results of this study provide preliminary support for the use of EAAT among children with SMA. PMID:24675128

  6. Spinal muscular atrophy: from tissue specificity to therapeutic strategies

    PubMed Central

    Iascone, Daniel M.; Lee, Justin C.

    2015-01-01

    Spinal muscular atrophy (SMA) is the most frequent genetic cause of death in infants and toddlers. All cases of spinal muscular atrophy result from reductions in levels of the survival motor neuron (SMN) protein, and so SMN upregulation is a focus of many preclinical and clinical studies. We examine four issues that may be important in planning for therapeutic success. First, neuromuscular phenotypes in the SMNΔ7 mouse model closely match those in human patients but peripheral disease manifestations differ, suggesting that endpoints other than mouse lifespan may be more useful in predicting clinical outcome. Second, SMN plays important roles in multiple central and peripheral cell types, not just motor neurons, and it remains unclear which of these cell types need to be targeted therapeutically. Third, should SMN-restoration therapy not be effective in all patients, blocking molecular changes downstream of SMN reduction may confer significant benefit, making it important to evaluate therapeutic targets other than SMN. Lastly, for patients whose disease progression is slowed, but who retain significant motor dysfunction, additional approaches used to enhance regeneration of the neuromuscular system may be of value. PMID:25705387

  7. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice.

    PubMed

    Heier, Christopher R; Satta, Rosalba; Lutz, Cathleen; DiDonato, Christine J

    2010-10-15

    Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there is a growing body of evidence that arrhythmia and/or cardiomyopathy may present in SMA patients at an increased frequency. Here, we ask whether SMA model mice possess such phenotypes. We find SMA mice suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms functional cardiac deficits in SMA mice. Additional investigations show evidence of both sympathetic innervation defects and dilated cardiomyopathy at late stages of disease. Based upon these data, we propose a model in which decreased sympathetic innervation causes autonomic imbalance. Such imbalance would be characterized by a relative increase in the level of vagal tone controlling heart rate, which is consistent with bradyarrhythmia and progressive heart block. Finally, treatment with the histone deacetylase inhibitor trichostatin A, a drug known to benefit phenotypes of SMA model mice, produces prolonged maturation of the SMA heartbeat and an increase in cardiac size. Treated mice maintain measures of motor function throughout extended survival though they ultimately reach death endpoints in association with a progression of bradyarrhythmia. These data represent the novel identification of cardiac arrhythmia as an early and progressive feature of murine SMA while providing several new, quantitative indices of mouse health. Together with clinical cases that report similar symptoms, this reveals a new area of investigation that will be important to address as we move SMA therapeutics towards clinical success.

  8. Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

    PubMed Central

    Butchbach, Matthew E. R.; Edwards, Jonathan D.; Burghes, Arthur H. M.

    2009-01-01

    Spinal muscular atrophy (SMA) is recessive motor neuron disease that affects motor neurons in the anterior horn of the spinal cord. SMA results from the reduction of SMN (survival motor neuron) protein. Even though SMN is ubiquitously expressed, motor neurons are more sensitive to the reduction in SMN than other cell types. We have previously generated mouse models of SMA with varying degrees of clinical severity. So as to more clearly understand the pathogenesis of motor neuron degeneration in SMA, we have characterized the phenotype of the SMNΔ7 SMA mouse which normally lives for 13.6 ± 0.7 days. These mice are smaller than their non-SMA littermates and begin to lose body mass at 10.4 ± 0.4 days. SMNΔ7 SMA mice exhibit impaired responses to surface righting, negative geotaxis and cliff aversion but not to tactile stimulation. Spontaneous motor activity and grip strength are also significantly impaired in SMNΔ7 SMA mice. In summary, we have demonstrated an impairment of neonatal motor responses in SMNΔ7 SMA mice. This phenotype characterization could be used to assess the effectiveness of potential therapies for SMA. PMID:17561409

  9. Gene therapy: a promising approach to treating spinal muscular atrophy.

    PubMed

    Mulcahy, Pádraig J; Iremonger, Kayleigh; Karyka, Evangelia; Herranz-Martín, Saúl; Shum, Ka-To; Tam, Janice Kal Van; Azzouz, Mimoun

    2014-07-01

    Spinal muscular atrophy (SMA) is a severe autosomal recessive disease caused by a genetic defect in the survival motor neuron 1 (SMN1) gene, which encodes SMN, a protein widely expressed in all eukaryotic cells. Depletion of the SMN protein causes muscle weakness and progressive loss of movement in SMA patients. The field of gene therapy has made major advances over the past decade, and gene delivery to the central nervous system (CNS) by in vivo or ex vivo techniques is a rapidly emerging field in neuroscience. Despite Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis being among the most common neurodegenerative diseases in humans and attractive targets for treatment development, their multifactorial origin and complicated genetics make them less amenable to gene therapy. Monogenic disorders resulting from modifications in a single gene, such as SMA, prove more favorable and have been at the fore of this evolution of potential gene therapies, and results to date have been promising at least. With the estimated number of monogenic diseases standing in the thousands, elucidating a therapeutic target for one could have major implications for many more. Recent progress has brought about the commercialization of the first gene therapies for diseases, such as pancreatitis in the form of Glybera, with the potential for other monogenic disease therapies to follow suit. While much research has been carried out, there are many limiting factors that can halt or impede translation of therapies from the bench to the clinic. This review will look at both recent advances and encountered impediments in terms of SMA and endeavor to highlight the promising results that may be applicable to various associated diseases and also discuss the potential to overcome present limitations.

  10. Spinal and Bulbar Muscular Atrophy Overview

    PubMed Central

    Fischbeck, Kenneth H.

    2016-01-01

    Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by an expanded repeat in the androgen receptor gene. The mutant protein is toxic to motor neurons and muscle. The toxicity is ligand-dependent and likely involves aberrant interaction of the mutant androgen receptor with other nuclear factors leading to transcriptional dysregulation. Various therapeutic strategies have been effective in transgenic animal models, and the challenge now is to translate these strategies into safe and effective treatment in patients. PMID:26547319

  11. Mapping of retrotransposon sequences in the unstable region surrounding the spinal muscular atrophy locus in 5q13

    SciTech Connect

    Francis, M.J.; Nesbit, M.A.; Theodosiou, A.M.

    1995-05-20

    The mutation that underlies the autosomal recessive disorder spinal muscular atrophy (SMA) is located on chromosome 5q13. Recent studies show that SMA patients frequently have deletions and rearrangements in this region compared to normal controls. During the isolation of candidate cDNAs for the disease, the authors identified a sequence that shows high homology to the THE-1 retrotransposon gene family. Using YAC fragmentation techniques, they have refined the localization of this sequence to the domain known to show instability in SMA patients. The implication of these results for the mechanism of the mutation in SMA is discussed. 20 refs., 1 fig.

  12. Using General Anesthesia plus Muscle Relaxant in a Patient with Spinal Muscular Atrophy Type IV: A Case Report

    PubMed Central

    Liu, Xiu-Fen; Wang, Dong-Xin; Ma, Daqing

    2011-01-01

    Spinal muscular atrophy (SMA) is a rare genetic disease characterized by degeneration of spinal cord motor neurons, which results in hypotonia and muscle weakness. Patients with type IV SMA often have onset of weakness from adulthood. Anesthetic management is often difficult in these patients as a result of muscle weakness and hypersensitivity to neuromuscular blocking agents as shown by (Lunn and Wang; 2008, Simic; 2008, and Cifuentes-Diaz et al.; 2002). Herein we report a case of anesthetic management of a patient with SMA type IV for mammectomy and review some other cases of SMA patients receiving different kinds of anesthesia. PMID:22606392

  13. Effect of the butyrate prodrug pivaloyloxymethyl butyrate (AN9) on a mouse model for spinal muscular atrophy

    PubMed Central

    Edwards, Jonathan D.; Butchbach, Matthew E. R.

    2016-01-01

    Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ7 SMA mice when compared to vehicle-treated SMNΔ7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on SMNΔ7 SMA mice. PMID:27911337

  14. Feeding problems and malnutrition in spinal muscular atrophy type II.

    PubMed

    Messina, Sonia; Pane, Marika; De Rose, Paola; Vasta, Isabella; Sorleti, Domenica; Aloysius, Annie; Sciarra, Federico; Mangiola, Fortunato; Kinali, Maria; Bertini, Enrico; Mercuri, Eugenio

    2008-05-01

    The aim of the study was to conduct a survey using a dedicated questionnaire to assess feeding difficulties and weight gain in a population of 122 Spinal Muscular Atrophy (SMA) type II patients, aged between 1 and 47 years. All the answers were entered in a database and were analysed subdividing the cohort into age groups (1-5, 6-10, 11-14, 15-19, 20-29, and 30-50 years). Six out of our 122 patients (5%), all younger than 11 years, had weights more than 2SD above the median for age matched controls, whilst 45 (37%) had weights less than 2SD below the median. Chewing difficulties were reported in 34 of the 122 patients (28%) and limitation in the ability to open the mouth in 36 (30%) and both were increasingly more frequent with age. Swallowing difficulties were reported in 30 patients (25%). The results of our survey suggest that a number of patients with SMA type II have limited jaw opening, and chewing and swallowing difficulties. Our findings raise a few issues concerning standards of care that should be implemented in the monitoring and management of feeding difficulties and weight gain.

  15. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy

    PubMed Central

    Mentis, George Z.; Blivis, Dvir; Liu, Wenfang; Drobac, Estelle; Crowder, Melissa E.; Kong, Lingling; Alvarez, Francisco J.; Sumner, Charlotte J.; O'Donovan, Michael J.

    2011-01-01

    SUMMARY To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes illustrating the reversibility of these synaptic defects. De-afferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention. PMID:21315257

  16. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy.

    PubMed

    Mentis, George Z; Blivis, Dvir; Liu, Wenfang; Drobac, Estelle; Crowder, Melissa E; Kong, Lingling; Alvarez, Francisco J; Sumner, Charlotte J; O'Donovan, Michael J

    2011-02-10

    To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes, illustrating the reversibility of these synaptic defects. Deafferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention.

  17. Electrophysiological biomarkers in spinal muscular atrophy: proof of concept

    PubMed Central

    David Arnold, W; Porensky, Paul N; McGovern, Vicki L; Iyer, Chitra C; Duque, Sandra; Li, Xiaobai; Meyer, Kathrin; Schmelzer, Leah; Kaspar, Brian K; Kolb, Stephen J; Kissel, John T; Burghes, Arthur H M

    2014-01-01

    Objective Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model. Methods Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 mice at ages 3–13 days and at 21 days in mice with SMN selectively reduced in motor neurons (ChATCre). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy. Results CMAP was significantly reduced in SMNΔ7 mice at days 6–13 (P < 0.01), and MUNE was reduced at days 7–13 (P < 0.01). Fibrillations were present on EMG in SMNΔ7 mice but not controls (P = 0.02). Similar findings were seen at 21 days in ChATCre mice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN. Interpretation These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials. PMID:24511555

  18. Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy

    PubMed Central

    Powis, Rachael A.; Karyka, Evangelia; Boyd, Penelope; Côme, Julien; Jones, Ross A.; Zheng, Yinan; Szunyogova, Eva; Groen, Ewout J.N.; Hunter, Gillian; Thomson, Derek; Wishart, Thomas M.; Becker, Catherina G.; Parson, Simon H.; Martinat, Cécile; Azzouz, Mimoun; Gillingwater, Thomas H.

    2016-01-01

    The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA. Loss of UBA1 was a conserved response across mouse and zebrafish models of SMA as well as in patient induced pluripotent stem cell–derive motor neurons. Restoration of UBA1 was sufficient to rescue motor axon pathology and restore motor performance in SMA zebrafish. Adeno-associated virus serotype 9–UBA1 (AAV9-UBA1) gene therapy delivered systemic increases in UBA1 protein levels that were well tolerated over a prolonged period in healthy control mice. Systemic restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular and organ pathology. AAV9-UBA1 therapy was also sufficient to reverse the widespread molecular perturbations in ubiquitin homeostasis that occur during SMA. We conclude that UBA1 represents a safe and effective therapeutic target for the treatment of both neuromuscular and systemic aspects of SMA. PMID:27699224

  19. Spinal muscular atrophy during human development: where are the early pathogenic findings?

    PubMed

    Tizzano, Eduardo

    2009-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects motor neurons. It is caused by mutations in the survival motor neuron gene 1 (SMN1). The SMN2 gene, which is the highly homologous SMN1 copy that is present in all patients, is unable to prevent the disease. SMA patients can be classified into four groups based on age at onset and acquired milestones (type I or severe acute disease, with onset before 6 months; type II, before 18 months; type III, after 18 months and type IV, in adult life). The human developmental period is believed to play an essential role in SMA pathogenesis. However, the neuropathologic study of SMA comes largely from postnatal necropsy samples, which describe the end-stage of the disease. With the exception of severe congenital SMA (or Type 0 SMA), type I patients tend to present a short but variable presymptomatic period after birth. Our main interest lies in studying SMA during human development so as to gain insight into the mechanism of the disease in the prenatal-presymptomatic stage. In fetuses of 12-15 weeks' gestational age we systematically studied histology, cell death and gene expression in spinal cord and muscle, the key tissues involved in the disease. Furthermore, ultrasound parameters were investigated at these stages. These studies may help to delineate an early intervention in SMA, in particular during the potential therapeutic window.

  20. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy

    PubMed Central

    Harms, M.B.; Ori-McKenney, K.M.; Scoto, M.; Tuck, E.P.; Bell, S.; Ma, D.; Masi, S.; Allred, P.; Al-Lozi, M.; Reilly, M.M.; Miller, L.J.; Jani-Acsadi, A.; Pestronk, A.; Shy, M.E.; Muntoni, F.; Vallee, R.B.

    2012-01-01

    Objective: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600). Methods: Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed. Results: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state—a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function. Conclusions: We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance. PMID:22459677

  1. Refined linkage map of chromosome 5 in the region of the spinal muscular atrophy gene

    SciTech Connect

    Melki, J.; Burlet, P.; Clermont, O.; Pascal, F.; Paul, B.; Abdelhak, S.; Munnich, A. ); Sherrington, R.; Gurling, H. Middlesex School of Medicine, London ); Nakamura, Yusuke ); Weissenbach, J. Genethon, Evry ); Lathrop, M. )

    1993-03-01

    The genetic map in the region of human chromosome 5 that harbors the gene for autosomal recessive forms of spinal muscular atrophy (SMA) has been refined by a multilocus linkage study in 50 SMA-segregating families. Among six markers spanning 8 cM for combined sexes, four were shown to be tightly linked to the SMA locus. Multipoing linkage analysis was used to establish the best estimate of the SMA gene location. The data suggest that the most likely location for the SMA locus is between blocks AFM114ye7 (D5S465)/EF5.15 (D5S125) and MAP-1B/JK53 (D5S112) at a sex-combined genetic distance of 2.4 and 1.7 cM, respectively. Thus the SMA gene lies in the 4-cM region between these two blocks. This information is of primary importance for designing strategies for isolating the SMA gene. 16 refs., 2 figs., 4 tabs.

  2. Spinal Muscular Atrophy: Diagnosis and Management in a New Therapeutic Era

    PubMed Central

    Arnold, W. David; Kassar, Darine; Kissel, John T.

    2014-01-01

    Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produce reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that the understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early phase clinical trials. PMID:25346245

  3. Small Molecules in Development for the Treatment of Spinal Muscular Atrophy.

    PubMed

    Calder, Alyssa N; Androphy, Elliot J; Hodgetts, Kevin J

    2016-11-23

    Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease resulting from pathologically low levels of survival motor neuron (SMN) protein. The majority of mRNA from the SMN2 allele undergoes alternative splicing and excludes critical codons, causing an SMN protein deficiency. While there is currently no FDA-approved treatment for SMA, early therapeutic efforts have focused on testing repurposed drugs such as phenylbutyrate (2), valproic acid (3), riluzole (6), hydroxyurea (7), and albuterol (9), none of which has demonstrated clinical effectiveness. More recently, clinical trials have focused on novel small-molecule compounds identified from high-throughput screening and medicinal chemistry optimization such as olesoxime (11), CK-2127107, RG7800, LMI070, and RG3039 (17). In this paper, we review both repurposed drugs and small-molecule compounds discovered following medicinal chemistry optimization for the potential treatment of SMA.

  4. [Self-produced locomotion and spatial cognition: a new light from spinal muscular atrophy].

    PubMed

    Rivière, J

    2007-03-01

    Various studies have shown that occurrence of locomotion in infancy is correlated with the development of visuospatial cognitive competencies, suggesting that locomotor experience might play a central role in spatial development, especially in the realm of manual search for hidden objects. However, recent studies indicate that young children with spinal muscular atrophy (SMA), a hereditary neuromuscular disease which results in severe motor impairments, excel in some spatial cognitive skills. Indeed, striking cognitive performances are exhibited by young SMA children in some areas such as the ability to search successfully for hidden objects and the acquisition of the spatial vocabulary. The performances of SMA children suggest that, despite their total deprivation of locomotor experience, they have the capacity to acquire and use rich spatial representations. As a result, locomotor impairment does not appear to be a key risk factor for dramatic slowing down or deviation in the development of spatial search skills.

  5. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases

    PubMed Central

    Butchbach, Matthew E. R.

    2016-01-01

    Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1) on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7) and produce a protein that is both unstable and less than fully functional. Although only 10–20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs) in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases. PMID:27014701

  6. Stathmin, a microtubule-destabilizing protein, is dysregulated in spinal muscular atrophy.

    PubMed

    Wen, Hsin-Lan; Lin, Yuan-Ta; Ting, Chen-Hung; Lin-Chao, Sue; Li, Hung; Hsieh-Li, Hsiu Mei

    2010-05-01

    Spinal muscular atrophy (SMA), a motor neuron degeneration disorder, is caused by either mutations or deletions of survival motor neuron 1 (SMN1) gene which result in insufficient SMN protein. Here, we describe a potential link between stathmin and microtubule defects in SMA. Stathmin was identified by screening Smn-knockdown NSC34 cells through proteomics analysis. We found that stathmin was aberrantly upregulated in vitro and in vivo, leading to a decreased level of polymerized tubulin, which was correlated with disease severity. Reduced microtubule densities and beta(III)-tubulin levels in distal axons of affected SMA-like mice and an impaired microtubule network in Smn-deficient cells were observed, suggesting an involvement of stathmin in those microtubule defects. Furthermore, knockdown of stathmin restored the microtubule network defects of Smn-deficient cells, promoted axon outgrowth and reduced the defect in mitochondria transport in SMA-like motor neurons. We conclude that aberrant stathmin levels may play a detrimental role in SMA; this finding suggests a novel approach to treating SMA by enhancing microtubule stability.

  7. ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice

    PubMed Central

    Abera, Mahlet B.; Xiao, Jingbo; Nofziger, Jonathan; Titus, Steve; Moritz, Kasey E.; Ferrer, Marc; Cherry, Jonathan J.; Androphy, Elliot J.; Wang, Amy; Xu, Xin; Austin, Christopher; Fischbeck, Kenneth H.; Marugan, Juan J.; Burnett, Barrington G.

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease and one of the leading inherited causes of infant mortality. SMA results from insufficient levels of the survival motor neuron (SMN) protein, and studies in animal models of the disease have shown that increasing SMN protein levels ameliorates the disease phenotype. Our group previously identified and optimized a new series of small molecules, with good potency and toxicity profiles and reasonable pharmacokinetics, that were able to increase SMN protein levels in SMA patient–derived cells. We show here that ML372, a representative of this series, almost doubles the half-life of residual SMN protein expressed from the SMN2 locus by blocking its ubiquitination and subsequent degradation by the proteasome. ML372 increased SMN protein levels in muscle, spinal cord, and brain tissue of SMA mice. Importantly, ML372 treatment improved the righting reflex and extended survival of a severe mouse model of SMA. These results demonstrate that slowing SMN degradation by selectively inhibiting its ubiquitination can improve the motor phenotype and lifespan of SMA model mice. PMID:27882347

  8. Apparent autosomal recessive inheritance in families with proximal spinal muscular atrophy affecting individuals in two generations

    SciTech Connect

    Rudnik-Schoeneborn, S.; Zerres, K.; Hahnen, E.

    1996-11-01

    With the evidence that deletions in the region responsible for childhood- and juvenile-onset proximal spinal muscular atrophy (SMA) are on chromosome 5 it is now possible to confirm autosomal recessive inheritance in most patients (denoted {open_quotes}SMA 5q{close_quotes}). Homozygous deletions in the telomeric copy of the survival motor neuron (SMN) gene can be detected in 95%-98% of patients with early-onset SMA (types I and II), whereas as many as 10%-20% of patients with the milder, juvenile-onset form (type III SMA) do not show deletions. In families with affected subjects in two generations, it is difficult to decide whether they are autosomal dominantly inherited or caused by three independent recessive mutations (pseudodominant inheritance). Given an incidence of >1/10,000 of SMA 5q, patients with autosomal recessive SMA have an {approximately}1% recurrence risk to their offspring. Although the dominant forms are not linked to chromosome 5q, pseudodominant families can now be identified by the presence of homozygous deletions in the SMN gene. 5 refs., 1 fig., 1 tab.

  9. [Physical study of big fragments and search strategy of genes. Application to locus of infant spinal muscular atrophies].

    PubMed

    Melki, J; Lefebvre, S; Burglen, L; Burlet, P; Clermont, O; Millasseau, P; Reboulet, S; Benichou, B; Zeviani, M; Le Paslier, D

    1994-01-01

    Spinal muscular atrophies (SMA) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood SMAs are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a YAC contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy-repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in 10 SMA patients. Moreover, deletions were strongly suggested in at least 18% of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of SMA.

  10. A large animal model of Spinal Muscular Atrophy and correction of phenotype

    PubMed Central

    Duque, Sandra I.; Arnold, W. David; Odermatt, Philipp; Li, Xiaohui; Porensky, Paul N.; Schmelzer, Leah; Meyer, Kathrin; Kolb, Stephen J.; Schümperli, Daniel; Kaspar, Brian K.; Burghes, Arthur H. M.

    2015-01-01

    Objectives Spinal muscular atrophy (SMA) is caused by reduced levels of SMN which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides or scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness and the response of clinically relevant biomarkers. Methods Using intrathecal delivery of scAAV9 expressing a shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN) and electrophysiology measures and pathology were performed. Results Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography (EMG) indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimates (MUNE), like human SMA. Neuropathology showed loss of motoneurons and motor axons. Pre-symptomatic delivery of scAAV9-SMN prevented SMA symptoms indicating all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures and pathology. Interpretation High SMN levels are critical in postnatal motoneurons and reduction of SMN results in a SMA phenotype which is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration and abrogation of phenotype can be achieved even after symptom onset. PMID:25516063

  11. Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy.

    PubMed

    Xu, Chong-Chong; Denton, Kyle R; Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2016-01-01

    Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs) and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC) mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA.

  12. Construction of a yeast artificial chromosome contig spanning the spinal muscular atrophy disease gene region.

    PubMed Central

    Kleyn, P W; Wang, C H; Lien, L L; Vitale, E; Pan, J; Ross, B M; Grunn, A; Palmer, D A; Warburton, D; Brzustowicz, L M

    1993-01-01

    The childhood spinal muscular atrophies (SMAs) are the most common, serious neuromuscular disorders of childhood second to Duchenne muscular dystrophy. A single locus for these disorders has been mapped by recombination events to a region of 0.7 centimorgan (range, 0.1-2.1 centimorgans) between loci D5S435 and MAP1B on chromosome 5q11.2-13.3. By using PCR amplification to screen yeast artificial chromosome (YAC) DNA pools and the PCR-vectorette method to amplify YAC ends, a YAC contig was constructed across the disease gene region. Nine walk steps identified 32 YACs, including a minimum of seven overlapping YAC clones (average size, 460 kb) that span the SMA region. The contig is characterized by a collection of 30 YAC-end sequence tag sites together with seven genetic markers. The entire YAC contig spans a minimum of 3.2 Mb; the SMA locus is confined to roughly half of this region. Microsatellite markers generated along the YAC contig segregate with the SMA locus in all families where the flanking markers (D5S435 and MAP1B) recombine. Construction of a YAC contig across the disease gene region is an essential step in isolation of the SMA-encoding gene. Images Fig. 1 PMID:8341701

  13. Construction of a yeast artifical chromosome contig spanning the spinal muscular atrophy disease gene region

    SciTech Connect

    Kleyn, P.W.; Wang, C.H.; Vitale, E.; Pan, J.; Ross, B.M.; Grunn, A.; Palmer, D.A.; Warburton, D.; Brzustowicz, L.M.; Gilliam, T.G. ); Lien, L.L.; Kunkel, L.M. )

    1993-07-15

    The childhood spinal muscular atrophies (SMAs) are the most common, serious neuromuscular disorders of childhood second to Duchenne muscular dystrophy. A single locus for these disorders has been mapped by recombination events to a region of 0.7 centimorgan (range, 0.1-2.1 centimorgans) between loci D5S435 and MAP1B on chromosome 5q11.2-13.3. By using PCR amplification to screen yeast artificial chromosome (YAC) DNA pools and the PCR-vectorette method to amplify YAC ends, a YAC contig was constructed across the disease gene region. Nine walk steps identified 32 YACs, including a minimum of seven overlapping YAC clones (average size, 460 kb) that span the SMA region. The contig is characterized by a collection of 30 YAC-end sequence tag sites together with seven genetic markers. The entire YAC contig spans a minimum of 3.2 Mb; the SMA locus is confined to roughly half of this region. Microsatellite markers generated along the YAC contig segregate with the SMA locus in all families where the flanking markers (D5S435 and MAP1B) recombine. Construction of a YAC contig across the disease gene region is an essential step in isolation of the SMA-encoding gene. 26 refs., 3 figs., 1 tab.

  14. Intrathecal Injections in Children With Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Sethna, Navil; Farrow-Gillespie, Alan; Khandji, Alexander; Xia, Shuting; Bishop, Kathie M.

    2016-01-01

    Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post–lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture–related adverse event frequency was similar to that previously reported in children. PMID:26823478

  15. Congenital segmental spinal muscular atrophy: a case report.

    PubMed

    Savaş, Tülin; Erol, Ilknur; Özkale, Yasemin; Saygi, Semra

    2015-03-01

    Spinal muscular atrophies are genetic disorders in which anterior horn cells in the spinal cord and motor nuclei of the brainstem are progressively lost. We present a patient with arthrogryposis due to congenital spinal muscular atrophy predominantly affecting the upper limbs. Spinal muscular atrophies with onset at birth may be a cause of arthrogryposis. Localized forms of neurogenic arthrogryposis have been divided into cervical and caudal forms. Our case is similar to the cases described by Hageman et al (J Neurol Neurosurg Psychiatry 1993;56:365-368): severe symmetric lower motor neuron deficit in the upper extremities at the time of birth, no history of injury to the cervical spinal cord or the brachial plexus during delivery, and severe muscle wasting suggesting chronic denervation in utero. Because there was improvement of our patient's situation, her disease was also possibly nonprogressive and sporadic. To our knowledge, this is the first reported case of a Turkish patient with congenital cervical spinal muscular atrophy. Congenital cervical spinal muscular atrophy affecting predominantly the upper limbs is a relatively rare form of motor neuron disease and should be considered in the differential diagnosis of infants with congenital contractures and severe muscle weakness by wasting mainly confined to the upper limbs.

  16. ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets.

    PubMed

    Coque, Emmanuelle; Raoul, Cédric; Bowerman, Mélissa

    2014-01-01

    Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.

  17. Molecular analysis of the SMN gene mutations in spinal muscular atrophy patients in China.

    PubMed

    Liu, W L; Li, F; He, Z X; Ai, R; Ma, H W

    2013-09-13

    Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases. Survival motor neuron1 (SMN1) is the SMA disease-determining gene. We examined the molecular basis of SMA in 113 Chinese SMA patients. Homozygous exon 7 and 8 deletions in SMN1 were detected by PCR-RFLP. Heterozygous deletion of SMN1 was analyzed based on variation of the sequencing peak height of the two different base pairs of exons 7 and 8 between SMN1 and SMN2. Subtle mutation was detected by genomic sequencing in the patients with heterozygous deletion of SMN1. In our study, the rate of deletion of SMN1 exon 7 and/or 8 was 91.2%; the rate of subtle mutations was 1.8%. We detected the same subtle mutation (p.Leu228X) of SMN exon 5 in two patients (one type I, one type III). The p.Ser8LysfsX23 and p.Leu228X mutations accounted for 13 of the 23 families with subtle mutations reported in the SMN1 gene of Chinese SMA. This is the first report where the phenotype of SMA-type III is associated with p.Leu228X. We found two subtle mutation hotspots (p.Ser8LysfsX23 and p.Leu228X) of SMN1 exons 1 and 5 in Chinese SMA patients. These two mutations have not been reported from America or Europe. It is proposed that the distribution of subtle mutations of SMN1 of SMA is associated with ethnicity or geographic origin.

  18. Refinement of the Spinal Muscular Atrophy Locus by Genetic and Physical Mapping

    PubMed Central

    Wang, C. H.; Kleyn, P. W.; Vitale, E.; Ross, B. M.; Lien, L.; Xu, J.; Carter, T. A.; Brzustowicz, L. M.; Obici, S.; Selig, S.; Pavone, L.; Parano, E.; Penchaszadeh, G. K.; Munsat, T.; Kunkel, L. M.; Gilliam, T. C.

    1995-01-01

    We report the mapping and characterization of 12 microsatellite markers including 11 novel markers. All markers were generated from overlapping YAC clones that span the spinal muscular atrophy (SMA) locus. PCR amplification of 32 overlapping YAC clones shows that 9 of the new markers (those set in italics) map to the interval between the two previous closest flanking markers (D5S629 and D5S557): cen - D5S6 - D5S125 - D5S435 - D5S1407-D5S629-D5S1410-D5S1411/D5S1412-D5S1413-D5S1414-D5Z8-D5Z9-CATT1-D5Z10/D5Z6-D5S557-D5S1408-D5S1409-D5S637-D5S351-MAP1B-tel. Four of these new markers detect multiple loci in and out of the SMA gene region. Genetic analysis of recombinant SMA families indicates that D5S1413 is a new proximal flanking locus for the SMA gene. Interestingly, among the 40 physically mapped loci, the 14 multilocus markers map contiguously to a genomic region that overlaps, and perhaps helps define, the minimum genetic region encompassing the SMA gene(s). ImagesFigure 2Figure 5 PMID:7825579

  19. Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy

    PubMed Central

    Kaifer, Kevin A.; Osman, Erkan Y.; Glascock, Jacqueline J.; Arnold, Laura L.; Cornelison, D.D.W.; Lorson, Christian L.

    2017-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death and is caused by the loss of survival motor neuron-1 (SMN1). Importantly, a nearly identical gene is present called SMN2; however, the majority of SMN2-derived transcripts are alternatively spliced and encode a truncated, dysfunctional protein. Recently, several compounds designed to increase SMN protein have entered clinical trials, including antisense oligonucleotides (ASOs), traditional small molecules, and gene therapy. Expanding beyond SMN-centric therapeutics is important, as it is likely that the breadth of the patient spectrum and the inherent complexity of the disease will be difficult to address with a single therapeutic strategy. Several SMN-independent pathways that could impinge upon the SMA phenotype have been examined with varied success. To identify disease-modifying pathways that could serve as stand-alone therapeutic targets or could be used in combination with an SMN-inducing compound, we investigated adeno-associated virus–mediated (AAV-mediated) gene therapy using plastin-3 (PLS3). Here, we report that AAV9-PLS3 extends survival in an intermediate model of SMA mice as well as in a pharmacologically induced model of SMA using a splice-switching ASO that increases SMN production. PLS3 coadministration improves the phenotype beyond the ASO, demonstrating the potential utility of combinatorial therapeutics in SMA that target SMN-independent and SMN-dependent pathways. PMID:28289706

  20. Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy

    SciTech Connect

    Rudnik-Schoeneborn, S.; Wirth, B.; Zerres, K. )

    1994-07-01

    Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explanation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (= .09[+-].06 for onset at 10-36 mo and .13[+-].07 for onset at >36 mo; and P = .09[+-]0.7 for SMA IIIa and .12[+-].07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given. 29 refs., 2 figs., 5 tabs.

  1. Congenital contractural arachnodactyly with neurogenic muscular atrophy: case report.

    PubMed

    Scola, R H; Werneck, L C; Iwamoto, F M; Ribas, L C; Raskin, S; Correa Neto, Y

    2001-06-01

    We report the case of a 3-(1/2)-year-old girl with hypotonia, multiple joint contractures, hip luxation, arachnodactyly, adducted thumbs, dolichostenomelia, and abnormal external ears suggesting the diagnosis of congenital contractural arachnodactyly (CCA). The serum muscle enzymes were normal and the needle electromyography showed active and chronic denervation. The muscle biopsy demonstrated active and chronic denervation compatible with spinal muscular atrophy. Analysis of exons 7 and 8 of survival motor neuron gene through polymerase chain reaction did not show deletions. Neurogenic muscular atrophy is a new abnormality associated with CCA, suggesting that CCA is clinically heterogeneous.

  2. Neuromuscular Junctions as Key Contributors and Therapeutic Targets in Spinal Muscular Atrophy

    PubMed Central

    Boido, Marina; Vercelli, Alessandro

    2016-01-01

    Spinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, representing the most common fatal pediatric pathology. Even though, classically and in a simplistic way, it is categorized as a motor neuron (MN) disease, there is an increasing general consensus that its pathogenesis is more complex than expected. In particular, neuromuscular junctions (NMJs) are affected by dramatic alterations, including immaturity, denervation and neurofilament accumulation, associated to impaired synaptic functions: these abnormalities may in turn have a detrimental effect on MN survival. Here, we provide a description of NMJ development/maintenance/maturation in physiological conditions and in SMA, focusing on pivotal molecules and on the time-course of pathological events. Moreover, since NMJs could represent an important target to be exploited for counteracting the pathology progression, we also describe several therapeutic strategies that, directly or indirectly, aim at NMJs. PMID:26869891

  3. Genetics Home Reference: spinal muscular atrophy

    MedlinePlus

    ... by a loss of specialized nerve cells, called motor neurons , in the spinal cord and the part ... the spinal cord ( the brainstem ). The loss of motor neurons leads to weakness and wasting ( atrophy ) of ...

  4. Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy.

    PubMed

    Woll, Matthew G; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G; Naryshkin, Nikolai A; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M

    2016-07-14

    The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM. Daily administration of these compounds to severe SMA Δ7 mice results in an increased production of SMN protein in disease-relevant tissues and a significant increase in median survival time in a dose-dependent manner. Our work supports the development of an orally administered small molecule for the treatment of patients with SMA.

  5. Molecular Genetic Analysis of Survival Motor Neuron Gene in 460 Turkish Cases with Suspicious Spinal Muscular Atrophy Disease

    PubMed Central

    RASHNONEJAD, Afrooz; ONAY, Huseyin; ATIK, Tahir; ATAN SAHIN, Ozlem; GOKBEN, Sarenur; TEKGUL, Hasan; OZKINAY, Ferda

    2016-01-01

    Objective To describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients. Materials & Methods A retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University’s Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014. The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation–dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers. Results Using PCR-RFLP test, 159 of 324 postnatal and 18 of 77 prenatal cases were detected to have SMN1 deletions. From positive samples, 88.13% had a homozygous deletion in both exon 7 and exon 8 of SMN1. Using MLPA, 54.5% of families revealed heterozygous deletions of SMN1, and 2 or 3 copies of SMN2, suggesting a healthy SMA carrier. Among patients referred for SMA testing, the annual percentage of patients diagnosed as SMA has decreased gradually from 90.62% (2003) down to 20.83% (2014). Conclusion Although PCR-RFLP method is a reliable test for SMA screening, MLPA is a necessary additional test and provide relevant data for genetic counseling of families having previously affected child. The gradual decrease in the percentage of patients molecularly diagnosed as SMA shows that clinicians have begun to use genetic tests in the differential diagnosis of muscular atrophies. Cost and availability of these genetic tests has greatly attributed to their use. PMID:27843464

  6. Non-Aggregating Tau Phosphorylation by Cyclin-Dependent Kinase 5 Contributes to Motor Neuron Degeneration in Spinal Muscular Atrophy

    PubMed Central

    Miller, Nimrod; Feng, Zhihua; Edens, Brittany M.; Yang, Ben; Shi, Han; Sze, Christie C.; Hong, Benjamin Taige; Su, Susan C.; Cantu, Jorge A.; Topczewski, Jacek; Crawford, Thomas O.; Ko, Chien-Ping; Sumner, Charlotte J.; Ma, Long

    2015-01-01

    Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35−/− compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration. PMID:25878277

  7. Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy.

    PubMed

    Tapia, Olga; Bengoechea, Rocío; Palanca, Ana; Arteaga, Rosa; Val-Bernal, J Fernando; Tizzano, Eduardo F; Berciano, María T; Lafarga, Miguel

    2012-05-01

    Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by loss or mutations of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to degeneration and death of motor neurons. In this study, we have analyzed the nuclear reorganization of Cajal bodies, PML bodies and nucleoli in type I SMA motor neurons with homozygous deletion of exons 7 and 8 of the SMN1 gene. Western blot analysis is is revealed a marked reduction of SMN levels compared to the control sample. Using a neuronal dissociation procedure to perform a careful immunocytochemical and quantitative analysis of nuclear bodies, we demonstrated a severe decrease in the mean number of Cajal bodies per neuron and in the proportion of motor neurons containing these structures in type I SMA. Moreover, most Cajal bodies fail to recruit SMN and spliceosomal snRNPs, but contain the proteasome activator PA28, a molecular marker associated with the cellular stress response. Neuronal stress in SMA motor neurons also increases PML body number. The existence of chromatolysis and eccentric nuclei in SMA motor neurons correlates with Cajal body disruption and nucleolar relocalization of coil in, a Cajal body marker. Our results indicate that the Cajal body is a pathophysiological target in type I SMA motor neurons. They also suggest the Cajal body-dependent dysfunction of snRNP biogenesis and, therefore, pre-mRNA splicing in these neurons seems to be an essential component for SMA pathogenesis.

  8. IPLEX administration improves motor neuron survival and ameliorates motor functions in a severe mouse model of spinal muscular atrophy.

    PubMed

    Murdocca, Michela; Malgieri, Arianna; Luchetti, Andrea; Saieva, Luciano; Dobrowolny, Gabriella; de Leonibus, Elvira; Filareto, Antonio; Quitadamo, Maria Chiara; Novelli, Giuseppe; Musarò, Antonio; Sangiuolo, Federica

    2012-09-25

    Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder and the first genetic cause of death in childhood. SMA is caused by low levels of survival motor neuron (SMN) protein that induce selective loss of α-motor neurons (MNs) in the spinal cord, resulting in progressive muscle atrophy and consequent respiratory failure. To date, no effective treatment is available to counteract the course of the disease. Among the different therapeutic strategies with potential clinical applications, the evaluation of trophic and/or protective agents able to antagonize MNs degeneration represents an attractive opportunity to develop valid therapies. Here we investigated the effects of IPLEX (recombinant human insulinlike growth factor 1 [rhIGF-1] complexed with recombinant human IGF-1 binding protein 3 [rhIGFBP-3]) on a severe mouse model of SMA. Interestingly, molecular and biochemical analyses of IGF-1 carried out in SMA mice before drug administration revealed marked reductions of IGF-1 circulating levels and hepatic mRNA expression. In this study, we found that perinatal administration of IPLEX, even if does not influence survival and body weight of mice, results in reduced degeneration of MNs, increased muscle fiber size and in amelioration of motor functions in SMA mice. Additionally, we show that phenotypic changes observed are not SMN-dependent, since no significant SMN modification was addressed in treated mice. Collectively, our data indicate IPLEX as a good therapeutic candidate to hinder the progression of the neurodegenerative process in SMA.

  9. Air stacking: effects on pulmonary function in patients with spinal muscular atrophy and in patients with congenital muscular dystrophy*,**

    PubMed Central

    Marques, Tanyse Bahia Carvalho; Neves, Juliana de Carvalho; Portes, Leslie Andrews; Salge, João Marcos; Zanoteli, Edmar; Reed, Umbertina Conti

    2014-01-01

    OBJECTIVE: Respiratory complications are the main causes of morbidity and mortality in patients with neuromuscular disease (NMD). The objectives of this study were to determine the effects that routine daily home air-stacking maneuvers have on pulmonary function in patients with spinal muscular atrophy (SMA) and in patients with congenital muscular dystrophy (CMD), as well as to identify associations between spinal deformities and the effects of the maneuvers. METHODS: Eighteen NMD patients (ten with CMD and eight with SMA) were submitted to routine daily air-stacking maneuvers at home with manual resuscitators for four to six months, undergoing pulmonary function tests before and after that period. The pulmonary function tests included measurements of FVC; PEF; maximum insufflation capacity (MIC); and assisted and unassisted peak cough flow (APCF and UPCF, respectively) with insufflations. RESULTS: After the use of home air-stacking maneuvers, there were improvements in the APCF and UPCF. In the patients without scoliosis, there was also a significant increase in FVC. When comparing patients with and without scoliosis, the increases in APCF and UPCF were more pronounced in those without scoliosis. CONCLUSIONS: Routine daily air-stacking maneuvers with a manual resuscitator appear to increase UPCF and APCF in patients with NMD, especially in those without scoliosis. PMID:25410841

  10. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

    PubMed Central

    Hazell, Gareth; Shabanpoor, Fazel; Saleh, Amer F.; Bowerman, Melissa; Meijboom, Katharina E.; Zhou, Haiyan; Muntoni, Francesco; Talbot, Kevin; Gait, Michael J.; Wood, Matthew J. A.

    2016-01-01

    The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA. PMID:27621445

  11. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    PubMed

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B; Corti, Stefania

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the survival motor neuron 1 gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. Even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches.

  12. Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene.

    PubMed

    Navon, R; Khosravi, R; Melki, J; Drucker, L; Fontaine, B; Turpin, J C; N'Guyen, B; Fardeau, M; Rondot, P; Baumann, N

    1997-05-01

    Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

  13. ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy

    PubMed Central

    Ottesen, Eric W.

    2017-01-01

    Abstract Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.

  14. CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy.

    PubMed

    Foran, Emily; Kwon, Deborah Y; Nofziger, Jonathan H; Arnold, Eveline S; Hall, Matthew D; Fischbeck, Kenneth H; Burnett, Barrington G

    2016-04-01

    The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system. Inhibiting the proteasome in a rodent model of SMA with bortezomib increases SMN protein levels in peripheral tissues but not the CNS, because bortezomib has poor CNS penetrance. We sought to determine if we could inhibit SMN degradation in the CNS of SMA mice with a combination of bortezomib and the ABC transporter inhibitor tariquidar. In cultured cells we show that bortezomib is a substrate of P-gp. Mass spectrometry analysis demonstrated that intraperitoneal co-administration of tariquidar increased the CNS penetrance of bortezomib, and reduced proteasome activity in the brain and spinal cord. This correlated with increased SMN protein levels and improved survival and motor function of SMA mice. These findings show that CNS penetrance of treatment for this neurological disorder can be improved by inhibiting drug efflux at the blood-brain barrier.

  15. Isolation of cDNAs from the spinal muscular atrophy gene region with yeast artificial chromosomes

    SciTech Connect

    Deng, H.X.; He, X.X.; Hung, W.Y.

    1994-09-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of anterior horn cells, leading to progressive paralysis of voluntary muscles. The SMA gene(s) is located at 5q11.2-q13.3, between D5S435 and D5S112. To isolate potential candidate gene(s) responsible for SMA, we used the YACs within the SMA gene region as probes to screen a human brainstem cDNA library. Thirteen cDNA clones were isolated. Their sizes range from 0.7 kb to 5 kb. Seven clones were found to be unique in sequence; the remaining six clones contain repetitive sequences. Five out of these seven unique clones have been used as probes to screen a phage genomic DNA library. Phage genomic clones isolated with individual unique cDNA were used for fluorescence in situ hybridization to identify the origin of cDNAs. These five unique sequences are all located in the 5q13 region, indicating the reliability of our screening method. All the thirteen clones have been partially sequenced (about 300 bp) from each end. No homology has been found with any known EST or known genes. No cross hybridization was detected among the unique clones, suggesting that there may be distinct new genes encoded in this region.

  16. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

    PubMed

    Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

    2012-06-20

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

  17. Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy.

    PubMed

    Azzouz, Mimoun; Le, Thanh; Ralph, G Scott; Walmsley, Lucy; Monani, Umrao R; Lee, Debbie C P; Wilkes, Fraser; Mitrophanous, Kyriacos A; Kingsman, Susan M; Burghes, Arthur H M; Mazarakis, Nicholas D

    2004-12-01

    Spinal muscular atrophy (SMA) is a frequent recessive autosomal disorder. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to depletion in SMN protein levels. The treatment rationale for SMA is to halt or delay the degeneration of motor neurons, but to date there are no effective drug treatments for this disease. We have previously demonstrated that pseudotyping of the nonprimate equine infectious anemia virus (using the lentivector gene transfer system) with the glycoprotein of the Evelyn-Rokitnicki-Abelseth strain of the rabies virus confers retrograde axonal transport on these vectors. Here, we report that lentivector expressing human SMN was successfully used to restore SMN protein levels in SMA type 1 fibroblasts. Multiple single injections of a lentiviral vector expressing SMN in various muscles of SMA mice restored SMN to motor neurons, reduced motor neuron death, and increased the life expectancy by an average of 3 and 5 days (20% and 38%) compared with LacZ and untreated animals, respectively. Further extension of survival by SMN expression constructs will likely require a knowledge of when and/or where high levels of SMN are needed.

  18. Characterization of a protein kinase gene in allelic association with the spinal muscular atrophy locus

    SciTech Connect

    Wang, C.H.; Carter, T.A.; Kleyn, P.W.

    1994-09-01

    A protein kinase gene has been identified from a 400 Kb minimal genetic region which defines the spinal muscular atrophy (SMA) locus. A highly polymorphic microsatellite marker (D5S1414) isolated from a yeast artificial chromosome (YAC) clone within this interval detects linkage disequilibrium with the SMA locus in 32 Polish families (Yule`s coefficient: 0.92) and maps to an intron of the protein kinase gene. Exon amplification was used to isolate coding sequences from a YAC-derived phage subclone containing D5S1414. Five exons were identified and a GenBank search using the BLAST program showed complete homology of these exons with a protein kinase gene. The gene is expressed in all tissues checked to far. Full-length cDNAs have been identified from both normal and SMA brain libraries and by reverse-transcriptase (RT) PCR from RNA of various tissues. The cDNA sequences will be reported. The genomic sequences flanking each exon were determined by direct sequencing of the homologous phage. The marker D5S1414 was located within the intronic sequence between exons 6 and 7. To screen for disease mutations, PCR was performed across each exon including the flanking splice sites in normal controls and SMA samples shown to be homozygous across the region by haplotyping. Comparative sequence analysis of the products together with the RT-PCR from normal and SMA brain RNA has identified several candidate polymorphisms. To date, the most interesting lead is an intronic polymorphism possibly affecting exon splicing in a homozygous SMA patient. An updated mutation search will be reported.

  19. Label-free proteomics identifies Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers for spinal muscular atrophy

    PubMed Central

    2013-01-01

    Background Spinal muscular atrophy (SMA) is a neuromuscular disease resulting from mutations in the survival motor neuron 1 (SMN1) gene. Recent breakthroughs in preclinical research have highlighted several potential novel therapies for SMA, increasing the need for robust and sensitive clinical trial platforms for evaluating their effectiveness in human patient cohorts. Given that most clinical trials for SMA are likely to involve young children, there is a need for validated molecular biomarkers to assist with monitoring disease progression and establishing the effectiveness of therapies being tested. Proteomics technologies have recently been highlighted as a potentially powerful tool for such biomarker discovery. Methods We utilized label-free proteomics to identify individual proteins in pathologically-affected skeletal muscle from SMA mice that report directly on disease status. Quantitative fluorescent western blotting was then used to assess whether protein biomarkers were robustly changed in muscle, skin and blood from another mouse model of SMA, as well as in a small cohort of human SMA patient muscle biopsies. Results By comparing the protein composition of skeletal muscle in SMA mice at a pre-symptomatic time-point with the muscle proteome at a late-symptomatic time-point we identified increased expression of both Calreticulin and GRP75/Mortalin as robust indicators of disease progression in SMA mice. We report that these protein biomarkers were consistently modified in different mouse models of SMA, as well as across multiple skeletal muscles, and were also measurable in skin biopsies. Furthermore, Calreticulin and GRP75/Mortalin were measurable in muscle biopsy samples from human SMA patients. Conclusions We conclude that label-free proteomics technology provides a powerful platform for biomarker identification in SMA, revealing Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers capable of reporting on disease progression in

  20. SMN2 copy number predicts acute or chronic spinal muscular atrophy but does not account for intrafamilial variability in siblings.

    PubMed

    Cuscó, I; Barceló, M J; Rojas-García, R; Illa, I; Gámez, J; Cervera, C; Pou, A; Izquierdo, G; Baiget, M; Tizzano, E F

    2006-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects motor neurons. It is caused by mutations in the survival motor neuron gene 1 (SMN1). The SMN2 gene, which is the highly homologous SMN1 copy that is present in all the patients, is unable to prevent the disease. An SMN2 dosage method was applied to 45 patients with the three SMA types (I-III) and to four pairs of siblings with chronic SMA (II-III) and different phenotypes. Our results confirm that the SMN2 copy number plays a key role in predicting acute or chronic SMA. However, siblings with different SMA phenotypes show an identical SMN2 copy number and identical markers, indicating that the genetic background around the SMA locus is insufficient to account for the intrafamilial variability. In our results, age of onset appears to be the most important predictor of disease severity in affected members of the same family. Given that SMN2 is regarded as a target for potential pharmacological therapies in SMA, the identification of genetic factors other than the SMN genes is necessary to better understand the pathogenesis of the disease in order to implement additional therapeutic approaches.

  1. [The role of RNA splicing in the pathogenesis of spinal muscular atrophy and development of its therapeutics].

    PubMed

    Sahashi, Kentaro; Sobue, Gen

    2014-12-01

    Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Degeneration of alpha-motor neurons that results in progressive paralysis is a pathological hallmark of SMA. Recently, peripheral-tissue involvement has also been reported in SMA. Patients have low levels of functional SMN which is attributed to alternative splicing in SMN2, a gene closely-related to SMN1. This decrease in the expression of SMN, a ubiquitously expressed protein involved in promoting snRNP assembly required for splicing, is responsible for SMA. However, the mechanism through which decrease in SMN levels causes SMA remains unclear. Currently, no curative treatment is available for SMA, but SMN restoration is thought to be necessary and sufficient for cure. Antisense oligonucleotides (ASOs) can be designed to specifically alter splicing patterns of target pre-mRNAs. We identified an ASO that redirects SMN2 splicing and is currently in clinical trials for use as RNA-targeting therapeutics. Further, we have also reported a novel application of splicing-modulating ASOs--creation of animal phenocopy models of diseases by inducing mis-splicing. Exploring the relationship between the spatial and temporal effects of therapeutic and pathogenic ASOs yields relevant insights into the roles of SMN in SMA pathogenesis and into its normal physiological functions. This knowledge, in turn, contributes to the ongoing development of targeted therapeutics.

  2. SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage.

    PubMed

    Jangi, Mohini; Fleet, Christina; Cullen, Patrick; Gupta, Shipra V; Mekhoubad, Shila; Chiao, Eric; Allaire, Norm; Bennett, C Frank; Rigo, Frank; Krainer, Adrian R; Hurt, Jessica A; Carulli, John P; Staropoli, John F

    2017-03-21

    Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death.

  3. SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

    PubMed Central

    Jangi, Mohini; Fleet, Christina; Cullen, Patrick; Gupta, Shipra V.; Mekhoubad, Shila; Chiao, Eric; Allaire, Norm; Bennett, C. Frank; Rigo, Frank; Krainer, Adrian R.; Hurt, Jessica A.; Carulli, John P.; Staropoli, John F.

    2017-01-01

    Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death. PMID:28270613

  4. Spinal muscular atrophy: development and implementation of potential treatments.

    PubMed

    Arnold, W David; Burghes, Arthur H M

    2013-09-01

    In neurodegenerative disorders, effective treatments are urgently needed, along with methods to determine whether treatment worked. In this review, we discuss the rapid progress in the understanding of recessive proximal spinal muscular atrophy and how this is leading to exciting potential treatments of the disease. Spinal muscular atrophy is caused by loss of the survival motor neuron 1 (SMN1) gene and reduced levels of SMN protein. The critical downstream targets of SMN deficiency that result in motor neuron loss are not known. However, increasing SMN levels has a marked impact in mouse models, and these therapeutics are rapidly moving toward clinical trials. Promising preclinical therapies, the varying degree of impact on the mouse models, and potential measures of treatment effect are reviewed. One key issue discussed is the variable outcome of increasing SMN at different stages of disease progression.

  5. Feasibility of Using Microsoft Kinect to Assess Upper Limb Movement in Type III Spinal Muscular Atrophy Patients

    PubMed Central

    Siebourg-Polster, Juliane; Wolf, Detlef; Czech, Christian; Bonati, Ulrike; Fischer, Dirk; Khwaja, Omar; Strahm, Martin

    2017-01-01

    Although functional rating scales are being used increasingly as primary outcome measures in spinal muscular atrophy (SMA), sensitive and objective assessment of early-stage disease progression and drug efficacy remains challenging. We have developed a game based on the Microsoft Kinect sensor, specifically designed to measure active upper limb movement. An explorative study was conducted to determine the feasibility of this new tool in 18 ambulant SMA type III patients and 19 age- and gender-matched healthy controls. Upper limb movement was analysed elaborately through derived features such as elbow flexion and extension angles, arm lifting angle, velocity and acceleration. No significant differences were found in the active range of motion between ambulant SMA type III patients and controls. Hand velocity was found to be different but further validation is necessary. This study presents an important step in the process of designing and handling digital biomarkers as complementary outcome measures for clinical trials. PMID:28122039

  6. Feasibility of Using Microsoft Kinect to Assess Upper Limb Movement in Type III Spinal Muscular Atrophy Patients.

    PubMed

    Chen, Xing; Siebourg-Polster, Juliane; Wolf, Detlef; Czech, Christian; Bonati, Ulrike; Fischer, Dirk; Khwaja, Omar; Strahm, Martin

    2017-01-01

    Although functional rating scales are being used increasingly as primary outcome measures in spinal muscular atrophy (SMA), sensitive and objective assessment of early-stage disease progression and drug efficacy remains challenging. We have developed a game based on the Microsoft Kinect sensor, specifically designed to measure active upper limb movement. An explorative study was conducted to determine the feasibility of this new tool in 18 ambulant SMA type III patients and 19 age- and gender-matched healthy controls. Upper limb movement was analysed elaborately through derived features such as elbow flexion and extension angles, arm lifting angle, velocity and acceleration. No significant differences were found in the active range of motion between ambulant SMA type III patients and controls. Hand velocity was found to be different but further validation is necessary. This study presents an important step in the process of designing and handling digital biomarkers as complementary outcome measures for clinical trials.

  7. Observational study of spinal muscular atrophy type I and implications for clinical trials

    PubMed Central

    McDermott, Michael P.; Kaufmann, Petra; Darras, Basil T.; Chung, Wendy K.; Sproule, Douglas M.; Kang, Peter B.; Foley, A. Reghan; Yang, Michelle L.; Martens, William B.; Oskoui, Maryam; Glanzman, Allan M.; Flickinger, Jean; Montes, Jacqueline; Dunaway, Sally; O'Hagen, Jessica; Quigley, Janet; Riley, Susan; Benton, Maryjane; Ryan, Patricia A.; Montgomery, Megan; Marra, Jonathan; Gooch, Clifton; De Vivo, Darryl C.

    2014-01-01

    Objectives: Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I). Methods: Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered. Results: Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1–22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p = 0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n = 10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21–2.33, p = 0.02). Conclusions: Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design. PMID:25080519

  8. Aquatic therapy for a child with type III spinal muscular atrophy: a case report.

    PubMed

    Salem, Yasser; Gropack, Stacy Jaffee

    2010-11-01

    Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of alpha motor neurons. This case report describes an aquatic therapy program and the outcomes for a 3-year-old girl with type III SMA. Motor skills were examined using the 88-item Gross Motor Function Measure (GMFM), the Peabody Developmental Motor Scales (PDMS-2), and the GAITRite system. The child received aquatic therapy twice per week for 45-min sessions, for 14 weeks. The intervention included aquatic activities designed to improve gross motor skills and age-appropriate functional mobility. The GMFM total score improved by 11% following the intervention. The Standing Dimension score improved by 28% and the Walking, Running, and Jumping Dimension score improved by 18%. The gross motor quotient for the PDMS-2 improved from 66 to 74. The child's gait showed improvement in walking velocity, stride length, and single-limb support time as a percentage of the gait cycle. The outcomes of this case report demonstrate the successful improvement of gross motor function and gait in a 3-year-old child with SMA. This study provides clinical information for therapists utilizing aquatic therapy as a modality for children with neuromuscular disorders.

  9. Prospective cohort study of spinal muscular atrophy types 2 and 3

    PubMed Central

    Kaufmann, Petra; McDermott, Michael P.; Darras, Basil T.; Finkel, Richard S.; Sproule, Douglas M.; Kang, Peter B.; Oskoui, Maryam; Constantinescu, Andrei; Gooch, Clifton L.; Foley, A. Reghan; Yang, Michele L.; Tawil, Rabi; Chung, Wendy K.; Martens, William B.; Montes, Jacqueline; Battista, Vanessa; O'Hagen, Jessica; Dunaway, Sally; Flickinger, Jean; Quigley, Janet; Riley, Susan; Glanzman, Allan M.; Benton, Maryjane; Ryan, Patricia A.; Punyanitya, Mark; Montgomery, Megan J.; Marra, Jonathan; Koo, Benjamin

    2012-01-01

    Objective: To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning. Methods: We conducted a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data. Results: In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up. Conclusion: The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers. PMID:23077013

  10. Splicing regulation in spinal muscular atrophy by an RNA structure formed by long-distance interactions.

    PubMed

    Singh, Natalia N; Lee, Brian M; Singh, Ravindra N

    2015-04-01

    Humans carry two copies of the survival motor neuron gene: SMN1 and SMN2. Loss of SMN1 coupled with skipping of SMN2 exon 7 causes spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Our discovery of intronic splicing silencer N1 (ISS-N1) is a promising target, currently in a phase III clinical trial, for an antisense oligonucleotide-mediated splicing correction in SMA. We have recently shown that the first residue of ISS-N1 is locked in a unique RNA structure that we term ISTL1 (internal stem through long-distance interaction-1). Complementary strands of ISTL1 are separated from each other by 279 nucleotides. Using site-specific mutations and chemical structure probing, we confirmed the formation and functional significance of ISTL1. Located in the middle of intron 7, the 3' strand of ISTL1 falls within an inhibitory region that we term ISS-N2. We demonstrate that an antisense oligonucleotide-mediated sequestration of ISS-N2 fully corrects SMN2 exon 7 splicing and restores high levels of SMN in SMA patient cells. These results underscore the therapeutic potential of the regulatory information present in a secondary and high-order RNA structure of a human intron.

  11. A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2.

    PubMed

    Jodelka, Francine M; Ebert, Allison D; Duelli, Dominik M; Hastings, Michelle L

    2010-12-15

    Spinal muscular atrophy (SMA) is a neurological disorder characterized by motor neuron degeneration and progressive muscle paralysis. The disease is caused by a reduction in survival of motor neuron (SMN) protein resulting from homozygous deletion of the SMN1 gene. SMN protein is also encoded by SMN2. However, splicing of SMN2 exon 7 is defective, and consequently, the majority of the transcripts produce a truncated, unstable protein. SMN protein itself has a role in splicing. The protein is required for the biogenesis of spliceosomal snRNPs, which are essential components of the splicing reaction. We now show that SMN protein abundance affects the splicing of SMN2 exon 7, revealing a feedback loop inSMN expression. The reduced SMN protein concentration observed in SMA samples and in cells depleted of SMN correlates with a decrease in cellular snRNA levels and a decrease in SMN2 exon 7 splicing. Furthermore, altering the relative abundance or activity of individual snRNPs has distinct effects on exon 7 splicing, demonstrating that core spliceosomal snRNPs influence SMN2 alternative splicing. Our results identify a feedback loop in SMN expression by which low SMN protein levels exacerbate SMN exon 7 skipping, leading to a further reduction in SMN protein. These results imply that a modest increase in SMN protein abundance may cause a disproportionately large increase in SMN expression, a finding that is important for assessing the therapeutic potential of SMA treatments and understanding disease pathogenesis.

  12. Systems biology investigation of cAMP modulation to increase SMN levels for the treatment of spinal muscular atrophy.

    PubMed

    Mack, Sean G; Cook, Daniel J; Dhurjati, Prasad; Butchbach, Matthew E R

    2014-01-01

    Spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an autosomal recessive disorder caused by the loss of SMN1 (survival motor neuron 1), which encodes the protein SMN. The loss of SMN1 causes a deficiency in SMN protein levels leading to motor neuron cell death in the anterior horn of the spinal cord. SMN2, however, can also produce some functional SMN to partially compensate for loss of SMN1 in SMA suggesting increasing transcription of SMN2 as a potential therapy to treat patients with SMA. A cAMP response element was identified on the SMN2 promoter, implicating cAMP activation as a step in the transcription of SMN2. Therefore, we investigated the effects of modulating the cAMP signaling cascade on SMN production in vitro and in silico. SMA patient fibroblasts were treated with the cAMP signaling modulators rolipram, salbutamol, dbcAMP, epinephrine and forskolin. All of the modulators tested were able to increase gem formation, a marker for SMN protein in the nucleus, in a dose-dependent manner. We then derived two possible mathematical models simulating the regulation of SMN2 expression by cAMP signaling. Both models fit well with our experimental data. In silico treatment of SMA fibroblasts simultaneously with two different cAMP modulators resulted in an additive increase in gem formation. This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA.

  13. Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches.

    PubMed

    Nizzardo, Monica; Simone, Chiara; Dametti, Sara; Salani, Sabrina; Ulzi, Gianna; Pagliarani, Serena; Rizzo, Federica; Frattini, Emanuele; Pagani, Franco; Bresolin, Nereo; Comi, Giacomo; Corti, Stefania

    2015-06-30

    Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (SMN) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous SMN2 gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1), and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating SMN2 RNA: ASO affects exon 7 splicing, TALE-TF increase SMN2 RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the in vitro SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on SMN2 RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as in vitro disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders.

  14. Decreasing disease severity in symptomatic, Smn(-/-);SMN2(+/+), spinal muscular atrophy mice following scAAV9-SMN delivery.

    PubMed

    Glascock, Jacqueline J; Osman, Erkan Y; Wetz, Mary J; Krogman, Megan M; Shababi, Monir; Lorson, Christian L

    2012-03-01

    Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the leading genetic cause of infant mortality. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). In humans, a nearly identical copy gene is present, SMN2. SMN2 is retained in all SMA patients and encodes the same protein as SMN1. However, SMN1 and SMN2 differ by a silent C-to-T transition at the 5' end of exon 7, causing alternative splicing of SMN2 transcripts and low levels of full-length SMN. SMA is monogenic and therefore well suited for gene-replacement strategies. Recently, self-complementary adeno-associated virus (scAAV) vectors have been used to deliver the SMN cDNA to an animal model of disease, the SMNΔ7 mouse. In this study, we examine a severe model of SMA, Smn(-/-);SMN2(+/+), to determine whether gene replacement is viable in a model in which disease development begins in utero. Using two delivery paradigms, intracerebroventricular injections and intravenous injections, we delivered scAAV9-SMN and demonstrated a two to four fold increase in survival, in addition to improving many of the phenotypic parameters of the model. This represents the longest extension in survival for this severe model for any therapeutic intervention and suggests that postsymptomatic treatment of SMA may lead to significant improvement of disease severity.

  15. Motor unit loss estimation by the multipoint incremental MUNE method in children with spinal muscular atrophy--a preliminary study.

    PubMed

    Gawel, Malgorzata; Kostera-Pruszczyk, Anna; Lusakowska, Anna; Jedrzejowska, Maria; Ryniewicz, Barbara; Lipowska, Marta; Gawel, Damian; Kaminska, Anna

    2015-03-01

    Quantitative EMG reflects denervation of muscles after lower motor neuron degeneration in spinal muscular atrophy (SMA) but does not reflect actual motor unit loss. The aim of our study was to assess the value of the multipoint incremental motor unit number estimation (MUNE) method in the modification by Shefner in estimating motor unit loss in SMA. The number of motor units, the mean amplitude of an average surface-detected single motor unit potential (SMUP), and the amplitude of compound motor action potentials (CMAP) were estimated in 14 children with SMA in the abductor pollicis brevis (ABP). Significant differences in MUNE values and SMUP and CMAP amplitude were found between the SMA and control groups (P < 0.0001). MUNE values correlated with Hammersmith Functional Motor Scale (HFMS) scores (P < 0.05). Increased SMUP amplitude values correlated with decreased HFMS scores (P < 0.05). The study confirms that MUNE method in the modification by Shefner is a useful tool reflecting motor unit loss in SMA, and it is easy to perform and well tolerated. MUNE and SMUP amplitude seemed to be sensitive parameters reflecting motor dysfunction in SMA but a longitudinal study in a larger number of subjects is needed.

  16. Mapping of human microtubule-associated protein 1B in proximity to the spinal muscular atrophy locus at 5q13

    SciTech Connect

    Lien, L.L. Children's Hospital, Boston, MA ); Boyce, F.M.; Kunkel, L.M. ); Kleyn, P.; Brzustowicz, L.M.; Gilliam, T.C. New York State Psychiatric Inst., New York, NY ); Menninger, J.; Ward, D.C. )

    1991-09-01

    A polyclonal antiserum directed against the C-terminal domain of dystrophin was used to isolate a cDNA clone encoding an antigenically cross-reactive protein, microtubule-associated protein 1B (MAP-1B). Physical mapping of the human MAP-1B locus places its chromosomal location at 5q13, in proximity to the spinal muscular atrophy (SMA) locus. SMA is a degenerative disorder primarily affecting motor neurons. Genetic linkage analysis of SMA families using a human dinucleotide repeat polymorphism just 3{prime} of the MAP-1B gene has shown tight linkage to SMA mutations. These mapping data together with the postulated role of MAP-1B in neuronal morphogenesis and its localization in anterior horn motor neurons suggest a possible association with SMA.

  17. An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy

    PubMed Central

    Yang, Chung-Wei; Chen, Chien-Lin; Chou, Wei-Chun; Lin, Ho-Chen; Jong, Yuh-Jyh; Tsai, Li-Kai; Chuang, Chun-Yu

    2016-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease resulting from a recessive mutation in the SMN1 gene. This disease affects multiple organ systems with varying degrees of severity. Exploration of the molecular pathological changes occurring in different cell types in SMA is crucial for developing new therapies. This study collected 39 human microarray datasets from ArrayExpress and GEO databases to build an integrative transcriptomic analysis for recognizing novel SMA targets. The transcriptomic analysis was conducted through combining weighted correlation network analysis (WGCNA) for gene module detection, gene set enrichment analysis (GSEA) for functional categorization and filtration, and Cytoscape (visual interaction gene network analysis) for target gene identification. Seven novel target genes (Bmp4, Serpine1, Gata6, Ptgs2, Bcl2, IL6 and Cntn1) of SMA were revealed, and are all known in the regulation of TNFα for controlling neural, cardiac and bone development. Sequentially, the differentially expressed patterns of these 7 target genes in mouse tissues (e.g., spinal cord, heart, muscles and bone) were validated in SMA mice of different severities (pre-symptomatic, mildly symptomatic, and severely symptomatic). In severely symptomatic SMA mice, TNFα was up-regulated with attenuation of Bmp4 and increase of Serpine1 and Gata6 (a pathway in neural and cardiac development), but not in pre-symptomatic and mildly symptomatic SMA mice. The severely symptomatic SMA mice also had the elevated levels of Ptgs2 and Bcl2 (a pathway in skeletal development) as well as IL6 and Cntn1 (a pathway in nervous system development). Thus, the 7 genes identified in this study might serve as potential target genes for future investigations of disease pathogenesis and SMA therapy. PMID:27331400

  18. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs.

    PubMed

    Gabanella, Francesca; Butchbach, Matthew E R; Saieva, Luciano; Carissimi, Claudia; Burghes, Arthur H M; Pellizzoni, Livio

    2007-09-26

    Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival motor neuron (SMN) protein. SMN together with Gemins2-8 and unrip proteins form a macromolecular complex that functions in the assembly of small nuclear ribonucleoproteins (snRNPs) of both the major and the minor splicing pathways. It is not known whether the levels of spliceosomal snRNPs are decreased in SMA. Here we analyzed the consequence of SMN deficiency on snRNP metabolism in the spinal cord of mouse models of SMA with differing phenotypic severities. We demonstrate that the expression of a subset of Gemin proteins and snRNP assembly activity are dramatically reduced in the spinal cord of severe SMA mice. Comparative analysis of different tissues highlights a similar decrease in SMN levels and a strong impairment of snRNP assembly in tissues of severe SMA mice, although the defect appears smaller in kidney than in neural tissue. We further show that the extent of reduction in both Gemin proteins expression and snRNP assembly activity in the spinal cord of SMA mice correlates with disease severity. Remarkably, defective SMN complex function in snRNP assembly causes a significant decrease in the levels of a subset of snRNPs and preferentially affects the accumulation of U11 snRNP--a component of the minor spliceosome--in tissues of severe SMA mice. Thus, impairment of a ubiquitous function of SMN changes the snRNP profile of SMA tissues by unevenly altering the normal proportion of endogenous snRNPs. These findings are consistent with the hypothesis that SMN deficiency affects the splicing machinery and in particular the minor splicing pathway of a rare class of introns in SMA.

  19. Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III

    PubMed Central

    Kölbel, Heike; Hauffa, Berthold P.; Wudy, Stefan A.; Bouikidis, Anastasios; Della Marina, Adela; Schara, Ulrike

    2017-01-01

    Background Autosomal-recessive proximal spinal muscular atrophies (SMA) are disorders characterized by a ubiquitous deficiency of the survival of motor neuron protein that leads to a multisystemic disorder, which mostly affects alpha motor neurons. Disease progression is clinically associated with failure to thrive or weight loss, mainly caused by chewing and swallowing difficulties. Although pancreatic involvement has been described in animal models, systematic endocrinological evaluation of the energy metabolism in humans is lacking. Methods In 43 patients with SMA type I-III (8 type I; 22 type II; 13 type III), aged 0.6–21.8 years, auxological parameters, pubertal stage, motor function (Motor Function Measurement 32 –MFM32) as well as levels of leptin, insulin glucose, hemoglobin A1c, Homeostasis Model Assessment index and an urinary steroid profile were determined. Results Hyperleptinemia was found in 15/35 (43%) of our patients; 9/15 (60%) of the hyperleptinemic patients were underweight, whereas 1/15 (7%) was obese. Hyperleptinemia was associated with SMA type (p = 0.018). There was a significant association with decreased motor function (MFM32 total score in hyperleptinemia 28.5%, in normoleptinemia 54.7% p = 0.008, OR 0.969; 95%-CI: 0.946–0.992). In addition, a higher occurrence of hirsutism, premature pubarche and a higher variability of the urinary steroid pattern were found. Conclusion Hyperleptinemia is highly prevalent in underweight children with SMA and is associated with disease severity and decreased motor function. Neuronal degradation of hypothalamic cells or an increase in fat content by muscle remodeling could be the cause of hyperleptinemia. PMID:28278160

  20. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy

    PubMed Central

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term “minipolyfasciculations” may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  1. Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

    PubMed

    Schwab, Andrew J; Ebert, Allison D

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

  2. Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

    PubMed

    Powis, Rachael A; Gillingwater, Thomas H

    2016-03-01

    Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared.

  3. Mitochondrial implications in bulbospinal muscular atrophy (Kennedy disease).

    PubMed

    Finsterer, Josef; Mishra, Anushree; Wakil, Salma; Pennuto, Maria; Soraru, Gianni

    2015-01-01

    There is increasing evidence that mitochondrial functions are secondarily disturbed in bulbospinal muscular atrophy (BSMA). This review focuses on the relation between BSMA and the effect of the expanded polyglutamine (poly-Q) androgen receptor (AR) on mitochondrial functions. Mitochondrial functions in bulbospinal muscular atrophy (SBMA) are affected on the molecular, clinical, and therapeutic level. On the molecular level there is down-regulation of various nuclear-DNA-encoded mitochondrial proteins by mutant androgen receptor (mAR), colocalization of the mAR with various mitochondrial proteins, association of mAR aggregates with mitochondria resulting in abnormal distribution of mitochondria, mtDNA depletion or multiple mtDNA deletions, mitochondrial membrane depolarization, increase in reactive oxidative species, and activation of the mitochondrial caspase pathway. On the clinical level various mitochondrial disorders mimic SBMA, and on the therapeutic level pioglitazone expresses PPAR-γ, cyclosporine-A restores mitochondrial membrane potentials, coenzyme-Q and idebenone reduce oxidative stress, and geldanamycin up-regulates protective mitochondrial heat shock proteins. In conclusion, in BSMA mitochondrial dysfunction results from various interactions of elongated poly-Q AR with mitochondria, mitochondrial proteins, nuclear or mitochondrial DNA, causing oxidative stress, decreased mitochondrial membrane potential, or activation of the mitochondrial caspase pathway. Additionally, mitochondrial disease may mimic BSMA and therapeutic approaches may depend on modifications of mitochondrial pathways.

  4. Neuroblastoma in a Patient With Spinal Muscular Atrophy Type I: Is It Just a Coincidence?

    PubMed

    Sag, Erdal; Sen, Hilal Susam; Haliloglu, Goknur; Yalcin, Bilgehan; Kutluk, Tezer

    2015-07-01

    Spinal muscular atrophy is an autosomal recessive disorder characterized by progressive degeneration of anterior horn cells of the spinal cord resulting in hypotonia, skeletal muscle atrophy, and weakness. Herein, we report a 4-month-old male infant who presented to our hospital with an abdominal mass that was diagnosed as neuroblastoma and spinal muscular atrophy type I. We would like to discuss the course and differential diagnosis with an algorithm leading to the diagnosis in this peculiar patient. To our knowledge, coexistence of spinal muscular atrophy type I and neuroblastoma is defined for the first time in the literature.

  5. False homozygous deletions of SMN1 exon 7 using Dra I PCR-RFLP caused by a novel mutation in spinal muscular atrophy.

    PubMed

    Kang, Seong-Ho; Cho, Sung Im; Chae, Jong-Hee; Chung, Kyu Nam; Ra, Eun Kyung; Kim, So Yeon; Seong, Moon-Woo; Kim, Ji Yeon; Park, Sung Sup

    2009-08-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, and about 95% of SMA patients are homozygous for deletions in the SMN1 gene. Herein, classical polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) using DraI yielded false homozygous deletions of SMN1 exon 7 in a patient with SMA, but multiple ligation-dependent probe amplification analysis revealed one remaining copy of SMN1 exon 7. Sequencing showed that this false deletion in the PCR-RFLP resulted from a novel mutation of one SMN1 copy that was not deleted (c.863G > T, p.R288M). This novel sequence variant introduced a mismatch that interfered with primer binding. These findings demonstrate that comprehensive analysis using PCR-RFLP, multiple ligation-dependent probe amplification, and sequencing can reliably and correctly diagnose SMA.

  6. Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy

    PubMed Central

    Zhao, Xin; Feng, Zhihua; Ling, Karen K. Y.; Mollin, Anna; Sheedy, Josephine; Yeh, Shirley; Petruska, Janet; Narasimhan, Jana; Dakka, Amal; Welch, Ellen M.; Karp, Gary; Chen, Karen S.; Metzger, Friedrich; Ratni, Hasane; Lotti, Francesco; Tisdale, Sarah; Naryshkin, Nikolai A.; Pellizzoni, Livio; Paushkin, Sergey; Ko, Chien-Ping; Weetall, Marla

    2016-01-01

    Spinal muscular atrophy (SMA) is caused by the loss or mutation of both copies of the survival motor neuron 1 (SMN1) gene. The related SMN2 gene is retained, but due to alternative splicing of exon 7, produces insufficient levels of the SMN protein. Here, we systematically characterize the pharmacokinetic and pharmacodynamics properties of the SMN splicing modifier SMN-C1. SMN-C1 is a low-molecular weight compound that promotes the inclusion of exon 7 and increases production of SMN protein in human cells and in two transgenic mouse models of SMA. Furthermore, increases in SMN protein levels in peripheral blood mononuclear cells and skin correlate with those in the central nervous system (CNS), indicating that a change of these levels in blood or skin can be used as a non-invasive surrogate to monitor increases of SMN protein levels in the CNS. Consistent with restored SMN function, SMN-C1 treatment increases the levels of spliceosomal and U7 small-nuclear RNAs and corrects RNA processing defects induced by SMN deficiency in the spinal cord of SMNΔ7 SMA mice. A 100% or greater increase in SMN protein in the CNS of SMNΔ7 SMA mice robustly improves the phenotype. Importantly, a ∼50% increase in SMN leads to long-term survival, but the SMA phenotype is only partially corrected, indicating that certain SMA disease manifestations may respond to treatment at lower doses. Overall, we provide important insights for the translation of pre-clinical data to the clinic and further therapeutic development of this series of molecules for SMA treatment. PMID:26931466

  7. Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

    PubMed Central

    Scoto, Mariacristina; Rossor, Alexander M.; Harms, Matthew B.; Cirak, Sebahattin; Calissano, Mattia; Robb, Stephanie; Manzur, Adnan Y.; Martínez Arroyo, Amaia; Rodriguez Sanz, Aida; Mansour, Sahar; Fallon, Penny; Hadjikoumi, Irene; Klein, Andrea; Yang, Michele; De Visser, Marianne; Overweg-Plandsoen, W.C.G. (Truus); Baas, Frank; Taylor, J. Paul; Benatar, Michael; Connolly, Anne M.; Al-Lozi, Muhammad T.; Nixon, John; de Goede, Christian G.E.L.; Foley, A. Reghan; Mcwilliam, Catherine; Pitt, Matthew; Sewry, Caroline; Phadke, Rahul; Hafezparast, Majid; Chong, W.K. “Kling”; Mercuri, Eugenio; Baloh, Robert H.; Reilly, Mary M.

    2015-01-01

    Objective: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Methods: Patients with a phenotype suggestive of a motor, non–length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. Results: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Conclusion: Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions. PMID:25609763

  8. Adiposity is increased among High-Functioning, Non-Ambulatory Patients with Spinal Muscular Atrophy

    PubMed Central

    Sproule, Douglas M.; Montes, Jacqueline; Dunaway, Sally; Montgomery, Megan; Battista, Vanessa; Koenigsberger, Dorcas; Martens, Bill; Shen, Wei; Punyanitya, Mark; Benton, Maryjane; Butler, Hailly; Caracciolo, Jayson; Mercuri, Eugenio; Finkel, Richard; Darras, Basil; De Vivo, Darryl C.; Kaufmann, Petra

    2010-01-01

    The relationship between body composition and function in spinal muscular atrophy (SMA) is poorly understood. 53 subjects with SMA were stratified by type and Hammersmith Functional Motor Scale, Expanded score into three cohorts: Low-Functioning Non-Ambulatory (type 2 with Hammersmith score <12, n=19), High-Functioning Non-Ambulatory (type 2 with Hammersmith Score ≥ 12 or non-ambulatory type 3, n=17), and Ambulatory (n=17). Lean and fat mass was estimated using dual-energy x-ray absorptiometry. Anthropometric data was incorporated to measure fat-free (lean mass in kg /stature in m2) and fat (fat mass in kg /stature in m2) mass indices, the latter compared to published age and sex norms. Feeding dysfunction among type 2 subjects was assessed by questionnaire. Fat mass index was increased in the High-Functioning Non-Ambulatory cohort (10.4 ± 4.5) compared with both the ambulatory (7.2 ± 2.1, p = 0.013) and Low-Functioning Non-Ambulatory (7.6 ± 3.1, p = 0.040) cohorts. 12 of 17 subjects (71%) in the High-Functioning Non-Ambulatory cohort had fat mass index >85th percentile for age and gender (connoting “at risk of overweight”) versus 9 of 19 subjects (47%) in the Low-Functioning Non-Ambulatory cohort and 8 of 17 ambulatory subjects (47%). Despite differences in clinical function, a similar proportion of low functioning (7/18, 39%) and high functioning (2/7, 29%) type 2 subjects reported swallowing or feeding dysfunction. Non-ambulatory patients with relatively high clinical function may be at particular risk of excess adiposity, perhaps reflecting access to excess calories despite relative immobility, emphasizing the importance of individualized nutritional management in SMA. PMID:20610154

  9. Oxidative Stress Triggers Body-Wide Skipping of Multiple Exons of the Spinal Muscular Atrophy Gene

    PubMed Central

    Seo, Joonbae; Singh, Natalia N.; Ottesen, Eric W.; Sivanesan, Senthilkumar; Shishimorova, Maria; Singh, Ravindra N.

    2016-01-01

    Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2. Loss of SMN1 leads to spinal muscular atrophy (SMA), the most frequent genetic cause of infant mortality. While SMN2 cannot compensate for the loss of SMN1 due to predominant skipping of exon 7, correction of SMN2 exon 7 splicing holds the promise of a cure for SMA. Previously, we used cell-based models coupled with a multi-exon-skipping detection assay (MESDA) to demonstrate the vulnerability of SMN2 exons to aberrant splicing under the conditions of oxidative stress (OS). Here we employ a transgenic mouse model and MESDA to examine the OS-induced splicing regulation of SMN2 exons. We induced OS using paraquat that is known to trigger production of reactive oxygen species and cause mitochondrial dysfunction. We show an overwhelming co-skipping of SMN2 exon 5 and exon 7 under OS in all tissues except testis. We also show that OS increases skipping of SMN2 exon 3 in all tissues except testis. We uncover several new SMN2 splice isoforms expressed at elevated levels under the conditions of OS. We analyze cis-elements and transacting factors to demonstrate the diversity of mechanisms for splicing misregulation under OS. Our results of proteome analysis reveal downregulation of hnRNP H as one of the potential consequences of OS in brain. Our findings suggest SMN2 as a sensor of OS with implications to SMA and other diseases impacted by low levels of SMN protein. PMID:27111068

  10. Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Barton, Elisabeth R.; Sweeney, H. Lee

    2016-01-01

    Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter. At 12 weeks of age, muscle mass and function were improved in treated C/C mice by both treatments, compared to controls. The fast fiber type muscles had a greater response to treatment than did slow muscles, and the greatest therapeutic effects were found with sActRIIB treatment. Myostatin/activin inhibition, however, did not rescue C/C mice from the reduction in motor unit numbers of the tibialis anterior muscle. Collectively, this study indicates that myostatin/activin inhibition represents a potential therapeutic strategy to increase muscle mass and strength, but not neuromuscular junction defects, in less severe forms of SMA. PMID:27870893

  11. RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns

    PubMed Central

    Doktor, Thomas Koed; Hua, Yimin; Andersen, Henriette Skovgaard; Brøner, Sabrina; Liu, Ying Hsiu; Wieckowska, Anna; Dembic, Maja; Bruun, Gitte Hoffmann; Krainer, Adrian R.; Andresen, Brage Storstein

    2017-01-01

    Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models. SMA is characterized by loss of motor neurons, but the underlying mechanism is largely unknown. It is likely that aberrant splicing of genes expressed in motor neurons is involved in SMA pathogenesis, but increasing evidence indicates that pathologies also exist in other tissues. We present here a comprehensive RNA-seq study that covers multiple tissues in an SMA mouse model. We show elevated U12-intron retention in all examined tissues from SMA mice, and that U12-dependent intron retention is induced upon siRNA knock-down of SMN in HeLa cells. Furthermore, we show that retention of U12-dependent introns is mitigated by ASO treatment of SMA mice and that many transcriptional changes are reversed. Finally, we report on missplicing of several Ca2+ channel genes that may explain disrupted Ca2+ homeostasis in SMA and activation of Cdk5. PMID:27557711

  12. SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR

    PubMed Central

    Stabley, Deborah L; Harris, Ashlee W; Holbrook, Jennifer; Chubbs, Nicholas J; Lozo, Kevin W; Crawford, Thomas O; Swoboda, Kathryn J; Funanage, Vicky L; Wang, Wenlan; Mackenzie, William; Scavina, Mena; Sol-Church, Katia; Butchbach, Matthew E R

    2015-01-01

    Proximal spinal muscular atrophy (SMA) is an early-onset motor neuron disease characterized by loss of α-motor neurons and associated muscle atrophy. SMA is caused by deletion or other disabling mutation of survival motor neuron 1 (SMN1). In the human genome, a large duplication of the SMN-containing region gives rise to a second copy of this gene (SMN2) that is distinguishable by a single nucleotide change in exon 7. Within the SMA population, there is substantial variation in SMN2 copy number; in general, those individuals with SMA who have a high SMN2 copy number have a milder disease. Because SMN2 functions as a disease modifier, its accurate copy number determination may have clinical relevance. In this study, we describe the development of an assay to assess SMN1 and SMN2 copy numbers in DNA samples using an array-based digital PCR (dPCR) system. This dPCR assay can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient-derived cell lines, the assay confirmed a strong inverse correlation between SMN2 copy number and disease severity. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 copy numbers from SMA samples. PMID:26247043

  13. [Development of therapeutics for spinal and bulbar muscular atrophy (SBMA)].

    PubMed

    Sobue, Gen

    2003-11-01

    Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a hereditary motor neuron disease that affects males, caused by the expansion of a polyglutamine (polyQ) tract in androgen receptor (AR). Female carriers are usually asymptomatic. The transgenic mouse (Tg) model carrying a full-length human AR with expanded polyQ has significant gender-related motor impairment. This phenotype is inhibited by castration, which prevents nuclear translocation of mutant AR. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, also rescues motor dysfunction and nuclear accumulation of mutant AR in the male Tg. Over-expression of a molecular chaperone HSP70, which renatures misfolded mutant AR, ameliorates neuromuscular phenotypes of the Tg by reducing nuclear-localized mutant AR. HSP70 appears to enhance the degradation of mutant AR via ubiquitin-proteasome pathway. These experimental approaches indicate the possibility of clinical application of drugs, such as leuprorelin, for SBMA patients.

  14. Neuroprotective Effect of Non-viral Gene Therapy Treatment Based on Tetanus Toxin C-fragment in a Severe Mouse Model of Spinal Muscular Atrophy.

    PubMed

    Oliván, Sara; Calvo, Ana C; Rando, Amaya; Herrando-Grabulosa, Mireia; Manzano, Raquel; Zaragoza, Pilar; Tizzano, Eduardo F; Aquilera, Jose; Osta, Rosario

    2016-01-01

    Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons "in vitro" and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3, and p62) and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild-type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln), TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease.

  15. Neuroprotective Effect of Non-viral Gene Therapy Treatment Based on Tetanus Toxin C-fragment in a Severe Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Oliván, Sara; Calvo, Ana C.; Rando, Amaya; Herrando-Grabulosa, Mireia; Manzano, Raquel; Zaragoza, Pilar; Tizzano, Eduardo F.; Aquilera, Jose; Osta, Rosario

    2016-01-01

    Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons “in vitro” and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3, and p62) and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild-type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln), TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease. PMID:27605908

  16. A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites.

    PubMed

    Chong, Jessica X; Oktay, A Afşin; Dai, Zunyan; Swoboda, Kathryn J; Prior, Thomas W; Ober, Carole

    2011-10-01

    Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as ∼1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22 Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10 Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for ∼1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity.

  17. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies

    PubMed Central

    Jordanova, Albena

    2014-01-01

    Hereditary spinal muscular atrophy is a motor neuron disorder characterized by muscle weakness and atrophy due to degeneration of the anterior horn cells of the spinal cord. Initially, the disease was considered purely as an autosomal recessive condition caused by loss-of-function SMN1 mutations on 5q13. Recent developments in next generation sequencing technologies, however, have unveiled a growing number of clinical conditions designated as non-5q forms of spinal muscular atrophy. At present, 16 different genes and one unresolved locus are associated with proximal non-5q forms, having high phenotypic variability and diverse inheritance patterns. This review provides an overview of the current knowledge regarding the phenotypes, causative genes, and disease mechanisms associated with proximal SMN1-negative spinal muscular atrophies. We describe the molecular and cellular functions enriched among causative genes, and discuss the challenges in the post-genomics era of spinal muscular atrophy research. PMID:24970098

  18. Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Katsuno, Masahisa; Tanaka, Fumiaki; Adachi, Hiroaki; Banno, Haruhiko; Suzuki, Keisuke; Watanabe, Hirohisa; Sobue, Gen

    2012-12-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by slowly progressive muscle weakness and atrophy. During the last two decades, basic and clinical research has provided important insights into the disease phenotype and pathophysiology. The cause of SBMA is the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. SBMA exclusively affects adult males, whereas females homozygous for the AR mutation do not manifest neurological symptoms. The ligand-dependent nuclear accumulation of the polyglutamine-expanded AR protein is central to the gender-specific pathogenesis of SBMA, although additional steps, e.g., DNA binding, inter-domain interactions, and post-translational modification of AR, modify toxicity. The interactions with co-regulators are another requisite for the toxic properties of the polyglutamine-expanded AR. It is also shown that the polyglutamine-expanded AR induces diverse molecular events, such as transcriptional dysregulation, axonal transport disruption, and mitochondrial dysfunction, which play causative roles in the neurodegeneration in SBMA. The pathogenic AR-induced myopathy also contributes to the non-cell autonomous degeneration of motor neurons. Pre-clinical studies using animal models show that the pathogenic AR-mediated neurodegeneration is suppressed by androgen inactivation, the efficacy of which has been tested in clinical trials. Pharmacological activation of cellular defense machineries, such as molecular chaperones, ubiquitin-proteasome system, and autophagy, also exerts neuroprotective effects in experimental models of SBMA.

  19. Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Katsuno, M; Adachi, H; Inukai, A; Sobue, G

    2003-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. Only males develop symptoms, while female carriers usually are asymptomatic. A specific treatment for SBMA has not been established. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract, in the first exon of the androgen receptor (AR) gene. The pathologic hallmark is nuclear inclusions (NIs) containing the mutant and truncated AR with expanded polyQ in the residual motor neurons in the brainstem and spinal cord as well as in some other visceral organs. Several transgenic (Tg) mouse models have been created for studying the pathogenesis of SBMA. The Tg mouse model carrying pure 239 CAGs under human AR promoter and another model carrying truncated AR with expanded CAGs show motor impairment and nuclear NIs in spinal motor neurons. Interestingly, Tg mice carrying full-length human AR with expanded polyQ demonstrate progressive motor impairment and neurogenic pathology as well as sexual difference of phenotypes. These models recapitulate the phenotypic expression observed in SBMA. The ligand-dependent nuclear localization of the mutant AR is found to be involved in the disease mechanism, and hormonal therapy is suggested to be a therapeutic approach applicable to SBMA.

  20. Fibrosis, adipogenesis, and muscle atrophy in congenital muscular torticollis.

    PubMed

    Chen, Huan-Xiong; Tang, Sheng-Ping; Gao, Fu-Tang; Xu, Jiang-Long; Jiang, Xian-Ping; Cao, Juan; Fu, Gui-Bing; Sun, Ke; Liu, Shi-Zhe; Shi, Wei

    2014-11-01

    In the traditional view, muscle atrophy and interstitial fibrosis were regarded as the basic pathological features of congenital muscular torticollis (CMT). But in the ultrastructure study, the mesenchyme-like cells, myoblasts, myofibroblasts, and fibroblasts were found in the proliferation of interstitium of CMT. To investigate the characteristics of pathological features and the mechanisms of muscle atrophy in CMT, we retrospectively reviewed the medical records of 185 CMT patients from July 2009 to July 2011 in Shenzhen Children's Hospital in China and performed pathological studies. According to age, the 185 CMT patients were divided into 4 groups. All resected surgical specimens were processed for hematoxylin and eosin staining and Masson trichromic staining. Sudan III staining was used for frozen sections, whereas immunohistochemical staining for S-100, calpain-1, ubiquitin, and 20S proteasome was carried out on 40 CMT specimens. Eight adductor muscle specimens from 8 patients with development dysplasia of the hip were taken as control group in the immunohistochemical staining. By Masson trichromic staining, the differences in the percent area of fibrous tissue in each CMT groups were significant. In Sudan III staining and immunostaining for S-100, adipocyte hyperplasia was the pathological feature of CMT. Moreover, compared with controls, most atrophic muscle fibers in CMT specimens were found to show strong immunoreactivity for calpain-1, ubiquitin, and 20S proteasome. With increasing age, fibrosis peaked at both sides and it was low in middle age group. Adipocytes increased with age. The characteristics of pathological features in CMT are changeable with age. The calpain and the ubiquitin-proteasome system may play a role in muscle atrophy of CMT. In the CMT, adipogenesis, fibrogenesis, and myogenesis may be the results of mesenchyme-like cells in SCM (sternocleidomastoid muscle). In conclusion, the present study furthermore supports maldevelopment of the

  1. Spinal muscular atrophy type II (intermediary) and III (Kugelberg-Welander). Evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool.

    PubMed

    Cunha, M C; Oliveira, A S; Labronici, R H; Gabbai, A A

    1996-09-01

    We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA) who were being treated with individual conventional physiotherapy. Hydrotherapy performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test), and the Barthel Ladder. Patients were reevaluated at 2-month intervals. After two years of ongoing treatment, we were able to observe that the deformities in hip, knee and foot were progressive in all SMA Type II patients, and in some Type III. Muscle strength stabilized in most SMA Type III patients, and improved in some. MMT was not done in SMA Type II. In all patients we were able to detect an improvement in the Barthel Ladder scale. This study suggests that a measurable improvement in the quality of daily living may be obtained in patients with SMA Types II and III subjected to conventional physiotherapy when associated with hydrotherapy.

  2. TIA1 prevents skipping of a critical exon associated with spinal muscular atrophy.

    PubMed

    Singh, Natalia N; Seo, Joonbae; Ottesen, Eric W; Shishimorova, Maria; Bhattacharya, Dhruva; Singh, Ravindra N

    2011-03-01

    Prevention of skipping of exon 7 during pre-mRNA splicing of Survival Motor Neuron 2 (SMN2) holds the promise for cure of spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Here, we report T-cell-restricted intracellular antigen 1 (TIA1) and TIA1-related (TIAR) proteins as intron-associated positive regulators of SMN2 exon 7 splicing. We show that TIA1/TIAR stimulate exon recognition in an entirely novel context in which intronic U-rich motifs are separated from the 5' splice site by overlapping inhibitory elements. TIA1 and TIAR are modular proteins with three N-terminal RNA recognition motifs (RRMs) and a C-terminal glutamine-rich (Q-rich) domain. Our results reveal that any one RRM in combination with a Q domain is necessary and sufficient for TIA1-associated regulation of SMN2 exon 7 splicing in vivo. We also show that increased expression of TIA1 counteracts the inhibitory effect of polypyrimidine tract binding protein, a ubiquitously expressed factor recently implicated in regulation of SMN exon 7 splicing. Our findings expand the scope of TIA1/TIAR in genome-wide regulation of alternative splicing under normal and pathological conditions.

  3. [Clinical features of a genetically identified spinal and 
bulbar muscular atrophy pedigree].

    PubMed

    Wang, Zhe; Chen, Qihua; Li, Qiuxiang; Bi, Fangfang

    2016-10-28

    Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked motor neuron disease with significant phenotypic viability. Here, we present a genetically identified SBMA family without bulbar paralysis or androgen insensitivity. All four male patients presented with progressive lower motor neuron paralysis in all limbs, with distal extremities more dominant. None of them had bulbar palsy or androgen insensitivity. A consistently mild elevated blood creatine phosphokinase (CPK) levels were detected in all patients and the EMG showed a chronic neurogenic damage. Muscle biopsy of propositus indicated a typical neurogenic amyotrophy. Genetic testing for SMA of mutation in SMN1 was negative, while for SBMA of androgen receptor showed the increased CAG repeat in exon 1, suggesting that although bulbar symptoms and androgen insensitivity are characteristic symptoms of SBMA, they are not obligatory for the diagnosis. In adult males with a chronic motor neuron syndrome without upper motor neuron signs, even in absence of the classical features of androgen insensitivity or bulbar findings, genetic testing for SBMA should be strongly considered.

  4. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.

    PubMed

    Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2013-03-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

  5. Founder effect in spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Tanaka, F; Doyu, M; Ito, Y; Matsumoto, M; Mitsuma, T; Abe, K; Aoki, M; Itoyama, Y; Fischbeck, K H; Sobue, G

    1996-09-01

    We analyzed the polymorphic (CAG)n and (GGC)n repeats of the androgen receptor gene in 113 unrelated X-linked spinal and bulbar muscular atrophy (SBMA) X chromosomes and 173 control X chromosomes in Japanese males. The control chromosomes had an average CAG repeat number of 21 +/- 3 with a range from 14-32 repeat units, and SBMA chromosomes had a range from 40-55 with a median of 47 +/- 3 copies. The control chromosomes had seven different alleles of the (GGC)n repeat with the range of 11 to 17; the most frequent size of (GGC)n was 16 (79%), while (GGC)17 was very rare (1%). However, in SBMA chromosomes only two alleles were seen; the most frequent size of (GGC)n was 16 (61%) followed by 17 (39%). (GGC)n size distribution was significantly different between SBMA and control chromosomes (P < 0.0001), indicating the presence of linkage disequilibrium. There was no allelic association between the (CAG)n and (GGC)n microsatellites among control subjects as well as SBMA patients, which suggests that a founder effect makes a more significant contribution to generation of Japanese SBMA chromosomes than new mutations.

  6. [Sanger sequencing for the diagnosis of spinal muscular atrophy patients with survival motor neuron gene 1 compound heterozygous mutation].

    PubMed

    Yang, L; Cao, Y Y; Qu, Y J; Bai, J L; Wang, H; Jin, Y W; Han, Y L; Song, F

    2017-02-14

    Objective: To detect the subtle variant of survival motor neuron gene 1(SMN1) by Sanger sequencing, and to assess the value of Sanger sequencing for the diagnosis of spinal muscular atrophy(SMA) with compound heterozygous mutation of SMN1. Methods: Fifty-two patients suspected SMA were recruited by the Capital Institute of Pediatrics from Jan.2014 to June.2016. PCR was used for amplifying exon7 of SMN1 and SMN2 in 52 patients. Natural different base peaks on the sequencing chromatogram in the SMN1 and SMN2 within the amplified segments were identified with Sanger DNA sequencing to detect the homozygous deletion or heterozygous deletion of SMN1. Then we screened the SMN1 subtle variants in heterozygous deletion patients by genomic Sanger sequencing for the other SMN exons. At last, multiplex ligation-dependent probe amplification(MLPA) was carried out to confirm the results of SMN1 heterozygous deletion, and T-A cloning confirmed the subtle variants were located in SMN1. Results: Forty-seven of 52 cases were homozygous deletion of SMN1, while 5 cases were heterozygous deletion which were confirmed by MLPA.Then, by genomic and T-A cloning sequencing, five SMN1 subtle mutations were separately identified in 5 cases of heterozygous deletion. Conclusion: Sanger sequencing is an effective method for the clinical diagnosis of compound heterozygous mutation of SMN1, and is meaningful for improving genetic diagnosis rate of SMA.

  7. Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy.

    PubMed

    Ottesen, Eric W; Howell, Matthew D; Singh, Natalia N; Seo, Joonbae; Whitley, Elizabeth M; Singh, Ravindra N

    2016-02-02

    Spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN), a multifunctional protein essential for higher eukaryotes. While SMN is one of the most scrutinized proteins associated with neurodegeneration, its gender-specific role in vertebrates remains unknown. We utilized a mild SMA model (C/C model) to examine the impact of low SMN on growth and development of mammalian sex organs. We show impaired testis development, degenerated seminiferous tubules, reduced sperm count and low fertility in C/C males, but no overt sex organ phenotype in C/C females. Underscoring an increased requirement for SMN expression, wild type testis showed extremely high levels of SMN protein compared to other tissues. Our results revealed severe perturbations in pathways critical to C/C male reproductive organ development and function, including steroid biosynthesis, apoptosis, and spermatogenesis. Consistent with enhanced apoptosis in seminiferous tubules of C/C testes, we recorded a drastic increase in cells with DNA fragmentation. SMN was expressed at high levels in adult C/C testis due to an adult-specific splicing switch, but could not compensate for low levels during early testicular development. Our findings uncover novel hallmarks of SMA disease progression and link SMN to general male infertility.

  8. Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy

    PubMed Central

    Ottesen, Eric W.; Howell, Matthew D.; Singh, Natalia N.; Seo, Joonbae; Whitley, Elizabeth M.; Singh, Ravindra N.

    2016-01-01

    Spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN), a multifunctional protein essential for higher eukaryotes. While SMN is one of the most scrutinized proteins associated with neurodegeneration, its gender-specific role in vertebrates remains unknown. We utilized a mild SMA model (C/C model) to examine the impact of low SMN on growth and development of mammalian sex organs. We show impaired testis development, degenerated seminiferous tubules, reduced sperm count and low fertility in C/C males, but no overt sex organ phenotype in C/C females. Underscoring an increased requirement for SMN expression, wild type testis showed extremely high levels of SMN protein compared to other tissues. Our results revealed severe perturbations in pathways critical to C/C male reproductive organ development and function, including steroid biosynthesis, apoptosis, and spermatogenesis. Consistent with enhanced apoptosis in seminiferous tubules of C/C testes, we recorded a drastic increase in cells with DNA fragmentation. SMN was expressed at high levels in adult C/C testis due to an adult-specific splicing switch, but could not compensate for low levels during early testicular development. Our findings uncover novel hallmarks of SMA disease progression and link SMN to general male infertility. PMID:26830971

  9. Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5

    SciTech Connect

    Steege, G. van der; Grootscholten, P.M.; Cobben, J.M.; Scheffer, H.; Buys, C.H.C.M.

    1996-10-01

    The survival motor neuron (SMN) gene has been described as a determining gene for spinal muscular atrophy (SMA). SMN has a closely flanking, nearly identical copy ({sup C}BCD541). Gene and copy gene can be discriminated by sequence differences in exons 7 and 8. The large majority of SMA patients show homozygous deletions of at least exons 7 and 8 of the SMN gene. A minority of patients show absence of SMN exon 7 but retention of exon 8. This is explained by results of our present analysis of 13 such patients providing evidence for apparent gene-conversion events between SMN and the centromeric copy gene. Instead of applying a separate analysis for absence or presence of SMN exons 7 and 8, we used a contiguous PCR from intron 6 to exon 8. In every case we found a chimeric gene with a fusion of exon 7 of the copy gene and exon 8 of SMN and absence of a normal SMN gene. Similar events, including the fusion counterpart, were observed in a group of controls, although in the presence of a normal SMN gene. Chimeric genes as the result of fusions of parts of SMN and {sup C}BCD541 apparently are far from rare and may partly explain the frequently observed SMN deletions in SMA patients. 23 refs., 4 figs.

  10. The loss of the snoRNP chaperone Nopp140 from Cajal bodies of patient fibroblasts correlates with the severity of spinal muscular atrophy.

    PubMed

    Renvoisé, Benoît; Colasse, Sabrina; Burlet, Philippe; Viollet, Louis; Meier, U Thomas; Lefebvre, Suzie

    2009-04-01

    Spinal muscular atrophy (SMA) is a common autosomal recessive neurodegenerative disease caused by reduced survival motor neuron (SMN) levels. The assembly machinery containing SMN is implicated in the biogenesis of the spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN is present in both the cytoplasm and nucleus, where it transiently accumulates in subnuclear domains named Cajal bodies (CBs) and functions in the maturation of snRNPs and small nucleolar (sno)RNPs. The impact of lowering SMN levels on the composition of CBs in SMA cells is still not completely understood. Here, we analyse the CB composition in immortalized and primary fibroblasts from SMA patients. We show that the U snRNA export factors PHAX and chromosome region maintenance 1 and the box C/D snoRNP core protein fibrillarin concentrate in CBs from SMA cells, whereas the box H/ACA core proteins GAR1 and NAP57/dyskerin show reduced CB localization. Remarkably, the functional deficiency in SMA cells is associated with decreased localization of the snoRNP chaperone Nopp140 in CBs that correlates with disease severity. Indeed, RNA interference knockdown experiments in control fibroblasts demonstrate that SMN is required for accumulation of Nopp140 in CBs. Conversely, overexpression of SMN in SMA cells restores the CB localization of Nopp140, whereas SMN mutants found in SMA patients are defective in promoting the association of Nopp140 with CBs. Taken together, we demonstrate that only a subset of CB functions (as indicated by the association of representative factors) are impaired in SMA cells and, importantly, we identify the decrease of Nopp140 localization in CBs as a phenotypic marker for SMA.

  11. The Spinal Muscular Atrophy Disease Gene Product, Smn

    PubMed Central

    Carvalho, Teresa; Almeida, Fátima; Calapez, Alexandre; Lafarga, Miguel; Berciano, Maria T.; Carmo-Fonseca, Maria

    1999-01-01

    The spliceosomal snRNAs U1, U2, U4, and U5 are synthesized in the nucleus, exported to the cytoplasm to assemble with Sm proteins, and reimported to the nucleus as ribonucleoprotein particles. Recently, two novel proteins involved in biogenesis of small nuclear ribonucleoproteins (snRNPs) were identified, the Spinal muscular atrophy disease gene product (SMN) and its associated protein SIP1. It was previously reported that in HeLa cells, SMN and SIP1 form discrete foci located next to Cajal (coiled) bodies, the so-called “gemini of coiled bodies” or “gems.” An intriguing feature of gems is that they do not appear to contain snRNPs. Here we show that gems are present in a variable but small proportion of rapidly proliferating cells in culture. In the vast majority of cultured cells and in all primary neurons analyzed, SMN and SIP1 colocalize precisely with snRNPs in the Cajal body. The presence of SMN and SIP1 in Cajal bodies is confirmed by immunoelectron microscopy and by microinjection of antibodies that interfere with the integrity of the structure. The association of SMN with snRNPs and coilin persists during cell division, but at the end of mitosis there is a lag period between assembly of new Cajal bodies in the nucleus and detection of SMN in these structures, suggesting that SMN is targeted to preformed Cajal bodies. Finally, treatment of cells with leptomycin B (a drug that blocks export of U snRNAs to the cytoplasm and consequently import of new snRNPs into the nucleus) is shown to deplete snRNPs (but not SMN or SIP1) from the Cajal body. This suggests that snRNPs flow through the Cajal body during their biogenesis pathway. PMID:10562276

  12. Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience.

    PubMed

    Haché, Manon; Swoboda, Kathryn J; Sethna, Navil; Farrow-Gillespie, Alan; Khandji, Alexander; Xia, Shuting; Bishop, Kathie M

    2016-06-01

    Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children.

  13. Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy.

    PubMed

    Montague, Karli; Malik, Bilal; Gray, Anna L; La Spada, Albert R; Hanna, Michael G; Szabadkai, Gyorgy; Greensmith, Linda

    2014-07-01

    Spinal and bulbar muscular atrophy is an X-linked degenerative motor neuron disease caused by an abnormal expansion in the polyglutamine encoding CAG repeat of the androgen receptor gene. There is evidence implicating endoplasmic reticulum stress in the development and progression of neurodegenerative disease, including polyglutamine disorders such as Huntington's disease and in motor neuron disease, where cellular stress disrupts functioning of the endoplasmic reticulum, leading to induction of the unfolded protein response. We examined whether endoplasmic reticulum stress is also involved in the pathogenesis of spinal and bulbar muscular atrophy. Spinal and bulbar muscular atrophy mice that carry 100 pathogenic polyglutamine repeats in the androgen receptor, and develop a late-onset neuromuscular phenotype with motor neuron degeneration, were studied. We observed a disturbance in endoplasmic reticulum-associated calcium homeostasis in cultured embryonic motor neurons from spinal and bulbar muscular atrophy mice, which was accompanied by increased endoplasmic reticulum stress. Furthermore, pharmacological inhibition of endoplasmic reticulum stress reduced the endoplasmic reticulum-associated cell death pathway. Examination of spinal cord motor neurons of pathogenic mice at different disease stages revealed elevated expression of markers for endoplasmic reticulum stress, confirming an increase in this stress response in vivo. Importantly, the most significant increase was detected presymptomatically, suggesting that endoplasmic reticulum stress may play an early and possibly causal role in disease pathogenesis. Our results therefore indicate that the endoplasmic reticulum stress pathway could potentially be a therapeutic target for spinal and bulbar muscular atrophy and related polyglutamine diseases.

  14. A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis

    PubMed Central

    Nishimura, Agnes L.; Mitne-Neto, Miguel; Silva, Helga C. A.; Richieri-Costa, Antônio; Middleton, Susan; Cascio, Duilio; Kok, Fernando; Oliveira, João R. M.; Gillingwater, Tom; Webb, Jeanette; Skehel, Paul; Zatz, Mayana

    2004-01-01

    Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking. PMID:15372378

  15. Preservation of VGLUT1 synapses on ventral calbindin-immunoreactive interneurons and normal locomotor function in a mouse model of spinal muscular atrophy.

    PubMed

    Thirumalai, Vatsala; Behrend, Rachel M; Birineni, Swetha; Liu, Wenfang; Blivis, Dvir; O'Donovan, Michael J

    2013-02-01

    Dysfunction in sensorimotor synapses is one of the earliest pathological changes observed in a mouse model [spinal muscular atrophy (SMA)Δ7] of spinal muscular atrophy. Here, we examined the density of proprioceptive and cholinergic synapses on calbindin-immunoreactive interneurons ventral to the lateral motor column. This population includes inhibitory Renshaw interneurons that are known to receive synaptic input from muscle spindle afferents and from motoneurons. At postnatal day (P)13, near the end stage of the disease, the somatic area of calbindin(+) neurons in the L1/L2 and L5/L6 segments was reduced in SMAΔ7 mice compared with controls. In addition, the number and density of terminals expressing the glutamate vesicular transporter (VGLUT1) and the vesicular acetylcholine transporter (VAChT) were increased on calbindin(+) cells in the L1-L2 but not in the L5-L6 segments of SMAΔ7 mice. In addition, the isolated spinal cord of SMA mice was able to generate locomotor-like activity at P4-P6 in the presence of a drug cocktail or in response to dorsal root stimulation. These results argue against a generalized loss of proprioceptive input to spinal circuits in SMA and suggest that the loss of proprioceptive synapses on motoneurons may be secondary to motoneuron pathology. The increased number of VGLUT1(+) and VAChT(+) synapses on calbindin(+) neurons in the L1/L2 segments may be the result of homeostatic mechanisms. Finally, we have shown that abnormal locomotor network function is unlikely to account for the motor deficits observed in SMA mice at P4-6.

  16. Preservation of VGLUT1 synapses on ventral calbindin-immunoreactive interneurons and normal locomotor function in a mouse model of spinal muscular atrophy

    PubMed Central

    Thirumalai, Vatsala; Behrend, Rachel M.; Birineni, Swetha; Liu, Wenfang; Blivis, Dvir

    2013-01-01

    Dysfunction in sensorimotor synapses is one of the earliest pathological changes observed in a mouse model [spinal muscular atrophy (SMA)Δ7] of spinal muscular atrophy. Here, we examined the density of proprioceptive and cholinergic synapses on calbindin-immunoreactive interneurons ventral to the lateral motor column. This population includes inhibitory Renshaw interneurons that are known to receive synaptic input from muscle spindle afferents and from motoneurons. At postnatal day (P)13, near the end stage of the disease, the somatic area of calbindin+ neurons in the L1/L2 and L5/L6 segments was reduced in SMAΔ7 mice compared with controls. In addition, the number and density of terminals expressing the glutamate vesicular transporter (VGLUT1) and the vesicular acetylcholine transporter (VAChT) were increased on calbindin+ cells in the L1-L2 but not in the L5-L6 segments of SMAΔ7 mice. In addition, the isolated spinal cord of SMA mice was able to generate locomotor-like activity at P4-P6 in the presence of a drug cocktail or in response to dorsal root stimulation. These results argue against a generalized loss of proprioceptive input to spinal circuits in SMA and suggest that the loss of proprioceptive synapses on motoneurons may be secondary to motoneuron pathology. The increased number of VGLUT1+ and VAChT+ synapses on calbindin+ neurons in the L1/L2 segments may be the result of homeostatic mechanisms. Finally, we have shown that abnormal locomotor network function is unlikely to account for the motor deficits observed in SMA mice at P4–6. PMID:23136344

  17. Cell-type-specific miR-431 dysregulation in a motor neuron model of spinal muscular atrophy.

    PubMed

    Wertz, Mary H; Winden, Kellen; Neveu, Pierre; Ng, Shi-Yan; Ercan, Ebru; Sahin, Mustafa

    2016-06-01

    Spinal muscular atrophy (SMA) is an autosomal-recessive pediatric neurodegenerative disease characterized by selective loss of spinal motor neurons. It is caused by mutation in the survival of motor neuron 1, SMN1, gene and leads to loss of function of the full-length SMN protein. microRNAs (miRNAs) are small RNAs that are involved in post-transcriptional regulation of gene expression. Prior studies have implicated miRNAs in the pathogenesis of motor neuron disease. We hypothesized that motor neuron-specific miRNA expression changes are involved in their selective vulnerability in SMA. Therefore, we sought to determine the effect of SMN loss on miRNAs and their target mRNAs in spinal motor neurons. We used microarray and RNAseq to profile both miRNA and mRNA expression in primary spinal motor neuron cultures after acute SMN knockdown. By integrating the miRNA:mRNA profiles, a number of dysregulated miRNAs were identified with enrichment in differentially expressed putative mRNA targets. miR-431 expression was highly increased, and a number of its putative mRNA targets were significantly downregulated in motor neurons after SMN loss. Further, we found that miR-431 regulates motor neuron neurite length by targeting several molecules previously identified to play a role in motor neuron axon outgrowth, including chondrolectin. Together, our findings indicate that cell-type-specific dysregulation of miR-431 plays a role in the SMA motor neuron phenotype.

  18. Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.

    PubMed

    Shababi, Monir; Feng, Zhihua; Villalon, Eric; Sibigtroth, Christine M; Osman, Erkan Y; Miller, Madeline R; Williams-Simon, Patricka A; Lombardi, Abby; Sass, Thalia H; Atkinson, Arleigh K; Garcia, Michael L; Ko, Chien-Ping; Lorson, Christian L

    2016-05-01

    Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disease occurring during childhood. The gene responsible for disease development is a ubiquitously expressed protein, IGHMBP2. Mutations in IGHMBP2 result in the loss of α-motor neurons leading to muscle atrophy in the distal limbs accompanied by respiratory complications. Although genetically and clinically distinct, proximal SMA is also caused by the loss of a ubiquitously expressed gene (SMN). Significant preclinical success has been achieved in proximal SMA using viral-based gene replacement strategies. We leveraged the technologies employed in SMA to demonstrate gene replacement efficacy in an SMARD1 animal model. Intracerebroventricular (ICV) injection of single-stranded AAV9 expressing the full-length cDNA of IGHMBP2 in a low dose led to a significant level of rescue in treated SMARD1 animals. Consistent with drastically increased survival, weight gain, and strength, the rescued animals demonstrated a significant improvement in muscle, NMJ, motor neurons, and axonal pathology. In addition, increased levels of IGHMBP2 in lumbar motor neurons verified the efficacy of the virus to transduce the target tissues. Our results indicate that AAV9-based gene replacement is a viable strategy for SMARD1, although dosing effects and potential negative impacts of high dose and ICV injection should be thoroughly investigated.

  19. Developmental milestones in type I spinal muscular atrophy.

    PubMed

    De Sanctis, Roberto; Coratti, Giorgia; Pasternak, Amy; Montes, Jacqueline; Pane, Marika; Mazzone, Elena S; Young, Sally Dunaway; Salazar, Rachel; Quigley, Janet; Pera, Maria C; Antonaci, Laura; Lapenta, Leonardo; Glanzman, Allan M; Tiziano, Danilo; Muntoni, Francesco; Darras, Basil T; De Vivo, Darryl C; Finkel, Richard; Mercuri, Eugenio

    2016-11-01

    The aim of this retrospective multicentric study was to assess developmental milestones longitudinally in type I SMA infants using the Hammersmith Infant Neurological Examination. Thirty-three type I SMA infants, who classically do not achieve the ability to sit unsupported, were included in the study. Our results confirmed that all patients had a score of 0 out of a scale of 4 on items assessing sitting, rolling, crawling, standing or walking. A score of more than 0 was only achieved in three items: head control (n = 13), kicking (n = 15) and hand grasp (n = 18). In these items, the maximal score achieved was 1 out of a scale of 4, indicating only partial achievement of the milestone. Infants with symptom onset after 6 months of age had longer preservation of a score of 1 when compared to those with onset before 6 months of age. Our results suggest that even when current standards of care are applied, developmental milestones are rarely even partially achieved as part of natural history in type I SMA infants. No infants in this study achieved a major milestone such as rolling over, or sitting independently, which would therefore represent robust outcomes in future interventional trials.

  20. A novel role for CARM1 in promoting nonsense-mediated mRNA decay: potential implications for spinal muscular atrophy.

    PubMed

    Sanchez, Gabriel; Bondy-Chorney, Emma; Laframboise, Janik; Paris, Geneviève; Didillon, Andréanne; Jasmin, Bernard J; Côté, Jocelyn

    2016-04-07

    Loss of 'Survival of Motor Neurons' (SMN) leads to spinal muscular atrophy (SMA), a disease characterized by degeneration of spinal cord alpha motor neurons, resulting in muscle weakness, paralysis and death during early childhood. SMN is required for assembly of the core splicing machinery, and splicing defects were documented in SMA. We previously uncovered that Coactivator-Associated Methyltransferase-1 (CARM1) is abnormally up-regulated in SMA, leading to mis-regulation of a number of transcriptional and alternative splicing events. We report here that CARM1 can promote decay of a premature terminating codon (PTC)-containing mRNA reporter, suggesting it can act as a mediator of nonsense-mediated mRNA decay (NMD). Interestingly, this pathway, while originally perceived as solely a surveillance mechanism preventing expression of potentially detrimental proteins, is now emerging as a highly regulated RNA decay pathway also acting on a subset of normal mRNAs. We further show that CARM1 associates with major NMD factor UPF1 and promotes its occupancy on PTC-containing transcripts. Finally, we identify a specific subset of NMD targets that are dependent on CARM1 for degradation and that are also misregulated in SMA, potentially adding exacerbated targeting of PTC-containing mRNAs to the already complex array of molecular defects associated with this disease.

  1. Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number.

    PubMed Central

    Parsons, D W; McAndrew, P E; Iannaccone, S T; Mendell, J R; Burghes, A H; Prior, T W

    1998-01-01

    The autosomal recessive neuromuscular disorder proximal spinal muscular atrophy (SMA) is caused by the loss or mutation of the survival motor neuron (SMN) gene, which exists in two nearly identical copies, telomeric SMN (telSMN) and centromeric SMN (cenSMN). Exon 7 of the telSMN gene is homozygously absent in approximately 95% of SMA patients, whereas loss of cenSMN does not cause SMA. We searched for other telSMN mutations among 23 SMA compound heterozygotes, using heteroduplex analysis. We identified telSMN mutations in 11 of these unrelated SMA-like individuals who carry a single copy of telSMN: these include two frameshift mutations (800ins11 and 542delGT) and three missense mutations (A2G, S262I, and T274I). The telSMN mutations identified to date cluster at the 3' end, in a region containing sites for SMN oligomerization and binding of Sm proteins. Interestingly, the novel A2G missense mutation occurs outside this conserved carboxy-terminal domain, closely upstream of an SIP1 (SMN-interacting protein 1) binding site. In three patients, the A2G mutation was found to be on the same allele as a rare polymorphism in the 5' UTR, providing evidence for a founder chromosome; Ag1-CA marker data also support evidence of an ancestral origin for the 800ins11 and 542delGT mutations. We note that telSMN missense mutations are associated with milder disease in our patients and that the severe type I SMA phenotype caused by frameshift mutations can be ameliorated by an increase in cenSMN gene copy number. PMID:9837824

  2. Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

    PubMed Central

    Bogdanik, Laurent P.; Osborne, Melissa A.; Davis, Crystal; Martin, Whitney P.; Austin, Andrew; Rigo, Frank; Bennett, C. Frank; Lutz, Cathleen M.

    2015-01-01

    Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system. PMID:26460027

  3. [Association of post-radiation focal muscular atrophy and hypertrophy].

    PubMed

    Serratrice, G; Sangla, I; Pouget, J; Azulay, J P

    1993-01-01

    We report a 48 year old woman who had radiotherapy for uterine carcinoma and who developed amyotrophy and muscle hypertrophy in one lower limb. Very few cases of post-radiation monomelic amyotrophy have been reported. On the other hand denervation hypertrophy was presumed to be well known. The seat of the lesions was presumed to be radicular and spinal. The mechanism of atrophy and hypertrophy is discussed.

  4. Juvenile Muscular Atrophy of a Unilateral Upper Extremity (Hirayama Disease) in a Patient with CHARGE Syndrome

    PubMed Central

    Yagihashi, T.; Hatori, K.; Ishii, K.; Torii, C.; Momoshima, S.; Takahashi, T.; Kosaki, K.

    2010-01-01

    CHARGE syndrome is an autosomal dominant congenital anomaly syndrome, and the causative gene is CHD7. We report a patient with a CHD7 mutation who presented with juvenile muscular atrophy of a unilateral upper extremity, a presumably heterogeneous condition that is also known as Hirayama disease. This association has not been previously described. Weakness and atrophy of the hands should be carefully examined in patients with CHARGE syndrome, since Hirayama disease might be a possible complication in adolescent patients with this syndrome. PMID:21046013

  5. [Alternative treatment forms used by patients with muscular atrophy. A questionnaire study of the use of alternative treatment by 345 patients with muscular atrophy].

    PubMed

    Hunsballe, J M; Mortensen, F V

    1990-04-30

    An investigation about the use of alternative treatment by a group of persons with muscular atrophy revealed that 24% had employed alternative treatment during the period 1.1.1983-1.4.1986. This is probably a greater proportion than in the Danish population as a whole. Patients with muscular atrophy were subdivided into three groups on the basis of their ability to function in daily life. No significant connection was found between the degree of loss of function and alternative treatment as regards the frequencies of alternative treatment and the numbers of treatments employed. A given form form of treatment was most frequently recommended by an unaffected acquaintance. Physical forms of treatment such as zone therapy and chiropractics were employed more frequently than chemical forms of therapy. Less than half of the patients were satisfied with the results of treatment. Treatment was often concluded in a negative manner. Patients considered that, in contrast to the alternative therapist, the doctor performs the best and most thorough examination and provides them with the best information about their condition.

  6. Upper limb module in non-ambulant patients with spinal muscular atrophy: 12 month changes.

    PubMed

    Sivo, Serena; Mazzone, Elena; Antonaci, Laura; De Sanctis, Roberto; Fanelli, Lavinia; Palermo, Concetta; Montes, Jacqueline; Pane, Marika; Mercuri, Eugenio

    2015-03-01

    Recent studies have suggested that in non-ambulant patients affected by spinal muscular atrophy the Upper Limb Module can increase the range of activities assessed by the Hammersmith Functional Motor Scale Expanded. The aim of this study was to establish 12-month changes in the Upper Limb Module in a cohort of non-ambulant spinal muscular atrophy patients and their correlation with changes on the Hammersmith Functional Motor Scale Expanded. The Upper Limb Module scores ranged between 0 and 17 (mean 10.23, SD 4.81) at baseline and between 1 and 17 at 12 months (mean 10.27, SD 4.74). The Hammersmith Functional Motor Scale Expanded scores ranged between 0 and 34 (mean 12.43, SD 9.13) at baseline and between 0 and 34 at 12 months (mean 12.08, SD 9.21). The correlation betweeen the two scales was 0.65 at baseline and 0.72 on the 12 month changes. Our results confirm that the Upper Limb Module can capture functional changes in non-ambulant spinal muscular atrophy patients not otherwise captured by the other scale and that the combination of the two measures allows to capture changes in different subgroups of patients in whom baseline scores and functional changes may be influenced by several variables such as age.

  7. Vitamin D Intake Is Inadequate in Spinal Muscular Atrophy Type I Cohort: Correlations With Bone Health

    PubMed Central

    Aton, Jennifer; Hurst Davis, Rebecca; Jordan, Kristine C.; Scott, Charles B.; Swoboda, Kathryn J.

    2014-01-01

    Children with type I spinal muscular atrophy commonly demonstrate reduced bone mineral density. Our objectives were to evaluate and assess adequacy of vitamin D intake, serum levels, and association with bone mineral density. Assessments were completed using 3-day food records and dual energy x-ray absorptiometry scans. The spinal muscular atrophy type I cohort included 22 males and 18 females (N = 40), with a mean age of 18.6 months. Data collection occurred from 2001 to 2011. Seventy-five percent of patients had inadequate intake of vitamin D at the initial visit. Using mixed-effects analyses, vitamin D and calcium intakes correlated positively with bone mineral density (r = 0.31 and r = 0.53, respectively). Increased vitamin D and calcium consumption were associated with an increase in bone mineral density (P = .04 and P = .01, respectively). Vitamin D intake correlated positively with serum levels (r = 0.65). Further study is needed to determine optimal intakes of vitamin D and calcium in the spinal muscular atrophy type I population. PMID:23334077

  8. Distinct domains of the spinal muscular atrophy protein SMN are required for targeting to Cajal bodies in mammalian cells.

    PubMed

    Renvoisé, Benoît; Khoobarry, Kevinee; Gendron, Marie-Claude; Cibert, Christian; Viollet, Louis; Lefebvre, Suzie

    2006-02-15

    Mutations of the survival motor neuron gene SMN1 cause the inherited disease spinal muscular atrophy (SMA). The ubiquitous SMN protein facilitates the biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs). The protein is detected in the cytoplasm, nucleoplasm and enriched with snRNPs in nuclear Cajal bodies. It is structurally divided into at least an amino-terminal region rich in basic amino acid residues, a central Tudor domain, a self-association tyrosine-glycine-box and an exon7-encoded C-terminus. To examine the domains required for the intranuclear localization of SMN, we have used fluorescently tagged protein mutants transiently overexpressed in mammalian cells. The basic amino acid residues direct nucleolar localization of SMN mutants. The Tudor domain promotes localization of proteins in the nucleus and it cooperates with the basic amino acid residues and the tyrosine-glycine-box for protein localization in Cajal bodies. Moreover, the most frequent disease-linked mutant SMNDeltaex7 reduces accumulation of snRNPs in Cajal bodies, suggesting that the C-terminus of SMN participates in targeting to Cajal bodies. A reduced number of Cajal bodies in patient fibroblasts associates with the absence of snRNPs in Cajal bodies, revealing that intranuclear snRNA organization is modified in disease. These results indicate that direct and indirect mechanisms regulate localization of SMN in Cajal bodies.

  9. Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study

    PubMed Central

    Tiziano, Francesco D; Lomastro, Rosa; Di Pietro, Lorena; Barbara Pasanisi, Maria; Fiori, Stefania; Angelozzi, Carla; Abiusi, Emanuela; Angelini, Corrado; Sorarù, Gianni; Gaiani, Alessandra; Mongini, Tiziana; Vercelli, Liliana; Vasco, Gessica; Vita, Giuseppe; Luca Vita, Gian; Messina, Sonia; Politano, Luisa; Passamano, Luigia; Di Gregorio, Grazia; Montomoli, Cristina; Orsi, Chiara; Campanella, Angela; Mantegazza, Renato; Morandi, Lucia

    2013-01-01

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognized (types I–III). All patients usually have 2–4 copies of a highly homologous gene (SMN2), which produces insufficient levels of functional survival motor neuron (SMN) protein due to the alternative splicing of exon 7. The availability of potential candidates to the treatment of SMA has raised a number of issues, including the availability of biomarkers. This study was aimed at evaluating whether the quantification of SMN2 products in peripheral blood is a suitable biomarker for SMA. Forty-five adult type III patients were evaluated by Manual Muscle Testing, North Star Ambulatory Assessment scale, 6-min walk test, myometry, forced vital capacity, and dual X-ray absorptiometry. Molecular assessments included SMN2 copy number, levels of full-length SMN2 (SMN2-fl) transcripts and those lacking exon 7 and SMN protein. Clinical outcome measures strongly correlated to each other. Lean body mass correlated inversely with years from diagnosis and with several aspects of motor performance. SMN2 copy number and SMN protein levels were not associated with motor performance or transcript levels. SMN2-fl levels correlated with motor performance in ambulant patients. Our results indicate that SMN2-fl levels correlate with motor performance only in patients preserving higher levels of motor function, whereas motor performance was strongly influenced by disease duration and lean body mass. If not taken into account, the confounding effect of disease duration may impair the identification of potential SMA biomarkers. PMID:23073312

  10. Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology.

    PubMed

    Comley, Laura H; Nijssen, Jik; Frost-Nylen, Johanna; Hedlund, Eva

    2016-05-01

    Neuromuscular junctions are primary pathological targets in the lethal motor neuron diseases spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Synaptic pathology and denervation of target muscle fibers has been reported prior to the appearance of clinical symptoms in mouse models of both diseases, suggesting that neuromuscular junctions are highly vulnerable from the very early stages, and are a key target for therapeutic intervention. Here we examined neuromuscular pathology longitudinally in three clinically relevant muscle groups in mouse models of ALS and SMA in order to assess their relative vulnerabilities. We show for the first time that neuromuscular junctions of the extraocular muscles (responsible for the control of eye movement) were resistant to degeneration in endstage SMA mice, as well as in late symptomatic ALS mice. Tongue muscle neuromuscular junctions were also spared in both animal models. Conversely, neuromuscular junctions of the lumbrical muscles of the hind-paw were vulnerable in both SMA and ALS, with a loss of neuronal innervation and shrinkage of motor endplates in both diseases. Thus, the pattern of selective vulnerability was conserved across these two models of motor neuron disease. However, the first evidence of neuromuscular pathology occurred at different timepoints of disease progression, with much earlier evidence of presynaptic involvement in ALS, progressing to changes on the postsynaptic side. Conversely, in SMA changes appeared concomitantly at the neuromuscular junction, suggesting that mechanisms of neuromuscular disruption are distinct in these diseases. J. Comp. Neurol. 524:1424-1442, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

  11. Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy.

    PubMed

    Armbruster, Nicole; Lattanzi, Annalisa; Jeavons, Matthieu; Van Wittenberghe, Laetitia; Gjata, Bernard; Marais, Thibaut; Martin, Samia; Vignaud, Alban; Voit, Thomas; Mavilio, Fulvio; Barkats, Martine; Buj-Bello, Ana

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease. We administered the scAAV9-coSMN1 vector in the intracerebroventricular (ICV) space in a dose-escalating mode, and analyzed survival, vector biodistribution and SMN protein expression in the spinal cord and peripheral tissues. All treated mice showed a significant, dose-dependent rescue of lifespan and growth with a median survival of 346 days. Additional administration of vector by an intravenous route (ICV+IV) did not improve survival, and vector biodistribution analysis 90 days postinjection indicated that diffusion from the cerebrospinal fluid to the periphery was sufficient to rescue the SMA phenotype. These results support the preclinical development of SMN1 gene therapy by CSF vector delivery.

  12. The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy

    PubMed Central

    Arnold, W. David; McGovern, Vicki L.; Sanchez, Benjamin; Li, Jia; Corlett, Kaitlyn M.; Kolb, Stephen J.; Rutkove, Seward B.; Burghes, Arthur H.

    2016-01-01

    Background Significant advances in the development of SMN-restoring therapeutics have occurred since 2010 when very effective biological treatments were reported in mouse models of spinal muscular atrophy. As these treatments are applied in human clinical trials, there is pressing need to define quantitative assessments of disease progression, treatment stratification, and therapeutic efficacy. The electrophysiological measures Compound Muscle Action Potential and Motor Unit Number Estimation are reliable measures of nerve function. In both the SMNΔ7 mouse and a pig model of spinal muscular atrophy, early SMN restoration results in preservation of electrophysiological measures. Currently, clinical trials are underway in patients at post-symptomatic stages of disease progression. In this study, we present results from both early and delayed SMN restoration using clinically-relevant measures including electrical impedance myography, compound muscle action potential, and motor unit number estimation to quantify the efficacy and time-sensitivity of SMN-restoring therapy. Methods SMAΔ7 mice were treated via intracerebroventricular injection with antisense oligonucleotides targeting ISS-N1 to increase SMN protein from the SMN2 gene on postnatal day 2, 4, or 6 and compared with sham-treated spinal muscular atrophy and control mice. Compound muscle action potential and motor unit number estimation of the triceps surae muscles were performed at day 12, 21, and 30 by a single evaluator blinded to genotype and treatment. Similarly, electrical impedance myography was measured on the biceps femoris muscle at 12 days for comparison. Results Electrophysiological measures and electrical impedance myography detected significant differences at 12 days between control and late-treated (4 or 6 days) and sham-treated spinal muscular atrophy mice, but not in mice treated at 2 days(p<0.01). EIM findings paralleled and correlated with compound muscle action potential and motor unit

  13. Quantifiable diagnosis of muscular dystrophies and neurogenic atrophies through network analysis

    PubMed Central

    2013-01-01

    Background The diagnosis of neuromuscular diseases is strongly based on the histological characterization of muscle biopsies. However, this morphological analysis is mostly a subjective process and difficult to quantify. We have tested if network science can provide a novel framework to extract useful information from muscle biopsies, developing a novel method that analyzes muscle samples in an objective, automated, fast and precise manner. Methods Our database consisted of 102 muscle biopsy images from 70 individuals (including controls, patients with neurogenic atrophies and patients with muscular dystrophies). We used this to develop a new method, Neuromuscular DIseases Computerized Image Analysis (NDICIA), that uses network science analysis to capture the defining signature of muscle biopsy images. NDICIA characterizes muscle tissues by representing each image as a network, with fibers serving as nodes and fiber contacts as links. Results After a ‘training’ phase with control and pathological biopsies, NDICIA was able to quantify the degree of pathology of each sample. We validated our method by comparing NDICIA quantification of the severity of muscular dystrophies with a pathologist’s evaluation of the degree of pathology, resulting in a strong correlation (R = 0.900, P <0.00001). Importantly, our approach can be used to quantify new images without the need for prior ‘training’. Therefore, we show that network science analysis captures the useful information contained in muscle biopsies, helping the diagnosis of muscular dystrophies and neurogenic atrophies. Conclusions Our novel network analysis approach will serve as a valuable tool for assessing the etiology of muscular dystrophies or neurogenic atrophies, and has the potential to quantify treatment outcomes in preclinical and clinical trials. PMID:23514382

  14. GRS defective axonal distribution as a potential contributor to distal spinal muscular atrophy type V pathogenesis in a new model of GRS-associated neuropathy.

    PubMed

    Seo, Ah Jung; Park, Byung Sun; Jung, Junyang

    2014-11-01

    Distal spinal muscular atrophy type V (dSMA-V), a hereditary axonal neuropathy, is a glycyl-tRNA synthetase (GRS)-associated neuropathy caused by a mutation in GRS. In this study, using an adenovirus vector system equipped with a neuron-specific promoter, we constructed a new GRS-associated neuropathy mouse model. We found that wild-type GRS (WT) is distributed in peripheral axons, dorsal root ganglion (DRG) cell bodies, central axon terminals and motor neuron cell bodies in the mouse model. In contrast, the L129P mutant GRS was localized in DRG and motor neuron cell bodies. Thus, we propose that the disease-causing L129P mutant is linked to a distribution defect in peripheral nerves in vivo.

  15. A Comparative Study of SMN Protein and mRNA in Blood and Fibroblasts in Patients with Spinal Muscular Atrophy and Healthy Controls

    PubMed Central

    Wadman, Renske I.; Stam, Marloes; Jansen, Marc D.; van der Weegen, Yana; Wijngaarde, Camiel A.; Harschnitz, Oliver; Sodaar, Peter; Braun, Kees P. J.; Dooijes, Dennis; Lemmink, Henny H.; van den Berg, Leonard H.; van der Pol, W. Ludo

    2016-01-01

    Background Clinical trials to test safety and efficacy of drugs for patients with spinal muscular atrophy (SMA) are currently underway. Biomarkers that document treatment-induced effects are needed because disease progression in childhood forms of SMA is slow and clinical outcome measures may lack sensitivity to detect meaningful changes in motor function in the period of 1–2 years of follow-up during randomized clinical trials. Objective To determine and compare SMN protein and mRNA levels in two cell types (i.e. PBMCs and skin-derived fibroblasts) from patients with SMA types 1–4 and healthy controls in relation to clinical characteristics and SMN2 copy numbers. Materials and methods We determined SMN1, SMN2-full length (SMN2-FL), SMN2-delta7 (SMN2-Δ7), GAPDH and 18S mRNA levels and SMN protein levels in blood and fibroblasts from a total of 150 patients with SMA and 293 healthy controls using qPCR and ELISA. We analyzed the association with clinical characteristics including disease severity and duration, and SMN2 copy number. Results SMN protein levels in PBMCs and fibroblasts were higher in controls than in patients with SMA (p<0.01). Stratification for SMA type did not show differences in SMN protein (p>0.1) or mRNA levels (p>0.05) in either cell type. SMN2 copy number was associated with SMN protein levels in fibroblasts (p = 0.01), but not in PBMCs (p = 0.06). Protein levels in PBMCs declined with age in patients (p<0.01) and controls (p<0.01)(power 1-beta = 0.7). Ratios of SMN2-Δ7/SMN2-FL showed a broad range, primarily explained by the variation in SMN2-Δ7 levels, even in patients with a comparable SMN2 copy number. Levels of SMN2 mRNA did not correlate with SMN2 copy number, SMA type or age in blood (p = 0.7) or fibroblasts (p = 0.09). Paired analysis between blood and fibroblasts did not show a correlation between the two different tissues with respect to the SMN protein or mRNA levels. Conclusions SMN protein levels differ considerably between

  16. The spinal muscular atrophy with pontocerebellar hypoplasia gene VRK1 regulates neuronal migration through an amyloid-β precursor protein-dependent mechanism.

    PubMed

    Vinograd-Byk, Hadar; Sapir, Tamar; Cantarero, Lara; Lazo, Pedro A; Zeligson, Sharon; Lev, Dorit; Lerman-Sagie, Tally; Renbaum, Paul; Reiner, Orly; Levy-Lahad, Ephrat

    2015-01-21

    Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH) is an infantile SMA variant with additional manifestations, particularly severe microcephaly. We previously identified a nonsense mutation in Vaccinia-related kinase 1 (VRK1), R358X, as a cause of SMA-PCH. VRK1-R358X is a rare founder mutation in Ashkenazi Jews, and additional mutations in patients of different origins have recently been identified. VRK1 is a nuclear serine/threonine protein kinase known to play multiple roles in cellular proliferation, cell cycle regulation, and carcinogenesis. However, VRK1 was not known to have neuronal functions before its identification as a gene mutated in SMA-PCH. Here we show that VRK1-R358X homozygosity results in lack of VRK1 protein, and demonstrate a role for VRK1 in neuronal migration and neuronal stem cell proliferation. Using shRNA in utero electroporation in mice, we show that Vrk1 knockdown significantly impairs cortical neuronal migration, and affects the cell cycle of neuronal progenitors. Expression of wild-type human VRK1 rescues both proliferation and migration phenotypes. However, kinase-dead human VRK1 rescues only the migration impairment, suggesting the role of VRK1 in neuronal migration is partly noncatalytic. Furthermore, we found that VRK1 deficiency in human and mouse leads to downregulation of amyloid-β precursor protein (APP), a known neuronal migration gene. APP overexpression rescues the phenotype caused by Vrk1 knockdown, suggesting that VRK1 affects neuronal migration through an APP-dependent mechanism.

  17. In Vitro and In Vivo Modeling of Spinal and Bulbar Muscular Atrophy.

    PubMed

    Pennuto, Maria; Basso, Manuela

    2016-03-01

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease characterized by late-onset, progressive degeneration of lower motor neurons and skeletal muscle atrophy. SBMA is caused by expansions of a CAG trinucleotide repeat in the gene encoding the androgen receptor (AR). One striking feature of SBMA is sex specificity: SBMA fully manifests only in males, whereas females show subclinical or mild disease manifestations even when homozygous for the mutation. Since the identification of the mutation responsible for SBMA in 1991, several cell and animal models have been developed to recapitulate the main features of disease in vitro and in vivo. In this review, we describe the most widely used cellular and animal models of SBMA, highlighting advantages and disadvantages in the use of these models to gain mechanistic and therapeutic insights into SBMA.

  18. Clinical features and molecular mechanisms of spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Katsuno, Masahisa; Banno, Haruhiko; Suzuki, Keisuke; Adachi, Hiroaki; Tanaka, Fumiaki; Sobue, Gen

    2010-01-01

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of this disease is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. Lower motor neurons in the anterior horn of the spinal cord and those in the brainstem motor nuclei are predominantly affected in SBMA, and other neuronal and nonneuronal tissues are also widely involved to some extent. Testosterone-dependent nuclear accumulation of the pathogenic AR protein has been considered to be a fundamental step of neurodegenerative process, which is followed by several molecular events such as transcriptional dysregulation, axonal transport disruption and mitochondrial dysfunction. Results of animal studies suggest that androgen deprivation and activation of protein quality control systems are potential therapies for SBMA.

  19. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: New insights into molecular mechanisms responsible for the disease

    SciTech Connect

    Hahnen, E.; Schoenling, J.; Zerres, K.

    1996-11-01

    Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor-neuron gene (SMN), a strong candidate for SMA, is present in two highly homologous copies (telSMN and cenSMN) within the SMA region. Only five nucleotide differences within the region between intron 6 and exon 8 distinguish these homologues. Independent of the severity of the disease, 90%-98% of all SMA patients carry homozygous deletions in telSMN, affecting either exon 7 or both exons 7 and 8. We present the molecular analysis of 42 SMA patients who carry homozygous deletions of telSMN exon 7 but not of exon 8. The question arises whether in these cases the telSMN is truncated upstream of exon 8 or whether hybrid SMN genes exist that are composed of centromeric and telomeric sequences. By a simple PCR-based assay we demonstrate that in each case the remaining telSMN exon 8 is part of a hybrid SMN gene. Sequencing of cloned hybrid SMN genes from seven patients revealed the same composition in all but two patients: the base-pair differences in introns 6 and 7 and exon 7 are of centromeric origin whereas exon 8 is of telomeric origin. Nonetheless, haplotype analysis with polymorphic multicopy markers, Ag1-CA and C212, localized at the 5{prime} end of the SMN genes, suggests different mechanisms of occurrence, unequal rearrangements, and gene conversion involving both copies of the SMN genes. In approximately half of all patients, we identified a consensus haplotype, suggesting a common origin. Interestingly, we identified a putative recombination hot spot represented by recombination-simulating elements (TGGGG and TGAGGT) in exon 8 that is homologous to the human deletion-hot spot consensus sequence in the immunoglobulin switch region, the {alpha}-globin cluster, and the polymerase {alpha} arrest sites. This may explain why independent hybrid SMN genes show identical sequences. 35 refs., 4 figs., 1 tab.

  20. Atrophy, fibrosis, and increased PAX7-positive cells in pharyngeal muscles of oculopharyngeal muscular dystrophy patients.

    PubMed

    Gidaro, Teresa; Negroni, Elisa; Perié, Sophie; Mirabella, Massimiliano; Lainé, Jeanne; Lacau St Guily, Jean; Butler-Browne, Gillian; Mouly, Vincent; Trollet, Capucine

    2013-03-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited dystrophy caused by an abnormal trinucleotide repeat expansion in the poly(A)-binding-protein-nuclear 1 (PABPN1) gene. Primary muscular targets of OPMD are the eyelid elevator and pharyngeal muscles, including the cricopharyngeal muscle (CPM), the progressive involution of which leads to ptosis and dysphagia, respectively. To understand the consequences of PABPN1 polyalanine expansion in OPMD, we studied muscle biopsies from 14 OPMD patients, 3 inclusion body myositis patients, and 9 healthy controls. In OPMD patient CPM (n = 6), there were typical dystrophic features with extensive endomysial fibrosis and marked atrophy of myosin heavy-chain IIa fibers. There were more PAX7-positive cells in all CPM versus other muscles (n = 5, control; n = 3, inclusion body myositis), and they were more numerous in OPMD CPM versus control normal CPM without any sign of muscle regeneration. Intranuclear inclusions were present in all OPMD muscles but unaffected OPMD patient muscles (i.e. sternocleidomastoid, quadriceps, or deltoid; n = 14) did not show evidence of fibrosis, atrophy, or increased PAX7-positive cell numbers. These results suggest that the specific involvement of CPM in OPMD might be caused by failure of the regenerative response with dysfunction of PAX7-positive cells and exacerbated fibrosis that does not correlate with the presence of PABPN1 inclusions.

  1. Linking amyotrophic lateral sclerosis and spinal muscular atrophy through RNA-transcriptome homeostasis: a genomics perspective.

    PubMed

    Gama-Carvalho, Margarida; L Garcia-Vaquero, Marina; R Pinto, Francisco; Besse, Florence; Weis, Joachim; Voigt, Aaron; Schulz, Jörg B; De Las Rivas, Javier

    2017-04-01

    In this review, we present our most recent understanding of key biomolecular processes that underlie two motor neuron degenerative disorders, amyotrophic lateral sclerosis, and spinal muscular atrophy. We focus on the role of four multifunctional proteins involved in RNA metabolism (TDP-43, FUS, SMN, and Senataxin) that play a causal role in these diseases. Recent results have led to a novel scenario of intricate connections between these four proteins, bringing transcriptome homeostasis into the spotlight as a common theme in motor neuron degeneration. We review reported functional and physical interactions between these four proteins, highlighting their common association with nuclear bodies and small nuclear ribonucleoprotein particle biogenesis and function. We discuss how these interactions are turning out to be particularly relevant for the control of transcription and chromatin homeostasis, including the recent identification of an association between SMN and Senataxin required to ensure the resolution of DNA-RNA hybrid formation and proper termination by RNA polymerase II. These connections strongly support the existence of common pathways underlying the spinal muscular atrophy and amyotrophic lateral sclerosis phenotype. We also discuss the potential of genome-wide expression profiling, in particular RNA sequencing derived data, to contribute to unravelling the underlying mechanisms. We provide a review of publicly available datasets that have addressed both diseases using these approaches, and highlight the value of investing in cross-disease studies to promote our understanding of the pathways leading to neurodegeneration.

  2. Mutant superoxide dismutase 1 (SOD1), a cause of amyotrophic lateral sclerosis, disrupts the recruitment of SMN, the spinal muscular atrophy protein to nuclear Cajal bodies.

    PubMed

    Kariya, Shingo; Re, Diane B; Jacquier, Arnaud; Nelson, Katelyn; Przedborski, Serge; Monani, Umrao R

    2012-08-01

    Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are among the most common motor neuron diseases to afflict the human population. A deficiency of the survival of motor neuron (SMN) protein causes SMA and is also reported to be an exacerbating factor in the development of ALS. However, pathways linking the two diseases have yet to be defined and it is not clear precisely how the pathology of ALS is aggravated by reduced SMN or whether mutant proteins underlying familial forms of ALS interfere with SMN-related biochemical pathways to exacerbate the neurodegenerative process. In this study, we show that mutant superoxide dismutase-1 (SOD1), a cause of familial ALS, profoundly alters the sub-cellular localization of the SMN protein, preventing the formation of nuclear 'gems' by disrupting the recruitment of the protein to Cajal bodies. Overexpressing the SMN protein in mutant SOD1 mice, a model of familial ALS, alleviates this phenomenon, most likely in a cell-autonomous manner, and significantly mitigates the loss of motor neurons in the spinal cord and in culture dishes. In the mice, the onset of the neuromuscular phenotype is delayed and motor function enhanced, suggestive of a therapeutic benefit for ALS patients treated with agents that augment the SMN protein. Nevertheless, this finding is tempered by an inability to prolong survival, a limitation most likely imposed by the inexorable denervation that characterizes ALS and eventually disrupts the neuromuscular synapses even in the presence of increased SMN.

  3. Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy.

    PubMed

    Garcia, Eric L; Wen, Ying; Praveen, Kavita; Matera, A Gregory

    2016-08-01

    Survival motor neuron (SMN) functions in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) that catalyze pre-mRNA splicing. Here, we used disruptions in Smn and two additional snRNP biogenesis genes, Phax and Ars2, to classify RNA processing differences as snRNP-dependent or gene-specific in Drosophila Phax and Smn mutants exhibited comparable reductions in snRNAs, and comparison of their transcriptomes uncovered shared sets of RNA processing changes. In contrast, Ars2 mutants displayed only small decreases in snRNA levels, and RNA processing changes in these mutants were generally distinct from those identified in Phax and Smn animals. Instead, RNA processing changes in Ars2 mutants support the known interaction of Ars2 protein with the cap-binding complex, as splicing changes showed a clear bias toward the first intron. Bypassing disruptions in snRNP biogenesis, direct knockdown of spliceosomal proteins caused similar changes in the splicing of snRNP-dependent events. However, these snRNP-dependent events were largely unaltered in three Smn mutants expressing missense mutations that were originally identified in human spinal muscular atrophy (SMA) patients. Hence, findings here clarify the contributions of Phax, Smn, and Ars2 to snRNP biogenesis in Drosophila, and loss-of-function mutants for these proteins reveal differences that help disentangle cause and effect in SMA model flies.

  4. [Triplet repeat disease, with particular emphasis of spinal and bulbar muscular atrophy (SBMA)].

    PubMed

    Sobue, G

    2000-12-01

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked neurodegenerative disease caused by the expansion of a CAG repeat in the first exon of the androgen receptor (AR) gene. To date, eight CAG-repeat diseases have been identified, including spinal and bulbar muscular atrophy (SBMA). Huntington's disease (HD), dentatorubralpallidoluysian atrophy (DRPLA) and five spinocerebellar ataxias (SCAs 1, 2, 3, 6, 7). These disorders likely share a common pathogenesis caused by the gain of a toxic function associated with the expanded polyglutamine tract. Several mechanisms have been postulated as a pathogenic process for neurodegeneration caused by the expanded polyglutamine tract. Processing of the polyglutamine containing proteins by proteases liberate truncated polyglutamine tract, which may cause neurodegeneration as demonstrated in transgenic mice and transfected cells. In addition to cellular toxicity, truncated and expanded polyglutamine tracts have been shown to form intranuclear inclusions (NI). The NIs formed by the disease protein are a common pathological feature of these diseases. In SBMA, NIs containing AR protein have been observed in regions of SBMA central nervous system susceptible to degenerations. Transcriptional factors or their cofactors, such as cerb or creb-binding protein (CBP) sequestrated in the NI may alter the major intracellular transcriptional signal transduction, and ultimately may result in neuronal degeneration. The ubiquitin-proteasome pathway may also contribute to the pathogenesis of CAG-repeat diseases. As for the therapeutic strategies, many possibilities have been demonstrated. Overexpression of Hsp70 and Hsp40 chaperones act together to protect a cultured neuronal cell model of SBMA from a cellular toxicity of expanded polyglutamine tract.

  5. Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy.

    PubMed

    Chua, Jason P; Reddy, Satya L; Merry, Diane E; Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen; Robins, Diane M; Lieberman, Andrew P

    2014-03-01

    Spinobulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract in exon 1 of the androgen receptor (AR) gene. SBMA demonstrates androgen-dependent toxicity due to unfolding and aggregation of the mutant protein. There are currently no disease-modifying therapies, but of increasing interest for therapeutic targeting is autophagy, a highly conserved cellular process mediating protein quality control. We have previously shown that genetic manipulations inhibiting autophagy diminish skeletal muscle atrophy and extend the lifespan of AR113Q knock-in mice. In contrast, manipulations inducing autophagy worsen muscle atrophy, suggesting that chronic, aberrant upregulation of autophagy contributes to pathogenesis. Since the degree to which autophagy is altered in SBMA and the mechanisms responsible for such alterations are incompletely defined, we sought to delineate autophagic status in SBMA using both cellular and mouse models. Here, we confirm that autophagy is induced in cellular and knock-in mouse models of SBMA and show that the transcription factors transcription factor EB (TFEB) and ZKSCAN3 operate in opposing roles to underlie these changes. We demonstrate upregulation of TFEB target genes in skeletal muscle from AR113Q male mice and SBMA patients. Furthermore, we observe a greater response in AR113Q mice to physiological stimulation of autophagy by both nutrient starvation and exercise. Taken together, our results indicate that transcriptional signaling contributes to autophagic dysregulation and provides a mechanistic framework for the pathologic increase of autophagic responsiveness in SBMA.

  6. Study of 962 patients indicates progressive muscular atrophy is a form of ALS

    PubMed Central

    Kim, W -K.; Liu, X; Sandner, J; Pasmantier, M; Andrews, J; Rowland, L P.; Mitsumoto, H

    2009-01-01

    Background: Progressive muscular atrophy (PMA) is clinically characterized by signs of lower motor neuron dysfunction and may evolve into amyotrophic lateral sclerosis (ALS). Whether PMA is actually a form of ALS has important consequences clinically and for therapeutic trials. We compared the survival of patients with PMA or ALS to analyze the clinical features that influence survival in PMA. Methods: We reviewed the medical records of patients with PMA (n = 91) or ALS (n = 871) from our ALS Center and verified survival by telephoning the families or using the National Death Index. Results: In PMA, patients were more likely to be male (p < 0.001), older (p = 0.007), and lived longer (p = 0.01) than in ALS. Cox model analysis suggested that the risk of death increased with age at onset in both patient groups (p < 0.005). Upper motor neuron (UMN) signs developed in 22% of patients with PMA within 61 months after diagnosis. Demographic and other clinical variables did not differ at diagnosis between those who did or did not develop UMN signs. In PMA, the factors present at diagnosis that predicted shorter survival were greater number of body regions affected, lower forced vital capacity, and lower ALS Functional Rating Scale–Revised score. Noninvasive ventilation and gastrostomy were used frequently in PMA. Conclusion: Although patients with progressive muscular atrophy (PMA) tended to live longer than those with amyotrophic lateral sclerosis (ALS), shorter survival in PMA is associated with the same risk factors that predict poor survival in ALS. Additionally, PMA is relentlessly progressive, and UMN involvement can occur, as also reported in imaging and postmortem studies. For these reasons, PMA should be considered a form of ALS. GLOSSARY ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale–Revised; CI = confidence interval; FVC = forced vital capacity; HR = hazard ratio; LMN = lower motor neuron; MND = motor neuron disease; MRS

  7. Juvenile distal spinal muscular atrophy of upper extremities in Chinese males: a single fibre electromyographic study of arms and legs.

    PubMed Central

    Chan, Y W; Kay, R; Schwartz, M S

    1991-01-01

    Single fibre electromyography (SFEMG) was performed on six young Chinese males with distal spinal muscular atrophy of the upper extremities. Abnormal SFEMG findings of increased fibre density, jitter and blocking were recorded over both arms and legs in all patients, suggesting a more generalised disturbance than would appear clinically. Images PMID:2019844

  8. Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy.

    PubMed

    Rinaldi, Carlo; Bott, Laura C; Chen, Ke-lian; Harmison, George G; Katsuno, Masahisa; Sobue, Gen; Pennuto, Maria; Fischbeck, Kenneth H

    2012-12-06

    Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by polyglutamine expansion in the androgen receptor. Patients develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations. Affected individuals often show gynecomastia, testicular atrophy and reduced fertility as a result of mild androgen insensitivity. No effective disease-modifying therapy is currently available for this disease. Our recent studies have demonstrated that insulinlike growth factor (IGF)-1 reduces the mutant androgen receptor toxicity through activation of Akt in vitro, and spinal and bulbar muscular atrophy transgenic mice that also overexpress a noncirculating muscle isoform of IGF-1 have a less severe phenotype. Here we sought to establish the efficacy of daily intraperitoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and, to reflect the clinical settings, the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1-treated transgenic mice showed improved motor performance, attenuated weight loss and increased survival. Our results suggest that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicate that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease.

  9. Linkage analysis in the spinal muscular atrophy type of facioscapulohumeral disease.

    PubMed Central

    Siddique, T; Roper, H; Pericak-Vance, M A; Shaw, J; Warner, K L; Hung, W Y; Phillips, K L; Lunt, P; Cumming, W J; Roses, A D

    1989-01-01

    Facioscapulohumeral disease is probably a heterogeneous disorder. We have ascertained and sampled two multigeneration families with the neurogenic form of this disorder, considered to be a type of spinal muscular atrophy (FSHSMA). The two families have 36 affected members. Linkage studies with 10 expressed and seven DNA restriction fragment length polymorphism (RFLP) markers failed to show significant linkage (Zmax greater than or equal to 3.00). However, two areas of probable linkage were defined on chromosomes 1p and 4q with the markers MNS (Zmax = 1.47 at theta max = 0.10) and PGM1 (Zmax = 0.94 at theta max = 0.001) respectively. We are using additional RFLPs from these and other areas of the human genome to screen these families for linkage to FSHSMA. PMID:2570155

  10. Clinical Trials in Spinal and Bulbar Muscular Atrophy-Past, Present, and Future.

    PubMed

    Weydt, Patrick; Sagnelli, Anna; Rosenbohm, Angela; Fratta, Pietro; Pradat, Pierre-François; Ludolph, Albert C; Pareyson, Davide

    2016-03-01

    Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy's disease, is a rare adult-onset lower motor neuron disorder with a classic X-linked inheritance pattern. It is caused by the abnormal expansion of the CAG-repeat tract in the androgen receptor gene. Despite important progress in the understanding of the molecular pathogenesis and the availability of a broad set of model organisms, successful translation of these insights into clinical interventions remains elusive. Here we review the available information on clinical trials in SBMA and discuss the challenges and pitfalls that impede therapy development. Two important factors are the variability of the complex neuro-endocrinological phenotype and the comparatively low incidence of the disease that renders recruitment for clinical trials demanding. We propose that these challenges can be and need to be overcome by fostering closer collaborations between clinical research centers, the patient communities and the industry and non-industry sponsors of clinical trials.

  11. Spinal muscular atrophy with respiratory distress syndrome (SMARD1): Case report and review of literature

    PubMed Central

    Lingappa, Lokesh; Shah, Nikit; Motepalli, Ananth Sagar; Shaik, Farhan

    2016-01-01

    Spinal muscular atrophy with respiratory distress syndrome (SMARD1) is a rare cause of early infantile respiratory failure and death. No cases have been currently described from India. Two low-birth-weight infants presented prior to 6 months of age with recurrent apnea and respiratory distress. Both required prolonged ventilation, and had distal arthrogryposis and diaphragmatic eventration. Nerve conduction study revealed motor sensory axonopathy. Genetic testing confirmed mutations in immunoglobulin mu binding protein (IGHMBP2). These two cases establish presence of SMARD1 in our population. Both infants died on discontinuation of ventilation. Antenatal diagnoses done in one pregnancy. Though rare, high index of suspicion is essential in view of poor outcome and aid antenatal counseling. PMID:27570397

  12. Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy.

    PubMed

    Todd, Tiffany W; Kokubu, Hiroshi; Miranda, Helen C; Cortes, Constanza J; La Spada, Albert R; Lim, Janghoo

    2015-08-26

    Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR) protein. Despite extensive research, the exact pathogenic mechanisms underlying SBMA remain elusive. In this study, we present evidence that Nemo-like kinase (NLK) promotes disease pathogenesis across multiple SBMA model systems. Most remarkably, loss of one copy of Nlk rescues SBMA phenotypes in mice, including extending lifespan. We also investigated the molecular mechanisms by which NLK exerts its effects in SBMA. Specifically, we have found that NLK can phosphorylate the mutant polyglutamine-expanded AR, enhance its aggregation, and promote AR-dependent gene transcription by regulating AR-cofactor interactions. Furthermore, NLK modulates the toxicity of a mutant AR fragment via a mechanism that is independent of AR-mediated gene transcription. Our findings uncover a crucial role for NLK in controlling SBMA toxicity and reveal a novel avenue for therapy development in SBMA.

  13. [Somatic mosaicism of expanded CAG trinucleotide repeat in spinal and bulbar muscular atrophy (SBMA)].

    PubMed

    Tanaka, F; Ito, Y; Sobue, G

    1999-04-01

    The CAG repeat in spinal and bulbar muscular atrophy (SBMA) is relatively stable in mitotic and meiotic processes as compared with other CAG repeat diseases. Previous reports indicate that SBMA does not manifest somatic mosaicism. However, detailed analysis in various tissues from 20 SBMA including 4 autopsied patients revealed the presence of the tissue-specific pattern of mosaicism. The prominent somatic mosaicism was observed in the cardiac and skeletal muscles, which are predominantly composed of postmitotic cells, and in the skin, prostate, and testis. The central nervous system (CNS) tissues, liver, and spleen showed smallest mosaicism. Such tissue-specific pattern of somatic mosaicism in SBMA is not explained by cell composition with different cell turnover rates. Other cell specific factors are likely more important for the somatic mosaicism in SBMA.

  14. Spinal and bulbar muscular atrophy (SBMA): somatic stability of an expanded CAG repeat in fetal tissues.

    PubMed

    Jedele, K B; Wahl, D; Chahrokh-Zadeh, S; Wirtz, A; Murken, J; Holinski-Feder, E

    1998-08-01

    Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked motor neuron degenerative disease caused by an expanded trinucleotide repeat. Unlike most other trinucleotide repeat diseases, SBMA shows limited meiotic instability, and evidence thus far indicates absence of somatic instability in adults. Data regarding the presence of fetal tissue somatic mosaicism is unavailable. We present a family in which a woman whose father had SBMA requested prenatal testing. After informed consent. molecular genetic evaluation showed the male fetus to carry the SBMA repeat elongation. Testing of fetal tissues after elective pregnancy termination showed no somatic mosaicism in the CAG repeat length. This is the first report of molecular genetic analysis of multiple tissues in an affected fetus, and only the second report of prenatal diagnosis in SBMA.

  15. [Anti-androgen therapy for spinal and bulbar muscular atrophy (SBMA)].

    PubMed

    Katsuno, Masahisa; Banno, Haruhiko; Suzuki, Keisuke; Hashizume, Atsushi; Adachi, Hiroaki; Tanaka, Fumiaki; Sobue, Gen

    2012-01-01

    Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is an adult-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The testosterone-dependent nuclear accumulation of polyglutamine-expanded AR protein is central to the pathogenesis. This hypothesis is supported by pre-clinical studies showing that testosterone deprivation ameliorates motor neuron degeneration in animal modes of SBMA. In a randomized placebo-controlled multi-centric clinical trial, leuprorelin, which suppresses secretion of testosterone, showed no definite effect on motor functions, although there was the improvement of swallowing function in a subgroup of patients whose disease duration was less than 10 years. Elucidation of the entire disease mechanism, early initiation of therapeutic intervention, and sensitive outcome measures to evaluate drug effect appear to be the key to a successful translational research on SBMA.

  16. X-linked lethal infantile spinal muscular atrophy: From clinical description to molecular mapping

    SciTech Connect

    Baumbach, L.; Schiavi, A.

    1994-09-01

    The proximal spinal muscular atrophies (PSMA), one of the most common forms of lower motor neuron disease in children, are characterized by progressive muscle weakness due to loss of anterior horn cells. All three autosomal recessive forms have been mapped to chromosome 5q11.2-11.3, implying an allelic association between these disorders. Recent evidence from our laboratories, as well as others, suggests that a distinct form of lethal neonatal spinal muscular atrophy, associated with early onset contractures, is determined by a gene on the X chromosome. We report our efforts in mapping this disease locus. Our original studies have focused on two unrelated multigenerational families with similar clinical presentations of severe hypotonia, muscle weakness, and a disease course similar to Werdnig Hoffman except for the additional finding of congenital or early onset contractures. Muscle biopsy and/or autopsy were indicative of anterior horn cell loss in affected males. Disease occurrence in each of the families was consistent with an X-linked recessive mode of inheritance. Subsequently, two additional families have been identified, as well as several sporadic male cases. Linkage analysis has been completed in one of these families using highly polymorphic repeats dispersed 10 cM on the X chromosome. Interpretation of results was achieved using an automated data acquisition program. Analysis of over 300 haplotypes generated using PCR-based DNA markers have identified two 16 cM regions on Xp with complete concordance to the disease phenotype. Our currents efforts are focused on the region surrounding the Kallman gene, in attempts to better define a candidate region, as well as analyze possible candidate genes within this region.

  17. Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Banno, Haruhiko; Katsuno, Masahisa; Suzuki, Keisuke; Tanaka, Fumiaki; Sobue, Gen

    2012-07-01

    Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an adult-onset, X-linked motor neuron disease characterized by muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA is caused by the expansion of a CAG triplet repeat, encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The histopathological finding in SBMA is the loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. There is no established disease-modifying therapy for SBMA. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation and/or stabilization of the pathogenic AR. Heat shock proteins, the ubiquitin-proteasome system and transcriptional regulation are also potential targets for development of therapy for SBMA. Among these therapeutic approaches, the luteinizing hormone-releasing hormone analogue, leuprorelin, prevents nuclear translocation of aberrant AR proteins, resulting in a significant improvement of disease phenotype in a mouse model of SBMA. In a phase 2 clinical trial of leuprorelin, the patients treated with this drug exhibited decreased mutant AR accumulation in scrotal skin biopsy. Phase 3 clinical trial showed the possibility that leuprorelin treatment is associated with improved swallowing function particularly in patients with a disease duration less than 10 years. These observations suggest that pharmacological inhibition of the toxic accumulation of mutant AR is a potential therapy for SBMA.

  18. [Disease-modifying therapy for spinal and bulbar muscular atrophy (SBMA)].

    PubMed

    Suzuki, Keisuke; Banno, Haruhiko; Katsuno, Masahisa; Adachi, Hiroaki; Tanaka, Fumiaki; Sobue, Gen

    2012-03-01

    Neurodegenerative diseases have long been construed as incurable disorders. However, therapeutic developments for these diseases are now facing a turning point, that is, analyses of cellular and animal models have provided insights into the pathogenesis of neurodegenerative diseases and have indicated rational therapeutic approaches. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease characterized by slowly progressive muscle weakness and atrophy. This disease is caused by the expansion of a trinucleotide CAG repeat within the androgen receptor (AR) gene. The results of animal studies suggest that testosterone-dependent nuclear accumulation of the pathogenic AR protein is a fundamental step in the neurodegenerative process. Androgen deprivation with a luteinizing hormone-releasing hormone (LHRH) analogue suppresses the toxicity of the mutant AR in animal models of SBMA. In a phase 3 trial, 48 weeks of treatment with leuprorelin acetate, an LHRH analogue, tended to improve swallowing function in a subgroup of SBMA patients with disease duration less than 10 years but did not significantly affect the total population. Disease duration might influence the efficacy of leuprorelin acetate, and therefore, a further clinical trial that involves sensitive outcome measures is in progress. Advances in basic and clinical research on SBMA are now paving the way for the clinical application of pathogenesis-targeting therapies. To optimize translational research related to the process of testing candidate therapies in humans, it is important to identify biomarkers that can be used as surrogate endpoints in clinical trials for neurodegenerative diseases.

  19. Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Katsuno, Masahisa; Adachi, Hiroaki; Waza, Masahiro; Banno, Haruhiko; Suzuki, Keisuke; Tanaka, Fumiaki; Doyu, Manabu; Sobue, Gen

    2006-07-01

    Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy of bulbar, facial, and limb muscles. The cause of SBMA is expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. SBMA chiefly occurs in adult males, whereas neurological symptoms are rarely detected in females having mutant AR gene. The cardinal histopathological finding of SBMA is loss of lower motor neurons in the anterior horn of spinal cord as well as in brainstem motor nuclei. Animal models carrying human mutant AR gene recapitulate polyglutamine-mediated motor neuron degeneration, providing clues to the pathogenesis of SBMA. There is increasing evidence that testosterone, the ligand of AR, plays a pivotal role in the pathogenesis of neurodegeneration in SBMA. The striking success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials. In addition, elucidation of pathophysiology using animal models leads to emergence of candidate drugs to treat this devastating disease: HSP inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Utilizing biomarkers such as scrotal skin biopsy would improve efficacy of clinical trials to verify the results from animal studies. Advances in basic and clinical researches on SBMA are now paving the way for clinical application of potential therapeutics.

  20. Pathogenesis-targeting therapeutics for spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Suzuki, Keisuke; Kastuno, Masahisa; Banno, Haruhiko; Sobue, Gen

    2009-08-01

    Spinal and bulbar muscular atrophy (SBMA) is an hereditary, adult-onset, lower motor neuron disease caused by an aberrant elongation of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. The main symptoms are slowly progressive muscle weakness and atrophy of bulbar, facial and limb muscles. The cardinal histopathological findings of SBMA are an extensive loss of lower motor neurons in the anterior horn of the spinal cord as well as in brainstem motor nuclei and intranuclear accumulations of mutant AR protein in the residual motor neurons. Androgen deprivation therapy rescues neuronal dysfunction in animal models of SBMA, suggesting that the molecular basis for motor neuron degeneration in this disorder is testosterone-dependent nuclear accumulation of the mutant AR. Suppression of disease progression by leuprorelin acetate has also been demonstrated in a phase 2 clinical trial. In addition, the clarification of pathophysiology leads to appearance of candidate drugs to treat this devastating disease: heat shock protein (HSP) inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Advances in basic and clinical research on SBMA are now paving the way for clinical application of pathogenesis-targeting therapeutics.

  1. [Molecular-targeted therapy for spinal and bulbar muscular atrophy (SBMA)].

    PubMed

    Sobue, Gen

    2010-11-01

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in males, whereas both heterozygous and homozygous females are usually asymptomatic. In a transgenic mouse model of SBMA, neuromuscular symptoms are markedly pronounced in the male mice, but far less severe in the female counterparts. Androgen deprivation through both surgical and chemical castration substantially suppresses nuclear accumulation of the pathogenic AR, and thereby improves symptoms in the male mice. Since the nuclear translocation of AR is ligand-dependent, testosterone appears to show toxic effects by accelerating nuclear translocation of the pathogenic AR. In a phase 2 clinical trial, 12-month treatment with leuprorelin significantly diminished the serum level of creatine kinase, and suppressed nuclear accumulation of the pathogenic AR. The ligand-dependent accumulation of the pathogenic AR, an initial step in the neurodegenerative process in SBMA, is followed by several downstream molecular events such as transcriptional dysregulation, axonal transport disruption, and mitochondrial insufficiency, indicating that both upstream and downstream molecular abnormalities should be corrected.

  2. Increased mitophagy in the skeletal muscle of spinal and bulbar muscular atrophy patients.

    PubMed

    Borgia, Doriana; Malena, Adriana; Spinazzi, Marco; Andrea Desbats, Maria; Salviati, Leonardo; Russell, Aaron P; Miotto, Giovanni; Tosatto, Laura; Pegoraro, Elena; Sorarù, Gianni; Pennuto, Maria; Vergani, Lodovica

    2017-01-13

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by polyglutamine expansion in the androgen receptor (AR) and characterized by the loss of lower motor neurons. Here we investigated pathological processes occurring in muscle biopsy specimens derived from SBMA patients and, as controls, age-matched healthy subjects and patients suffering from amyotrophic lateral sclerosis (ALS) and neurogenic atrophy. We detected atrophic fibers in the muscle of SBMA, ALS and neurogenic atrophy patients. In addition, SBMA muscle was characterized by the presence of a large number of hypertrophic fibers, with oxidative fibers having a larger size compared to glycolytic fibers. Polyglutamine-expanded AR expression was decreased in whole muscle, yet enriched in the nucleus, and localized to mitochondria. Ultrastructural analysis revealed myofibrillar disorganization and streaming in zones lacking mitochondria and degenerating mitochondria. Using molecular (mtDNA copy number), biochemical (citrate synthase and respiratory chain enzymes) and morphological (dark blue area in NADH-stained muscle cross sections) analyses, we found a depletion of the mitochondria associated with enhanced mitophagy. Mass spectrometry analysis revealed an increase of phosphatidylethanolamines and phosphatidylserines in mitochondria isolated from SBMA muscles, as well as a 50% depletion of cardiolipin associated with decreased expression of the cardiolipin synthase gene. These observations suggest a causative link between nuclear polyglutamine-expanded AR accumulation, depletion of mitochondrial mass, increased mitophagy and altered mitochondrial membrane composition in SBMA muscle patients. Given the central role of mitochondria in cell bioenergetics, therapeutic approaches towards improving the mitochondrial network are worth considering to support SBMA patients.

  3. Androgen-dependent impairment of myogenesis in spinal and bulbar muscular atrophy.

    PubMed

    Malena, Adriana; Pennuto, Maria; Tezze, Caterina; Querin, Giorgia; D'Ascenzo, Carla; Silani, Vincenzo; Cenacchi, Giovanna; Scaramozza, Annarita; Romito, Silvia; Morandi, Lucia; Pegoraro, Elena; Russell, Aaron P; Sorarù, Gianni; Vergani, Lodovica

    2013-07-01

    Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disease caused by expansion of a polyglutamine (polyQ) tract in the androgen receptor (AR). SBMA is triggered by the interaction between polyQ-AR and its natural ligands, testosterone and dihydrotestosterone (DHT). SBMA is characterized by the loss of lower motor neurons and skeletal muscle fasciculations, weakness, and atrophy. To test the hypothesis that the interaction between polyQ-AR and androgens exerts cell-autonomous toxicity in skeletal muscle, we characterized the process of myogenesis and polyQ-AR expression in DHT-treated satellite cells obtained from SBMA patients and age-matched healthy control subjects. Treatment with androgens increased the size and number of myonuclei in myotubes from control subjects, but not from SBMA patients. Myotubes from SBMA patients had a reduced number of nuclei, suggesting impaired myotube fusion and altered contractile structures. The lack of anabolic effects of androgens on myotubes from SBMA patients was not due to defects in myoblast proliferation, differentiation or apoptosis. DHT treatment of myotubes from SBMA patients increased nuclear accumulation of polyQ-AR and decreased the expression of interleukin-4 (IL-4) when compared to myotubes from control subjects. Following DHT treatment, exposure of myotubes from SBMA patients with IL-4 treatment rescued myonuclear number and size to control levels. This supports the hypothesis that androgens alter the fusion process in SBMA myogenesis. In conclusion, these results provide evidence of an androgen-dependent impairment of myogenesis in SBMA that could contribute to disease pathogenesis.

  4. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients.

    PubMed

    Atsuta, Naoki; Watanabe, Hirohisa; Ito, Mizuki; Banno, Haruhiko; Suzuki, Keisuke; Katsuno, Masahisa; Tanaka, Fumiaki; Tamakoshi, Akiko; Sobue, Gen

    2006-06-01

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motoneuron disease caused by a CAG-repeat expansion in the androgen receptor (AR) gene and for which no curative therapy exists. However, since recent research may provide opportunities for medical treatment, information concerning the natural history of SBMA would be beneficial in planning future clinical trials. We investigated the natural course of SBMA as assessed by nine activities of daily living (ADL) milestones in 223 Japanese SBMA patients (mean age at data collection = 55.2 years; range = 30-87 years) followed from 1 to 20 years. All the patients were diagnosed by genetic analysis. Hand tremor was an early event that was noticed at a median age of 33 years. Muscular weakness occurred predominantly in the lower limbs, and was noticed at a median age of 44 years, followed by the requirement of a handrail to ascend stairs at 49, dysarthria at 50, dysphagia at 54, use of a cane at 59 and a wheelchair at 61 years. Twenty-one of the patients developed pneumonia at a median age of 62 and 15 of them died at a median age of 65 years. The most common cause of death in these cases was pneumonia and respiratory failure. The ages at onset of each ADL milestone were strongly correlated with the length of CAG repeats in the AR gene. However CAG-repeat length did not correlate with the time intervals between each ADL milestone, suggesting that although the onset age of each ADL milestone depends on the CAG-repeat length in the AR gene, the rate of disease progression does not. The levels of serum testosterone, an important triggering factor for polyglutamine-mediated motoneuron degeneration, were maintained at relatively high levels even at advanced ages. These results provide beneficial information for future clinical therapeutic trials, although further detailed prospective studies are also needed.

  5. Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres.

    PubMed

    Trollet, Capucine; Anvar, Seyed Yahya; Venema, Andrea; Hargreaves, Iain P; Foster, Keith; Vignaud, Alban; Ferry, Arnaud; Negroni, Elisa; Hourde, Christophe; Baraibar, Martin A; 't Hoen, Peter A C; Davies, Janet E; Rubinsztein, David C; Heales, Simon J; Mouly, Vincent; van der Maarel, Silvère M; Butler-Browne, Gillian; Raz, Vered; Dickson, George

    2010-06-01

    Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)(8-13) expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets.

  6. Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene.

    PubMed

    Dlamini, Nomazulu; Josifova, Dragana J; Paine, Simon M L; Wraige, Elizabeth; Pitt, Matthew; Murphy, Amanda J; King, Andrew; Buk, Stefan; Smith, Frances; Abbs, Stephen; Sewry, Caroline; Jacques, Thomas S; Jungbluth, Heinz

    2013-05-01

    Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a rare lethal disorder linked to mutations in the UBA1 (previously UBE1) gene, encoding ubiquitin-activating enzyme 1 that has an important role in the ubiquitin-proteasome pathway. Published pathological reports are scarce. Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements. He had a myopathic face, profound weakness, multiple contractures and areflexia. Creatine kinase was moderately raised. Brain MRI showed non-specific symmetrical periventricular white matter changes. Neurophysiology revealed evidence of motor and sensory involvement and muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation. UBA1 sequencing revealed a novel hemizygous missense mutation (c.1670A>T; p.Glu557Val). He died from progressive respiratory failure at 4 months. On post mortem assessment, in addition to severe ventral motor neuron pathology, there was widespread involvement of the sensory system, as well as developmental and degenerative cerebellar abnormalities. In contrast to typical SMN1-associated SMA, the thalamus was unaffected. These findings indicate that SMAX2 is more accurately classified as a motor sensory neuronopathy rather than a pure anterior horn cell disorder. Ubiquitin-proteasome pathway defects may not only cause neurodegeneration but also affect normal neuronal development.

  7. Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy

    PubMed Central

    Maier, Verena K.; Davey, Roshni; Brennan, James; Li, Guangde; Brothers, John; Schwartz, Brian; Gordo, Susana; Kasper, Anne; Okamoto, Trevor R.; Johansson, Hans E.; Mandefro, Berhan; Sareen, Dhruv; Bialek, Peter; Chau, B. Nelson; Bhat, Balkrishen; Bullough, David; Barsoum, James

    2017-01-01

    Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive motor neuron loss and caused by mutations in SMN1 (Survival Motor Neuron 1). The disease severity inversely correlates with the copy number of SMN2, a duplicated gene that is nearly identical to SMN1. We have delineated a mechanism of transcriptional regulation in the SMN2 locus. A previously uncharacterized long noncoding RNA (lncRNA), SMN-antisense 1 (SMN-AS1), represses SMN2 expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus. Chemically modified oligonucleotides that disrupt the interaction between SMN-AS1 and PRC2 inhibit the recruitment of PRC2 and increase SMN2 expression in primary neuronal cultures. Our approach comprises a gene-up-regulation technology that leverages interactions between lncRNA and PRC2. Our data provide proof-of-concept that this technology can be used to treat disease caused by epigenetic silencing of specific loci. PMID:28193854

  8. Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy.

    PubMed

    Woo, Caroline J; Maier, Verena K; Davey, Roshni; Brennan, James; Li, Guangde; Brothers, John; Schwartz, Brian; Gordo, Susana; Kasper, Anne; Okamoto, Trevor R; Johansson, Hans E; Mandefro, Berhan; Sareen, Dhruv; Bialek, Peter; Chau, B Nelson; Bhat, Balkrishen; Bullough, David; Barsoum, James

    2017-02-21

    Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive motor neuron loss and caused by mutations in SMN1 (Survival Motor Neuron 1). The disease severity inversely correlates with the copy number of SMN2, a duplicated gene that is nearly identical to SMN1. We have delineated a mechanism of transcriptional regulation in the SMN2 locus. A previously uncharacterized long noncoding RNA (lncRNA), SMN-antisense 1 (SMN-AS1), represses SMN2 expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus. Chemically modified oligonucleotides that disrupt the interaction between SMN-AS1 and PRC2 inhibit the recruitment of PRC2 and increase SMN2 expression in primary neuronal cultures. Our approach comprises a gene-up-regulation technology that leverages interactions between lncRNA and PRC2. Our data provide proof-of-concept that this technology can be used to treat disease caused by epigenetic silencing of specific loci.

  9. Accuracy of marker analysis, quantitative real-time polymerase chain reaction, and multiple ligation-dependent probe amplification to determine SMN2 copy number in patients with spinal muscular atrophy.

    PubMed

    Alías, Laura; Bernal, Sara; Barceló, Maria J; Also-Rallo, Eva; Martínez-Hernández, Rebeca; Rodríguez-Alvarez, Francisco J; Hernández-Chico, Concepción; Baiget, Montserrat; Tizzano, Eduardo F

    2011-09-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by absence of or mutations in the survival motor neuron1 gene (SMN1). All SMA patients have a highly homologous copy of SMN1, the SMN2 gene. Severe (type I) SMA patients present one or two SMN2 copies, whereas milder chronic forms (type II-III) usually have three or four SMN2 copies. SMN2 dosage is important to stratify patients for motor function tests and clinical trials. Our aim was to compare three methods, marker analysis, real-time quantitative polymerase chain reaction using the LightCycler instrument, and multiple ligation-dependent probe amplification (MLPA), to characterize their accuracy in quantifying SMN2 genes. We studied a group of 62 genetically confirmed SMA patients, 54 with homozygous absence of exons 7 and 8 of SMN1 and 8 with SMN2-SMN1 hybrid genes. A complete correlation using the three methods was observed in 32 patients (51.6%). In the remaining 30 patients, discordances between the three methods were found, including under or overestimation of SMN2 copies by marker analysis with respect to the quantitative methods (LightCycler and MLPA) because of lack of informativeness of markers, 3' deletions of SMN genes, and breakpoints in SMN2-SMN1 hybrid genes. The technical limitations and advantages and disadvantages of these methods are discussed. We conclude that the three methods complement each other in estimating the SMN2 copy number in most cases. However, MLPA offers additional information to characterize SMA cases with particular rearrangements such as partial deletions and hybrid genes.

  10. Correlation of clinical and molecular features in spinal bulbar muscular atrophy

    PubMed Central

    Nirmalananthan, Niranjanan; Masset, Luc; Skorupinska, Iwona; Collins, Toby; Cortese, Andrea; Pemble, Sally; Malaspina, Andrea; Fisher, Elizabeth M.C.; Greensmith, Linda; Hanna, Michael G.

    2014-01-01

    Objectives: To characterize the clinical and genetic features of spinal bulbar muscular atrophy (SBMA), a rare neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene, in the United Kingdom. Methods: We created a national register for SBMA in the United Kingdom and recruited 61 patients between 2005 and 2013. In our cross-sectional study, we assessed, by direct questioning, impairment of activities of daily living (ADL) milestones, functional rating, and subjective disease impact, and performed correlations with both CAG repeat size and degree of somatic mosaicism. Ten patients were deceased, 46 patients participated in the study, and 5 declined. Results: Subjects had an average age at onset of 43.4 years, and weakness onset most frequently occurred in the lower limbs (87%). Impaired mobility was the most frequently reported problem by patients, followed by bulbar dysfunction. Age distribution of the impairment of ADL milestones showed remarkable overlap with a Japanese study. We have identified a significant correlation between the number of CAG repeats and both age at onset and ADL milestones. Somatic mosaicism also showed a correlation with CAG expansion size and age at onset. Conclusions: Clinical features in SBMA show a substantial overlap when comparing populations with different genetic backgrounds. This finding has major implications, because multicenter trials will be necessary to obtain sufficient power in future clinical trials. Clinical-genetic correlations are strong in SBMA and should inform any clinical research strategy in this condition. PMID:24814851

  11. Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy.

    PubMed

    Poort, Jessica E; Rheuben, Mary B; Breedlove, S Marc; Jordan, Cynthia L

    2016-09-01

    Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease causing motor dysfunction in men. While the morphology of the neuromuscular junction (NMJ) is typically affected by neuromuscular disease, whether NMJs in SBMA are similarly affected by disease is not known. Such information will shed light on whether defective NMJs might contribute to the loss of motor function and represent a potential therapeutic target for treating symptoms of SBMA. To address this gap in information, the morphology of NMJs was examined in two mouse models of SBMA, a myogenic model that overexpresses wildtype androgen receptor (AR) exclusively in muscle fibres and a knockin (KI) model expressing a humanized mutant AR gene. The tripartite motor synapse consisting of motor nerve terminal, terminal Schwann cells (tSCs) and postsynaptic specialization were visualized and analysed using confocal microscopy. Counter to expectation, we found no evidence of denervation in either model, but junctions in both models show pathological fragmentation and an abnormal synaptophysin distribution consistent with functionally weak synapses. Neurofilament accumulations were observed only in the myogenic model, even though axonal transport dysfunction is characteristic of both models. The ultrastructure of NMJs revealed additional pathology, including deficits in docked vesicles presynaptically, wider synaptic clefts, and simpler secondary folds postsynaptically. The observed pathology of NMJs in diseased SBMA mice is likely the morphological correlates of defects in synaptic function which may underlie motor impairments associated with SBMA.

  12. MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy.

    PubMed

    Pourshafie, Naemeh; Lee, Philip R; Chen, Ke-Lian; Harmison, George G; Bott, Laura C; Katsuno, Masahisa; Sobue, Gen; Burnett, Barrington G; Fischbeck, Kenneth H; Rinaldi, Carlo

    2016-05-01

    Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins.

  13. MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Pourshafie, Naemeh; Lee, Philip R; Chen, Ke-lian; Harmison, George G; Bott, Laura C; Katsuno, Masahisa; Sobue, Gen; Burnett, Barrington G; Fischbeck, Kenneth H; Rinaldi, Carlo

    2016-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins. PMID:26755334

  14. Minor cognitive disturbances in X-linked spinal and bulbar muscular atrophy, Kennedy's disease.

    PubMed

    Kasper, Elisabeth; Wegrzyn, Martin; Marx, Ivo; Korp, Christin; Kress, Wolfram; Benecke, Reiner; Teipel, Stefan J; Prudlo, Johannes

    2014-03-01

    Spinal and bulbar muscular atrophy (SBMA), Kennedy's disease, is an adult-onset hereditary neurodegenerative disorder, associated predominantly with a lower motor neuron syndrome and eventually endocrine and sensory disturbances. In contrast to other motor neuron diseases such as amyotrophic lateral sclerosis (ALS), the impairment of cognition in SBMA is not well documented. We conducted a systematic cross-sectional neuropsychological study in order to investigate cognition in SBMA patients more thoroughly. We investigated 20 genetically proven SBMA patients compared to 20 age- and education-matched control subjects using a comprehensive neuropsychological test battery, measuring executive functioning, attention, memory and visuospatial abilities. The SBMA patients performed significantly worse than healthy controls in three sub-tests in the executive and attention domains. This low performance was in the working memory (digit span backward task), verbal fluency category (single letter fluency task) and memory storage capacity (digit span forward task). No disturbances were detected in other cognitive domains. The impairments were subclinical and not relevant to the patients' everyday functioning. In addition, no correlations were found between cognitive scores and the CAG repeat length. In conclusion, we found minor cognitive disturbances in patients with SBMA, which could indicate subtle frontal lobe dysfunction. These findings extend our neurobiological understanding of SBMA.

  15. Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world.

    PubMed

    Lund, A; Udd, B; Juvonen, V; Andersen, P M; Cederquist, K; Davis, M; Gellera, C; Kölmel, C; Ronnevi, L O; Sperfeld, A D; Sörensen, S A; Tranebjaerg, L; Van Maldergem, L; Watanabe, M; Weber, M; Yeung, L; Savontaus, M L

    2001-06-01

    SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases often show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms are and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.

  16. Convenient diagnosis of spinal and bulbar muscular atrophy using a microchip electrophoresis system.

    PubMed

    Maruyama, Hirofumi; Morino, Hiroyuki; Izumi, Yuishin; Noda, Kouichi; Kawakami, Hideshi

    2013-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive motor neuron disease. Lower and primary sensory neuronopathy is one of the major neuropathological changes that occurs in SBMA. However, many sings are common to SBMA and amyotrophic lateral sclerosis (ALS), and SBMA patients are sometimes diagnosed with ALS. Leuprorelin may be used to treat SBMA, but an accurate diagnosis is necessary for treatment and care. Genetic diagnosis can be performed to detect the expansion of a CAG repeat in the androgen receptor gene in SBMA patients. To screen for this expansion, we used a microchip electrophoresis system. The discrepancy between the actual repeat length and that found by the microchip electrophoresis system was roughly dependent on the repeat length. The mean difference was -6.8 base pairs (bp) in SBMA patients, -0.30 bp in controls. The microchip electrophoresis results were approximately 2 CAG repeats shorter than the actual repeat length in SBMA patients. Using this method, we screened our ALS samples (31 were familial, 271 were sporadic): 4 subjects were diagnosed with SBMA; 2 had familial ALS, and 2 had sporadic ALS (0.7%). The microchip electrophoresis system is semi-quantitative, convenient and useful for screening a large number of samples.

  17. Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia.

    PubMed

    Lund, A; Udd, B; Juvonen, V; Andersen, P M; Cederquist, K; Ronnevi, L O; Sistonen, P; Sörensen, S A; Tranebjaerg, L; Wallgren-Pettersson, C; Savontaus, M L

    2000-08-01

    We haplotyped 13 Finnish, 10 Swedish, 12 Danish and 2 Norwegian SBMA (spinal and bulbar muscular atrophy, Kennedy disease) families with a total of 45 patients and 7 carriers for 17 microsatellite markers spanning a 25.2 cM region around the androgen receptor gene on chromosome Xq11-q12 in search of a genetic founder effect. In addition, the haplotypes of 50 Finnish, 20 Danish and 22 Swedish control males were examined. All the Scandinavian SBMA families shared the same 18 repeat allele for the intragenic GGC repeat, which was present in only 24% of the controls. Linkage disequilibrium was also seen for the closest microsatellite markers. In addition, extended haplotypes of the Finnish, Swedish and Danish SBMA families revealed country-specific common founder haplotypes, which over time became gradually shortened by recombinations. No common haplotype was found among the controls. The data suggest that the SBMA mutation was introduced into western Finland 20 generations ago. Haplotype analysis implies a common ancestor for the majority of Scandinavian SBMA patients.

  18. Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: a pathological study.

    PubMed Central

    Hirayama, K; Tomonaga, M; Kitano, K; Yamada, T; Kojima, S; Arai, K

    1987-01-01

    A new clinical entity under the name of "juvenile muscular atrophy of unilateral upper extremity" was first described in 1959. Although about 150 cases in Japan, and several additional cases in other countries, have been clinically reported in the literature, the pathology has remained unknown because of the benign course of the disease. The first necropsy findings are reported, obtained from a patient with this disease, who died of lung cancer at the age of 38, 23 years after the onset of the disease. The lesions existed only in the anterior horns of the spinal cord at C5 approximately T1, particularly marked at C7 and C8, showing shrinkage and necrosis, degeneration of various degrees of large and small nerve cells, and mild gliosis. The pathological findings differ from those of reported cases of spinal vascular disorders, but some circulatory insufficiency in the territory of the spinal cord would seem to be suggested, although the underlying aetiology remains unknown. Images PMID:3559609

  19. Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy.

    PubMed

    Oki, Kentaro; Halievski, Katherine; Vicente, Laura; Xu, Youfen; Zeolla, Donald; Poort, Jessica; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Wiseman, Robert W; Breedlove, S Marc; Jordan, Cynthia L

    2015-04-01

    Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics.

  20. Effect of prolonged ischaemic time on muscular atrophy and regenerating nerve fibres in transplantation of the rat hind limb.

    PubMed

    Tsuji, Naoko; Yamashita, Shuji; Sugawara, Yasushi; Kobayashi, Eiji

    2012-09-01

    Our aim was to test the influence of cold ischaemia on replanted limbs, focusing on muscular atrophy and neurological recovery. Inbred wild-type and green fluorescent protein (GFP) transgenic (Tg) Lewis rats aged 8-10 weeks were used. The amputated limbs were transplanted at several cold ischaemic times (0, 1, 8, 12, 24, 48, and 72 hours). An arterial ischaemic model and a denervation model were used as controls. To study nerve regeneration, a GFP limb was transplanted on to the syngenic wild Lewis rat. These animals were evaluated histologically, electrophysiologically, and immunohistochemically. The longer the ischaemic time, the more evident was atrophy of the muscles. Electrophysiological investigation showed that the latency at 3 weeks was longer in the transplantation models than in the normal controls, particularly in the longer ischaemia group. Larger numbers of migrating Schwann cells were seen in the group with no delay than in the group that had been preserved for 12 hours. Ischaemia after amputation of a limb causes muscle cells to necrose and atrophy, and these changes worsen in proportion to the ischaemic preservation time. A delay in nerve regeneration and incomplete paralysis caused by malregeneration also affect muscular atrophy.

  1. Hypothermia improves disease manifestations in SMA mice via SMN augmentation.

    PubMed

    Tsai, Li-Kai; Chen, Chien-Lin; Tsai, Yi-Chieh; Ting, Chen-Hung; Chien, Yin-Hsio; Lee, Ni-Chong; Hwu, Wuh-Liang

    2016-02-15

    Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by a deficiency of survival motor neuron (SMN) protein. In this study, we evaluated the efficacy of intermittent transient hypothermia in a mouse model of SMA. SMA mice were exposed to ice for 50 s to achieve transient hypothermia (below 25°C) daily beginning on postnatal day 1. Neonatal SMA mice (Smn(-/-)SMN2(+/-)) who received daily transient hypothermia exhibited reduced motor neuron degeneration and muscle atrophy and preserved the architecture of neuromuscular junction when compared with untreated controls at day 8 post-treatment. Daily hypothermia also prolonged the lifespan, increased body weight and improved motor coordination in SMA mice. Quantitative polymerase chain reaction and western blot analyses showed that transient hypothermia led to an increase in SMN transcript and protein levels in the spinal cord and brain. In in vitro studies using an SMN knockdown motor neuron-like cell-line, transient hypothermia increased intracellular SMN protein expression and length of neurites, confirming the direct effect of hypothermia on motor neurons. These data indicate that the efficacy of intermittent transient hypothermia in improving outcome in an SMA mouse model may be mediated, in part, via an upregulation of SMN levels in the motor neurons.

  2. TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy.

    PubMed

    Sferra, Antonella; Baillat, Gilbert; Rizza, Teresa; Barresi, Sabina; Flex, Elisabetta; Tasca, Giorgio; D'Amico, Adele; Bellacchio, Emanuele; Ciolfi, Andrea; Caputo, Viviana; Cecchetti, Serena; Torella, Annalaura; Zanni, Ginevra; Diodato, Daria; Piermarini, Emanuela; Niceta, Marcello; Coppola, Antonietta; Tedeschi, Enrico; Martinelli, Diego; Dionisi-Vici, Carlo; Nigro, Vincenzo; Dallapiccola, Bruno; Compagnucci, Claudia; Tartaglia, Marco; Haase, Georg; Bertini, Enrico

    2016-10-06

    Tubulinopathies constitute a family of neurodevelopmental/neurodegenerative disorders caused by mutations in several genes encoding tubulin isoforms. Loss-of-function mutations in TBCE, encoding one of the five tubulin-specific chaperones involved in tubulin folding and polymerization, cause two rare neurodevelopmental syndromes, hypoparathyroidism-retardation-dysmorphism and Kenny-Caffey syndrome. Although a missense mutation in Tbce has been associated with progressive distal motor neuronopathy in the pmn/pmn mice, no similar degenerative phenotype has been recognized in humans. We report on the identification of an early-onset and progressive neurodegenerative encephalopathy with distal spinal muscular atrophy resembling the phenotype of pmn/pmn mice and caused by biallelic TBCE mutations, with the c.464T>A (p.Ile155Asn) change occurring at the heterozygous/homozygous state in six affected subjects from four unrelated families originated from the same geographical area in Southern Italy. Western blot analysis of patient fibroblasts documented a reduced amount of TBCE, suggestive of rapid degradation of the mutant protein, similarly to what was observed in pmn/pmn fibroblasts. The impact of TBCE mutations on microtubule polymerization was determined using biochemical fractionation and analyzing the nucleation and growth of microtubules at the centrosome and extracentrosomal sites after treatment with nocodazole. Primary fibroblasts obtained from affected subjects displayed a reduced level of polymerized α-tubulin, similarly to tail fibroblasts of pmn/pmn mice. Moreover, markedly delayed microtubule re-polymerization and abnormal mitotic spindles with disorganized microtubule arrangement were also documented. Although loss of function of TBCE has been documented to impact multiple developmental processes, the present findings provide evidence that hypomorphic TBCE mutations primarily drive neurodegeneration.

  3. Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy.

    PubMed

    Nakatsuji, Hideaki; Araki, Amane; Hashizume, Atsushi; Hijikata, Yasuhiro; Yamada, Shinichiro; Inagaki, Tomonori; Suzuki, Keisuke; Banno, Haruhiko; Suga, Noriaki; Okada, Yohei; Ohyama, Manabu; Nakagawa, Tohru; Kishida, Ken; Funahashi, Tohru; Shimomura, Iichiro; Okano, Hideyuki; Katsuno, Masahisa; Sobue, Gen

    2017-02-22

    This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices. SBMA patients had lower body mass index, blood glucose, and Hemoglobin A1c, but higher blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR, a marker of insulin resistance), total cholesterol, and adiponectin levels than the control subjects. There were no differences in visceral fat areas, high-density lipoprotein-cholesterol (HDL-C), or triglyceride levels in two groups. Revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) correlated positively with HDL-C, but negatively with HOMA-IR. Through stepwise multiple regression analysis, we identified HOMA-IR as a significant metabolic determinant of ALSFRS-R. In biochemical analysis, we found that decreased expressions of insulin receptors, insulin receptor substrate-1 and insulin receptor-β, in autopsied muscles and fibroblasts of SBMA patients. This study demonstrates that SBMA patients have insulin resistance, which is associated with the disease severity. The expressions of insulin receptors are attenuated in the skeletal muscle of SBMA, providing a possible pathomechanism of metabolic alterations. These findings suggested that insulin resistance is a metabolic index reflecting disease severity and pathogenesis as well as a potential therapeutic target for SBMA.

  4. A randomized controlled trial of exercise in spinal and bulbar muscular atrophy

    PubMed Central

    Shrader, Joseph A; Kats, Ilona; Kokkinis, Angela; Zampieri, Cris; Levy, Ellen; Joe, Galen O; Woolstenhulme, Joshua G; Drinkard, Bart E; Smith, Michaele R; Ching, Willie; Ghosh, Laboni; Fox, Derrick; Auh, Sungyoung; Schindler, Alice B; Fischbeck, Kenneth H; Grunseich, Christopher

    2015-01-01

    Objective To determine the safety and efficacy of a home-based functional exercise program in spinal and bulbar muscular atrophy (SBMA). Methods Subjects were randomly assigned to participate in 12 weeks of either functional exercises (intervention) or a stretching program (control) at the National Institutes of Health in Bethesda, MD. A total of 54 subjects enrolled, and 50 completed the study with 24 in the functional exercise group and 26 in the stretching control group. The primary outcome measure was the Adult Myopathy Assessment Tool (AMAT) total score, and secondary measures included total activity by accelerometry, muscle strength, balance, timed up and go, sit-to-stand test, health-related quality of life, creatine kinase, and insulin-like growth factor-1. Results Functional exercise was well tolerated but did not lead to significant group differences in the primary outcome measure or any of the secondary measures. The functional exercise did not produce significantly more adverse events than stretching, and was not perceived to be difficult. To determine whether a subset of the subjects may have benefited, we divided them into high and low functioning based on baseline AMAT scores and performed a post hoc subgroup analysis. Low-functioning individuals receiving the intervention increased AMAT functional subscale scores compared to the control group. Interpretation Although these trial results indicate that functional exercise had no significant effect on total AMAT scores or on mobility, strength, balance, and quality of life, post hoc findings indicate that low-functioning men with SBMA may respond better to functional exercises, and this warrants further investigation with appropriate exercise intensity. PMID:26273686

  5. Differences in F-Wave Characteristics between Spinobulbar Muscular Atrophy and Amyotrophic Lateral Sclerosis

    PubMed Central

    Fang, Jia; Cui, Liying; Liu, Mingsheng; Guan, Yuzhou; Li, Xiaoguang; Li, Dawei; Cui, Bo; Shen, Dongchao; Ding, Qingyun

    2016-01-01

    There is limited data on the differences in F-wave characteristics between spinobulbar muscular atrophy (SBMA) and lower motor neuron dominant (LMND) amyotrophic lateral sclerosis (ALS). We compared the parameters of F-waves recorded bilaterally from the median, ulnar, tibial, and deep peroneal nerves in 32 SBMA patients, 37 patients with LMND ALS, and 30 normal controls. The maximum F-wave amplitudes, frequencies of giant F-waves, and frequencies of patients with giant F-waves in all nerves examined were significantly higher in the SBMA patients than in the ALS patients and the normal controls. The mean F-wave amplitude, maximum F-wave amplitude, frequency of giant F-waves, and frequency of patients with giant F-waves in the median and deep peroneal nerves were comparable between the ALS patients and normal controls. Giant F-waves were detected in multiple nerves and were often symmetrical in the SBMA patients compared with the ALS patients. The number of nerves with giant F-waves seems to be the most robust variable for differentiation of SBMA from ALS, with an area under the curve of 0.908 (95% CI: 0.835–0.982). A cut-off value of the number of nerves with giant F-waves (≥3) for diagnosing SBMA showed high sensitivity and specificity: 85% sensitivity and 81% specificity vs. ALS patients. No significant correlations were found between the pooled frequency of giant F-waves and disease duration in the SBMA (r = 0.162, P = 0.418) or ALS groups (r = 0.107, P = 0.529). Our findings suggested that F-waves might be used to discriminate SBMA from ALS, even at early stages of disease. PMID:27014057

  6. Differences in F-Wave Characteristics between Spinobulbar Muscular Atrophy and Amyotrophic Lateral Sclerosis.

    PubMed

    Fang, Jia; Cui, Liying; Liu, Mingsheng; Guan, Yuzhou; Li, Xiaoguang; Li, Dawei; Cui, Bo; Shen, Dongchao; Ding, Qingyun

    2016-01-01

    There is limited data on the differences in F-wave characteristics between spinobulbar muscular atrophy (SBMA) and lower motor neuron dominant (LMND) amyotrophic lateral sclerosis (ALS). We compared the parameters of F-waves recorded bilaterally from the median, ulnar, tibial, and deep peroneal nerves in 32 SBMA patients, 37 patients with LMND ALS, and 30 normal controls. The maximum F-wave amplitudes, frequencies of giant F-waves, and frequencies of patients with giant F-waves in all nerves examined were significantly higher in the SBMA patients than in the ALS patients and the normal controls. The mean F-wave amplitude, maximum F-wave amplitude, frequency of giant F-waves, and frequency of patients with giant F-waves in the median and deep peroneal nerves were comparable between the ALS patients and normal controls. Giant F-waves were detected in multiple nerves and were often symmetrical in the SBMA patients compared with the ALS patients. The number of nerves with giant F-waves seems to be the most robust variable for differentiation of SBMA from ALS, with an area under the curve of 0.908 (95% CI: 0.835-0.982). A cut-off value of the number of nerves with giant F-waves (≥3) for diagnosing SBMA showed high sensitivity and specificity: 85% sensitivity and 81% specificity vs. ALS patients. No significant correlations were found between the pooled frequency of giant F-waves and disease duration in the SBMA (r = 0.162, P = 0.418) or ALS groups (r = 0.107, P = 0.529). Our findings suggested that F-waves might be used to discriminate SBMA from ALS, even at early stages of disease.

  7. A genetic and phenotypic analysis in Spanish spinal muscular atrophy patients with c.399_402del AGAG, the most frequently found subtle mutation in the SMN1 gene.

    PubMed

    Cuscó, Ivon; López, Eva; Soler-Botija, Carolina; Jesús Barceló, María; Baiget, Montserrat; Tizzano, Eduardo F

    2003-08-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 (survival motor neuron) gene. It is classified by age of onset and maximal motor milestones achieved in type I, II, and III (severe, intermediate, and mild form, respectively). Of 369 unrelated SMA patients who were investigated for homozygous deletions in the SMN1 gene, 18 patients (4.8%) revealed at least one copy of exon 7. A 4-bp deletion in exon 3 (c.399_402delAGAG) was detected in 15 patients from 10 families. This mutation was associated with a large spectrum of phenotypes from type I to asymptomatic patients. Five patients from two consanguineous families were homozygous for the mutation with diverse mild phenotypes. Determination of the SMN2 copy number showed that the presence of two or three copies generally correlated with a better evolution. RT-PCR studies of SMN transcripts in control and patients with the same SMN2 copy number showed that the full-length/Delta7 ratio is influenced by the SMN1 genotype although it seems independent of the SMN2 copy number. Moreover, protein analysis in these patients showed a reduction in SMN protein in compound heterozygous patients (c.399_402delAGAG/deletion) when compared with homozygous c.399_402delAGAG/c.399_402delAGAG patients. Microsatellite DNA markers flanking the SMA locus revealed the occurrence of the 4-bp deletion in the background of the same haplotype, suggesting that a single mutational event was involved in the 10 families. The geographic origins of ancestors point to a founder effect from the south and east of Spain. The c.399_402delAGAG, which is to date unique to the Spanish population, constitutes the most frequently found subtle mutation in SMA. Hum Mutat 22:136-143, 2003.

  8. Defects in Neuromuscular Transmission May Underlie Motor Dysfunction in Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Xu, Youfen; Halievski, Katherine; Henley, Casey; Atchison, William D.; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Breedlove, S. Marc

    2016-01-01

    Spinal and bulbar muscular atrophy (SBMA) in men is an androgen-dependent neuromuscular disease caused by expanded CAG repeats in the androgen receptor (AR). Whether muscle or motor neuron dysfunction or both underlies motor impairment in SBMA is unknown. Muscles of SBMA mice show significant contractile dysfunction, implicating them as a likely source of motor dysfunction, but whether disease also impairs neuromuscular transmission is an open question. Thus, we examined synaptic function in three well-studied SBMA mouse models—the AR97Q, knock-in (KI), and myogenic141 models—by recording in vitro miniature and evoked end-plate potentials (MEPPs and EPPs, respectively) intracellularly from adult muscle fibers. We found striking defects in neuromuscular transmission suggesting that toxic AR in SBMA impairs both presynaptic and postsynaptic mechanisms. Notably, SBMA causes neuromuscular synapses to become weak and muscles to become hyperexcitable in all three models. Presynaptic defects included deficits in quantal content, reduced size of the readily releasable pool, and impaired short-term facilitation. Postsynaptic defects included prolonged decay times for both MEPPs and EPPs, marked resistance to μ-conotoxin (a sodium channel blocker), and enhanced membrane excitability. Quantitative PCR revealed robust upregulation of mRNAs encoding neonatal isoforms of the AChR (γ-subunit) and the voltage-gated sodium channel (NaV1.5) in diseased adult muscles of all three models, consistent with the observed slowing of synaptic potentials and resistance to μ-conotoxin. These findings suggest that muscles of SBMA patients regress to an immature state that impairs neuromuscular function. SIGNIFICANCE STATEMENT We have discovered that SBMA is accompanied by marked defects in neuromuscular synaptic transmission involving both presynaptic and postsynaptic mechanisms. For three different mouse models, we find that diseased synapses are weak, having reduced quantal content

  9. Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures

    PubMed Central

    Knierim, Ellen; Hirata, Hiromi; Wolf, Nicole I.; Morales-Gonzalez, Susanne; Schottmann, Gudrun; Tanaka, Yu; Rudnik-Schöneborn, Sabine; Orgeur, Mickael; Zerres, Klaus; Vogt, Stefanie; van Riesen, Anne; Gill, Esther; Seifert, Franziska; Zwirner, Angelika; Kirschner, Janbernd; Goebel, Hans Hilmar; Hübner, Christoph; Stricker, Sigmar; Meierhofer, David; Stenzel, Werner; Schuelke, Markus

    2016-01-01

    Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system. PMID:26924529

  10. Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons.

    PubMed

    Lee, Young Il; Mikesh, Michelle; Smith, Ian; Rimer, Mendell; Thompson, Wesley

    2011-08-15

    A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precede the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any significant impairment in neuromuscular transmission, even when animals were maintained up to 5days longer via a supplementary diet. However, the muscles were clearly weaker, generating less than half their normal tension. Weakness in 3 muscles examined in the study appears due to a severe but uniform reduction in muscle fiber size. The size reduction results from a failure of muscle fibers to grow during early postnatal development and, in soleus, to a reduction in number of fibers generated. Neuromuscular development is severely delayed in these mutant animals: expression of myosin heavy chain isoforms, the elimination of polyneuronal innervation, the maturation in the shape of the AChR plaque, the arrival of SCs at the junctions and their coverage of the nerve terminal, the development of junctional folds. Thus, if SMA in this particular mouse is a disease of motor neurons, it can act in a manner that does not result in their death or disconnection from their targets but nonetheless alters many aspects of neuromuscular development.

  11. Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons

    PubMed Central

    Lee, Young il; Mikesh, Michelle; Smith, Ian; Rimer, Mendell; Thompson, Wesley

    2011-01-01

    A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precedes the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any significant impairment in neuromuscular transmission, even when animals were maintained up to 5 days longer via a supplementary diet. However, the muscles were clearly weaker, generating less than half their normal tension. Weakness in 3 muscles examined in the study appears due to a severe but uniform reduction in muscle fiber size. The size reduction results from a failure of muscle fibers to grow during early postnatal development and, in soleus, to a reduction in number of fibers generated. Neuromuscular development is severely delayed in these mutant animals: expression of myosin heavy chain isoforms, the elimination of polyneuronal innervation, the maturation in the shape of the AChR plaque, the arrival of SCs at the junctions and their coverage of the nerve terminal, the development of junctional folds. Thus, if SMA in this particular mouse is a disease of motor neurons, it can act in a manner that does not result in their death or disconnection from their targets but nonetheless alters many aspects of neuromuscular development. PMID:21658376

  12. Antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy.

    PubMed

    Renier, Kayla J; Troxell-Smith, Sandra M; Johansen, Jamie A; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Chua, Jason P; Sun Kim, Hong; Lieberman, Andrew P; Breedlove, S Marc; Jordan, Cynthia L

    2014-07-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset, progressive neurodegenerative disease linked to a polyglutamine (polyQ) expansion in the androgen receptor (AR). Men affected by SBMA show marked muscle weakness and atrophy, typically emerging midlife. Given the androgen-dependent nature of this disease, one might expect AR antagonists to have therapeutic value for treating SBMA. However, current work from animal models suggests otherwise, raising questions about whether polyQ-expanded AR exerts androgen-dependent toxicity through mechanisms distinct from normal AR function. In this study, we asked whether the nonsteroidal AR antagonist flutamide, delivered via a time-release pellet, could reverse or prevent androgen-dependent AR toxicity in three different mouse models of SBMA: the AR97Q transgenic (Tg) model, a knock-in (KI) model, and a myogenic Tg model. We find that flutamide protects mice from androgen-dependent AR toxicity in all three SBMA models, preventing or reversing motor dysfunction in the Tg models and significantly extending the life span in KI males. Given that flutamide effectively protects against androgen-dependent disease in three different mouse models of SBMA, our data are proof of principle that AR antagonists have therapeutic potential for treating SBMA in humans and support the notion that toxicity caused by polyQ-expanded AR uses at least some of the same mechanisms as normal AR before diverging to produce disease and muscle atrophy.

  13. Columbia SMA Project: A Randomized, Control Trial of the Effects of Exercise on Motor Function and Strength in Patients with Spinal Muscular Atrophy (SMA)

    DTIC Science & Technology

    2012-06-01

    function in patients with Parkinson’s disease. Neurology. 2003;60:1119-1124 Merlini L, Mazzone ES, Solari A, Morandi L. Reliability of hand-held...The Six Minute Walk Test (6MWT) is a reliable clinical measure of fatigue. Mean power frequency (MPF) and root mean square amplitude (RMS) are

  14. Frontotemporal cognitive function in X-linked spinal and bulbar muscular atrophy (SBMA): a controlled neuropsychological study of 20 patients.

    PubMed

    Soukup, Georg Rüdiger; Sperfeld, Anne-Dorte; Uttner, Ingo; Karitzky, Jochen; Ludolph, Albert Christian; Kassubek, Jan; Schreiber, Herbert

    2009-11-01

    A cross-sectional neuropsychological study of cognitive functions in 20 male patients with genetically proven spinal and bulbar muscular atrophy (SBMA) was performed, with a comparison of their cognitive performance with that of 20 age- and education-matched control subjects. Neuropsychological assessment covered executive functioning, memory, and attentional control. The SBMA patients revealed deficits in verbal and non-verbal fluency as well as concept formation. Additionally, they showed significant memory deficits in all of the investigated domains of working memory, short-term and long-term memory. With respect to attentional control, the SBMA patients underperformed in relevant subtests, although performance differences did not reach significance overall. We conclude that fronto-temporal cognitive functions are impaired in SMBA, although at a subclinical level. Thus, functional deficits in SBMA are not confined to motor neurons but also affect extramotor networks.

  15. Protein Arginine Methyltransferase 6 Enhances Polyglutamine-Expanded Androgen Receptor Function and Toxicity in Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Scaramuzzino, Chiara; Casci, Ian; Parodi, Sara; Lievens, Patricia M.J.; Polanco, Maria J.; Milioto, Carmelo; Chivet, Mathilde; Monaghan, John; Mishra, Ashutosh; Badders, Nisha; Aggarwal, Tanya; Grunseich, Christopher; Sambataro, Fabio; Basso, Manuela; Fackelmayer, Frank O.; Taylor, J. Paul; Pandey, Udai Bhan; Pennuto, Maria

    2015-01-01

    Summary Polyglutamine expansion in androgen receptor (AR) is responsible for spinobulbar muscular atrophy (SBMA) that leads to selective loss of lower motor neurons. Using SBMA as a model, we explored the relationship between protein structure/function and neurodegeneration in polyglutamine diseases. We show here that protein arginine methyltransferase 6 (PRMT6) is a specific co-activator of normal and mutant AR and that the interaction of PRMT6 with AR is significantly enhanced in the AR mutant. AR and PRMT6 interaction occurs through the PRMT6 steroid receptor interaction motif, LXXLL, and the AR activating function 2 surface. AR transactivation requires PRMT6 catalytic activity and involves methylation of arginine residues at Akt consensus site motifs, which is mutually exclusive with serine phosphorylation by Akt. The enhanced interaction of PRMT6 and mutant AR leads to neurodegeneration in cell and fly models of SBMA. These findings demonstrate a direct role of arginine methylation in polyglutamine disease pathogenesis. PMID:25569348

  16. Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy

    PubMed Central

    Nedelsky, Natalia B.; Pennuto, Maria; Smith, Rebecca B.; Palazzolo, Isabella; Moore, Jennifer; Nie, Zhiping; Neale, Geoffrey; Taylor, J. Paul

    2012-01-01

    Summary Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of its hormone ligand, suggesting that pathogenesis involves ligand-induced changes in AR. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated events downstream of ligand-dependent AR activation in a Drosophila model of SBMA. We show that nuclear translocation of AR is necessary but not sufficient for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. These findings indicate that SBMA pathogenesis is mediated by misappropriation of native protein function, a mechanism that may apply broadly to polyglutamine diseases. PMID:20869592

  17. Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy.

    PubMed

    Rusmini, Paola; Polanco, Maria Josefa; Cristofani, Riccardo; Cicardi, Maria Elena; Meroni, Marco; Galbiati, Mariarita; Piccolella, Margherita; Messi, Elio; Giorgetti, Elisa; Lieberman, Andrew P; Milioto, Carmelo; Rocchi, Anna; Aggarwal, Tanya; Pennuto, Maria; Crippa, Valeria; Poletti, Angelo

    2015-10-22

    Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFβ1 and PGC-1α were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments.

  18. X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron

    PubMed Central

    Hodgkinson, Victoria L.; Dale, Jeffery M.; Garcia, Michael L.; Weisman, Gary A.; Lee, Jaekwon; Gitlin, Jonathan D.; Petris, Michael J.

    2015-01-01

    ATP7A is a copper transporting P-type ATPase that is essential for cellular copper homeostasis. Loss-of-function mutations in the ATP7A gene result in Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia, and failure to thrive due to systemic copper deficiency. Most recently, rare missense mutations in ATP7A that do not impact systemic copper homeostasis have been shown to cause X-linked Spinal Muscular Atrophy type 3 (SMAX3), a distal hereditary motor neuropathy. An understanding of the mechanistic and pathophysiological basis of SMAX3 is currently lacking, in part because the disease-causing mutations have been shown to confer both loss- and gain-of-function properties to ATP7A, and because there is currently no animal model of the disease. In this study, the Atp7a gene was specifically deleted in the motor neurons of mice resulting in a degenerative phenotype consistent with the clinical features in affected patients with SMAX3, including the progressive deterioration of gait, age-dependent muscle atrophy, denervation of neuromuscular junctions, and a loss of motor neuron cell bodies. Taken together these data reveal autonomous requirements for ATP7A that reveal essential roles for copper in the maintenance and function of the motor neuron, and suggest that SMAX3 is caused by a loss of ATP7A function that specifically impacts in the spinal motor neuron. PMID:25639447

  19. Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Rusmini, Paola; Polanco, Maria Josefa; Cristofani, Riccardo; Cicardi, Maria Elena; Meroni, Marco; Galbiati, Mariarita; Piccolella, Margherita; Messi, Elio; Giorgetti, Elisa; Lieberman, Andrew P.; Milioto, Carmelo; Rocchi, Anna; Aggarwal, Tanya; Pennuto, Maria; Crippa, Valeria; Poletti, Angelo

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFβ1 and PGC-1α were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments. PMID:26490709

  20. Nosology of Juvenile Muscular Atrophy of Distal Upper Extremity: From Monomelic Amyotrophy to Hirayama Disease—Indian Perspective

    PubMed Central

    Hassan, Kaukab Maqbool; Sahni, Hirdesh

    2013-01-01

    Since its original description by Keizo Hirayama in 1959, “juvenile muscular atrophy of the unilateral upper extremity” has been described under many nomenclatures from the east. Hirayama disease (HD), also interchangeably referred to as monomelic amyotrophy, has been more frequently recognised in the west only in the last two decades. HD presents in adolescence and young adulthood with insidious onset unilateral or bilateral asymmetric atrophy of hand and forearm with sparing of brachioradialis giving the characteristic appearance of oblique amyotrophy. Symmetrically bilateral disease has also been recognized. Believed to be a cervical flexion myelopathy, HD differs from motor neuron diseases because of its nonprogressive course and pathologic findings of chronic microcirculatory changes in the lower cervical cord. Electromyography shows features of acute and/or chronic denervation in C7, C8, and T1 myotomes in clinically affected limb and sometimes also in clinically unaffected contralateral limb. Dynamic forward displacement of dura in flexion causes asymmetric flattening of lower cervical cord. While dynamic contrast magnetic resonance imaging is diagnostic, routine study has high predictive value. There is a need to lump all the nomenclatures under the rubric of HD as prognosis in this condition is benign and prompt diagnosis is important to institute early collar therapy. PMID:24063005

  1. Nosology of juvenile muscular atrophy of distal upper extremity: from monomelic amyotrophy to Hirayama disease--Indian perspective.

    PubMed

    Hassan, Kaukab Maqbool; Sahni, Hirdesh

    2013-01-01

    Since its original description by Keizo Hirayama in 1959, "juvenile muscular atrophy of the unilateral upper extremity" has been described under many nomenclatures from the east. Hirayama disease (HD), also interchangeably referred to as monomelic amyotrophy, has been more frequently recognised in the west only in the last two decades. HD presents in adolescence and young adulthood with insidious onset unilateral or bilateral asymmetric atrophy of hand and forearm with sparing of brachioradialis giving the characteristic appearance of oblique amyotrophy. Symmetrically bilateral disease has also been recognized. Believed to be a cervical flexion myelopathy, HD differs from motor neuron diseases because of its nonprogressive course and pathologic findings of chronic microcirculatory changes in the lower cervical cord. Electromyography shows features of acute and/or chronic denervation in C7, C8, and T1 myotomes in clinically affected limb and sometimes also in clinically unaffected contralateral limb. Dynamic forward displacement of dura in flexion causes asymmetric flattening of lower cervical cord. While dynamic contrast magnetic resonance imaging is diagnostic, routine study has high predictive value. There is a need to lump all the nomenclatures under the rubric of HD as prognosis in this condition is benign and prompt diagnosis is important to institute early collar therapy.

  2. X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron.

    PubMed

    Hodgkinson, Victoria L; Dale, Jeffery M; Garcia, Michael L; Weisman, Gary A; Lee, Jaekwon; Gitlin, Jonathan D; Petris, Michael J

    2015-06-01

    ATP7A is a copper-transporting P-type ATPase that is essential for cellular copper homeostasis. Loss-of-function mutations in the ATP7A gene result in Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia and failure to thrive, due to systemic copper deficiency. Most recently, rare missense mutations in ATP7A that do not impact systemic copper homeostasis have been shown to cause X-linked spinal muscular atrophy type 3 (SMAX3), a distal hereditary motor neuropathy. An understanding of the mechanistic and pathophysiological basis of SMAX3 is currently lacking, in part because the disease-causing mutations have been shown to confer both loss- and gain-of-function properties to ATP7A, and because there is currently no animal model of the disease. In this study, the Atp7a gene was specifically deleted in the motor neurons of mice, resulting in a degenerative phenotype consistent with the clinical features in affected patients with SMAX3, including the progressive deterioration of gait, age-dependent muscle atrophy, denervation of neuromuscular junctions and a loss of motor neuron cell bodies. Taken together, these data reveal autonomous requirements for ATP7A that reveal essential roles for copper in the maintenance and function of the motor neuron, and suggest that SMAX3 is caused by a loss of ATP7A function that specifically impacts the spinal motor neuron.

  3. The Use of Korean Medicine to Treat Patients with Spinobulbar Muscular Atrophy, Kennedy’s Disease - A Case Study

    PubMed Central

    Lee, Seongjin; Cha, Eunhye; Lee, Jongcheol; Lee, Jongdeok; Song, Inja

    2017-01-01

    Objectives: Studies involving patients with spinobulbar muscular atrophy (SBMA), which is often referred to as Kennedy’s disease, similar to those involving patients with progressive muscular disease (PMD), are rare. This paper reports a case study involving the use of Korean medicine to treat a patient with SBMA. Methods: We treated a patient with SBMA with unique symptoms by using various kinds of pharmacopuncture and herbal medicines for about two and a half years. After the treatment had ended, we evaluated the patient’s conditions and the side effects of the treatment. Results: After treatment, the patient’s symptoms were stabilized, and the patient suffered no abnormalities or side effects. No special changes in condition were noted during treatment period, and the patient was very satisfied with his response to treatment. Conclusion: Existing treatments have some considerable after effects and are difficult to apply in domestic clinics. In this regard, our findings should open possibilities for new clinical guidelines. Nevertheless, the limitations associated with this case study should be resolved, and more studies need to be conducted. PMID:28392964

  4. Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels.

    PubMed

    Cea, Luis A; Balboa, Elisa; Puebla, Carlos; Vargas, Aníbal A; Cisterna, Bruno A; Escamilla, Rosalba; Regueira, Tomás; Sáez, Juan C

    2016-10-01

    Long-term treatment with high glucocorticoid doses induces skeletal muscle atrophy. However, the molecular mechanism of such atrophy remains unclear. We evaluated the possible involvement of connexin-based hemichannels (Cx HCs) in muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, on control (Cx43(fl/fl)Cx45(fl/fl)) and Cx43/Cx45 expression-deficient (Cx43(fl/fl)Cx45(fl/fl):Myo-Cre) skeletal myofibers. Myofibers of Cx43(fl/fl)Cx45(fl/fl) mice treated with DEX (5h) expressed several proteins that form non-selective membrane channels (Cx39, Cx43, Cx45, Panx1, P2X7 receptor and TRPV2). After 5h DEX treatment in vivo, myofibers of Cx43(fl/fl)Cx45(fl/fl) mice showed Evans blue uptake, which was absent in myofibers of Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice. Similar results were obtained in vitro using ethidium as an HC permeability probe, and DEX-induced dye uptake in control myofibers was blocked by P2X7 receptor inhibitors. DEX also induced a significant increase in basal intracellular Ca(2+) signal and a reduction in resting membrane potential in Cx43(fl/fl)Cx45(fl/fl) myofibers, changes that were not elicited by myofibers deficient in Cx43/Cx45 expression. Moreover, treatment with DEX induced NFκB activation and increased mRNA levels of TNF-α in control but not in Cx43/Cx45 expression-deficient myofibers. Finally, a prolonged DEX treatment (7days) increased atrogin-1 and Murf-1 and reduced the cross sectional area of Cx43(fl/fl)Cx45(fl/fl) myofibers, but these parameters remained unaffected in Cx43(fl/fl)Cx45(fl/fl):Myo-Cre myofibers. Therefore, DEX-induced expression of Cx43 and Cx45 plays a critical role in early sarcolemma changes that lead to atrophy. Consequently, this side effect of chronic glucocorticoid treatment might be avoided by co-administration with a Cx HC blocker.

  5. Temporal requirement for high SMN expression in SMA mice

    PubMed Central

    Le, Thanh T.; McGovern, Vicki L.; Alwine, Isaac E.; Wang, Xueyong; Massoni-Laporte, Aurelie; Rich, Mark M.; Burghes, Arthur H.M.

    2011-01-01

    Spinal muscular atrophy (SMA) is caused by loss of the survival motor neuron 1 gene (SMN1) and retention of the SMN2 gene, resulting in reduced SMN. SMA mice can be rescued with high expression of SMN in neurons, but when is this high expression required? We have developed a SMA mouse with inducible expression of SMN to address the temporal requirement for high SMN expression. Both embryonic and early postnatal induction of SMN resulted in a dramatic increase in survival with some mice living greater than 200 days. The mice had no marked motor deficits and neuromuscular junction (NMJ) function was near normal thus it appears that induction of SMN in postnatal SMA mice rescues motor function. Early postnatal SMN induction, followed by a 1-month removal of induction at 28 days of age, resulted in no morphological or electrophysiological abnormalities at the NMJ and no overt motor phenotype. Upon removal of SMN induction, five mice survived for just over 1 month and two female mice have survived past 8 months of age. We suggest that there is a postnatal period of time when high SMN levels are required. Furthermore, two copies of SMN2 provide the minimal amount of SMN necessary to maintain survival during adulthood. Finally, in the course of SMA, early induction of SMN is most efficacious. PMID:21672919

  6. Enhanced aggregation of androgen receptor in induced pluripotent stem cell-derived neurons from spinal and bulbar muscular atrophy.

    PubMed

    Nihei, Yoshihiro; Ito, Daisuke; Okada, Yohei; Akamatsu, Wado; Yagi, Takuya; Yoshizaki, Takahito; Okano, Hideyuki; Suzuki, Norihiro

    2013-03-22

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. Ligand-dependent nuclear accumulation of mutant AR protein is a critical characteristic of the pathogenesis of SBMA. SBMA has been modeled in AR-overexpressing animals, but precisely how the polyglutamine (polyQ) expansion leads to neurodegeneration is unclear. Induced pluripotent stem cells (iPSCs) are a new technology that can be used to model human diseases, study pathogenic mechanisms, and develop novel drugs. We established SBMA patient-derived iPSCs, investigated their cellular biochemical characteristics, and found that SBMA-iPSCs can differentiate into motor neurons. The CAG repeat numbers in the AR gene of SBMA-iPSCs and also in the atrophin-1 gene of iPSCs derived from another polyQ disease, dentato-rubro-pallido-luysian atrophy (DRPLA), remain unchanged during reprogramming, long term passage, and differentiation, indicating that polyQ disease-associated CAG repeats are stable during maintenance of iPSCs. The level of AR expression is up-regulated by neuronal differentiation and treatment with the AR ligand dihydrotestosterone. Filter retardation assays indicated that aggregation of ARs following dihydrotestosterone treatment in neurons derived from SBMA-iPSCs increases significantly compared with neurological control iPSCs, easily recapitulating the pathological feature of mutant ARs in SBMA-iPSCs. This phenomenon was not observed in iPSCs and fibroblasts, thereby showing the neuron-dominant phenotype of this disease. Furthermore, the HSP90 inhibitor 17-allylaminogeldanamycin sharply decreased the level of aggregated AR in neurons derived from SBMA-iPSCs, indicating a potential for discovery and validation of candidate drugs. We found that SBMA-iPSCs possess disease-specific biochemical features and could thus open new avenues of research into not only SBMA, but also other polyglutamine diseases.

  7. Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients

    PubMed Central

    Querin, Giorgia; Bertolin, Cinzia; Da Re, Elisa; Volpe, Marco; Zara, Gabriella; Pegoraro, Elena; Caretta, Nicola; Foresta, Carlo; Silvano, Maria; Corrado, Domenico; Iafrate, Massimo; Angelini, Lorenzo; Sartori, Leonardo; Pennuto, Maria; Gaiani, Alessandra; Bello, Luca; Semplicini, Claudio; Pareyson, Davide; Silani, Vincenzo; Ermani, Mario; Ferlin, Alberto; Sorarù, Gianni

    2016-01-01

    Objective To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). Methods 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. Results Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. Conclusions Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients. PMID:26503015

  8. A young man with spinal muscular atrophy and impending respiratory arrest.

    PubMed

    Winters, Janine Penfield; Weisleder, Pedro

    2011-02-01

    From a statutory standpoint, the decision-making capacity of adolescents differs significantly from that of adults because adolescents are considered to lack the experience and judgment necessary to make legally binding decisions. Furthermore, in the case of minors, the principle of protection of life tends to outweigh the principle of autonomy. Here we present the hypothetical case of a 16-year-old boy with spinalmuscular atrophy type II who was admitted to the intensive care unit for severe respiratory distress. We focus on the tension that developed among the patient, his parents, and his physicians when the need for emergency mechanical ventilation became apparent. We review the legal and ethical premises under which adolescents are permitted to make legally binding decisions, ie, the emancipated minor and the mature minor doctrines. Finally, we discuss the concepts of protectionism and liberationism as they apply to adolescents' decision-making capacity.

  9. Selective Neuromuscular Denervation in Taiwanese Severe SMA Mouse Can Be Reversed by Morpholino Antisense Oligonucleotides

    PubMed Central

    Lin, Te-Lin; Chen, Tai-Heng; Hsu, Ya-Yun; Cheng, Yu-Hua; Juang, Bi-Tzen; Jong, Yuh-Jyh

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by deficiency of the survival of motor neuron (SMN) protein, which leads to synaptic defects and spinal motor neuron death. Neuromuscular junction (NMJ) abnormalities have been found to be involved in SMA pathogenesis in the SMNΔ7 SMA mouse model. However, whether similar NMJ pathological findings present in another commonly used mouse model, the Taiwanese SMA mouse, has not been fully investigated. To examine the NMJs of the Taiwanese severe SMA mouse model (Smn-/-; SMN2tg/0), which is characterized by severe phenotype and death before postnatal day (P) 9, we investigated 25 axial and appendicular muscles from P1 to P9. We labelled the muscles with anti-neurofilament and anti-synaptophysin antibodies for nerve terminals and α-bungarotoxin for acetylcholine receptors (AChRs). We found that severe NMJ denervation (<50% fully innervated endplates) selectively occurred in the flexor digitorum brevis 2 and 3 (FDB-2/3) muscles from P5, and an increased percentage of fully denervated endplates correlated with SMA progression. Furthermore, synaptophysin signals were absent at the endplate compared to control littermate mice, suggesting that vesicle transport might only be affected at the end stage. Subsequently, we treated the Taiwanese severe SMA mice with morpholino (MO) antisense oligonucleotides (80 μg/g) via subcutaneous injection at P0. We found that MO significantly reversed the NMJ denervation in FDB-2/3 muscles and extended the survival of Taiwanese severe SMA mice. We conclude that early NMJ denervation in the FDB-2/3 muscles of Taiwanese severe SMA mice can be reversed by MO treatment. The FDB-2/3 muscles of Taiwanese severe SMA mice provide a very sensitive platform for assessing the effectiveness of drug treatments in SMA preclinical studies. PMID:27124114

  10. Selective Neuromuscular Denervation in Taiwanese Severe SMA Mouse Can Be Reversed by Morpholino Antisense Oligonucleotides.

    PubMed

    Lin, Te-Lin; Chen, Tai-Heng; Hsu, Ya-Yun; Cheng, Yu-Hua; Juang, Bi-Tzen; Jong, Yuh-Jyh

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by deficiency of the survival of motor neuron (SMN) protein, which leads to synaptic defects and spinal motor neuron death. Neuromuscular junction (NMJ) abnormalities have been found to be involved in SMA pathogenesis in the SMNΔ7 SMA mouse model. However, whether similar NMJ pathological findings present in another commonly used mouse model, the Taiwanese SMA mouse, has not been fully investigated. To examine the NMJs of the Taiwanese severe SMA mouse model (Smn-/-; SMN2tg/0), which is characterized by severe phenotype and death before postnatal day (P) 9, we investigated 25 axial and appendicular muscles from P1 to P9. We labelled the muscles with anti-neurofilament and anti-synaptophysin antibodies for nerve terminals and α-bungarotoxin for acetylcholine receptors (AChRs). We found that severe NMJ denervation (<50% fully innervated endplates) selectively occurred in the flexor digitorum brevis 2 and 3 (FDB-2/3) muscles from P5, and an increased percentage of fully denervated endplates correlated with SMA progression. Furthermore, synaptophysin signals were absent at the endplate compared to control littermate mice, suggesting that vesicle transport might only be affected at the end stage. Subsequently, we treated the Taiwanese severe SMA mice with morpholino (MO) antisense oligonucleotides (80 μg/g) via subcutaneous injection at P0. We found that MO significantly reversed the NMJ denervation in FDB-2/3 muscles and extended the survival of Taiwanese severe SMA mice. We conclude that early NMJ denervation in the FDB-2/3 muscles of Taiwanese severe SMA mice can be reversed by MO treatment. The FDB-2/3 muscles of Taiwanese severe SMA mice provide a very sensitive platform for assessing the effectiveness of drug treatments in SMA preclinical studies.

  11. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy.

    PubMed

    Cortes, Constanza J; Ling, Shuo-Chien; Guo, Ling T; Hung, Gene; Tsunemi, Taiji; Ly, Linda; Tokunaga, Seiya; Lopez, Edith; Sopher, Bryce L; Bennett, C Frank; Shelton, G Diane; Cleveland, Don W; La Spada, Albert R

    2014-04-16

    X-linked spinal and bulbar muscular atrophy (SBMA) is characterized by adult-onset muscle weakness and lower motor neuron degeneration. SBMA is caused by CAG-polyglutamine (polyQ) repeat expansions in the androgen receptor (AR) gene. Pathological findings include motor neuron loss, with polyQ-AR accumulation in intranuclear inclusions. SBMA patients exhibit myopathic features, suggesting a role for muscle in disease pathogenesis. To determine the contribution of muscle, we developed a BAC mouse model featuring a floxed first exon to permit cell-type-specific excision of human AR121Q. BAC fxAR121 mice develop systemic and neuromuscular phenotypes, including shortened survival. After validating termination of AR121 expression and full rescue with ubiquitous Cre, we crossed BAC fxAR121 mice with Human Skeletal Actin-Cre mice. Muscle-specific excision prevented weight loss, motor phenotypes, muscle pathology, and motor neuronopathy and dramatically extended survival. Our results reveal a crucial role for muscle expression of polyQ-AR in SBMA and suggest muscle-directed therapies as effective treatments.

  12. Assessing Function and Endurance in Adults with Spinal and Bulbar Muscular Atrophy: Validity of the Adult Myopathy Assessment Tool

    PubMed Central

    Harris-Love, Michael O.; Fernandez-Rhodes, Lindsay; Joe, Galen; Shrader, Joseph A.; Kokkinis, Angela; La Pean Kirschner, Alison; Auh, Sungyoung; Chen, Cheunju; Li, Li; Levy, Ellen; Davenport, Todd E.; Di Prospero, Nicholas A.; Fischbeck, Kenneth H.

    2014-01-01

    Purpose. The adult myopathy assessment tool (AMAT) is a performance-based battery comprised of functional and endurance subscales that can be completed in approximately 30 minutes without the use of specialized equipment. The purpose of this study was to determine the construct validity and internal consistency of the AMAT with a sample of adults with spinal and bulbar muscular atrophy (SBMA). Methods. AMAT validity was assessed in 56-male participants with genetically confirmed SBMA (mean age, 53 ± 10 years). The participants completed the AMAT and assessments for disease status, strength, and functional status. Results. Lower AMAT scores were associated with longer disease duration (r = −0.29; P < 0.03) and lower serum androgen levels (r = 0.49–0.59; P < 0.001). The AMAT was significantly correlated with strength and functional status (r = 0.82–0.88; P < 0.001). The domains of the AMAT exhibited good internal consistency (Cronbach's α = 0.77–0.89; P < 0.001). Conclusions. The AMAT is a standardized, performance-based tool that may be used to assess functional limitations and muscle endurance. The AMAT has good internal consistency, and the construct validity of the AMAT is supported by its significant associations with hormonal, strength, and functional characteristics of adults with SBMA. This trial is registered with Clinicaltrials.gov identifier NCT00303446. PMID:24876969

  13. Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy

    PubMed Central

    Yamada, Shinichiro; Hashizume, Atsushi; Hijikata, Yasuhiro; Inagaki, Tomonori; Suzuki, Keisuke; Kondo, Naohide; Kawai, Kaori; Noda, Seiya; Nakanishi, Hirotaka; Banno, Haruhiko; Hirakawa, Akihiro; Koike, Haruki; Halievski, Katherine; Jordan, Cynthia L.; Katsuno, Masahisa; Sobue, Gen

    2016-01-01

    The aim of this study was to characterize the respiratory function profile of subjects with spinal and bulbar muscular atrophy (SBMA), and to explore the underlying pathological mechanism by comparing the clinical and biochemical indices of this disease with those of amyotrophic lateral sclerosis (ALS). We enrolled male subjects with SBMA (n = 40) and ALS (n = 25) along with 15 healthy control subjects, and assessed their respiratory function, motor function, and muscle strength. Predicted values of peak expiratory flow (%PEF) and forced vital capacity were decreased in subjects with SBMA compared with controls. In SBMA, both values were strongly correlated with the trunk subscores of the motor function tests and showed deterioration relative to disease duration. Compared with activities of daily living (ADL)-matched ALS subjects, %PEF, tongue pressure, and grip power were substantially decreased in subjects with SBMA. Both immunofluorescence and RT-PCR demonstrated a selective decrease in the expression levels of the genes encoding the myosin heavy chains specific to fast-twitch fibers in SBMA subjects. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and peroxisome proliferator-activated receptor delta were up-regulated in SBMA compared with ALS and controls. In conclusion, %PEF is a disease-specific respiratory marker for the severity and progression of SBMA. Explosive muscle strength, including %PEF, was selectively affected in subjects with SBMA and was associated with activation of the mitochondrial biogenesis-related molecular pathway in skeletal muscles. PMID:28005993

  14. Sleep disorders in spinal and bulbar muscular atrophy (Kennedy's disease): a controlled polysomnographic and self-reported questionnaires study.

    PubMed

    Romigi, Andrea; Liguori, Claudio; Placidi, Fabio; Albanese, Maria; Izzi, Francesca; Uasone, Elisabetta; Terracciano, Chiara; Marciani, Maria Grazia; Mercuri, Nicola Biagio; Ludovisi, Raffaella; Massa, Roberto

    2014-05-01

    No data are available regarding the occurrence of sleep disorders in spinal and bulbar muscular atrophy (SBMA). We investigated the sleep-wake cycle in SBMA patients compared with healthy subjects. Nine SBMA outpatients and nine age-matched and sex-matched healthy controls were evaluated. Subjective quality of sleep was assessed by means of the Pittsburgh Sleep Quality Index (PSQI). The Epworth Sleepiness Scale was used in order to evaluate excessive daytime sleepiness. All participants underwent a 48-h polysomnography followed by the multiple sleep latency test. Time in bed, total sleep time and sleep efficiency were significantly lower in SBMA than controls. Furthermore, the apnea-hypopnea index (AHI) was significantly higher in SBMA than controls. Obstructive sleep apnea (OSA: AHI >5/h) was evident in 6/9 patients (66.6 %). REM sleep without atonia was evident in three patients also affected by OSA and higher AHI in REM; 2/9 (22.2 %) SBMA patients showed periodic limb movements in sleep. The global PSQI score was higher in SBMA versus controls. Sleep quality in SBMA is poorer than in controls. OSA is the most common sleep disorder in SBMA. The sleep impairment could be induced both by OSA or/and the neurodegenerative processes involving crucial areas regulating the sleep-wake cycle.

  15. Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy.

    PubMed

    Yamada, Shinichiro; Hashizume, Atsushi; Hijikata, Yasuhiro; Inagaki, Tomonori; Suzuki, Keisuke; Kondo, Naohide; Kawai, Kaori; Noda, Seiya; Nakanishi, Hirotaka; Banno, Haruhiko; Hirakawa, Akihiro; Koike, Haruki; Halievski, Katherine; Jordan, Cynthia L; Katsuno, Masahisa; Sobue, Gen

    2016-01-01

    The aim of this study was to characterize the respiratory function profile of subjects with spinal and bulbar muscular atrophy (SBMA), and to explore the underlying pathological mechanism by comparing the clinical and biochemical indices of this disease with those of amyotrophic lateral sclerosis (ALS). We enrolled male subjects with SBMA (n = 40) and ALS (n = 25) along with 15 healthy control subjects, and assessed their respiratory function, motor function, and muscle strength. Predicted values of peak expiratory flow (%PEF) and forced vital capacity were decreased in subjects with SBMA compared with controls. In SBMA, both values were strongly correlated with the trunk subscores of the motor function tests and showed deterioration relative to disease duration. Compared with activities of daily living (ADL)-matched ALS subjects, %PEF, tongue pressure, and grip power were substantially decreased in subjects with SBMA. Both immunofluorescence and RT-PCR demonstrated a selective decrease in the expression levels of the genes encoding the myosin heavy chains specific to fast-twitch fibers in SBMA subjects. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and peroxisome proliferator-activated receptor delta were up-regulated in SBMA compared with ALS and controls. In conclusion, %PEF is a disease-specific respiratory marker for the severity and progression of SBMA. Explosive muscle strength, including %PEF, was selectively affected in subjects with SBMA and was associated with activation of the mitochondrial biogenesis-related molecular pathway in skeletal muscles.

  16. Morphological changes of skeletal muscle in spinal and bulbar muscular atrophy (SBMA), Kennedy's disease: a case report.

    PubMed

    Acewicz, Albert; Wierzba-Bobrowicz, Teresa; Lewandowska, Eliza; Sienkiewicz-Jarosz, Halina; Sulek, Anna; Antczak, Jakub; Rakowicz, Maria; Ryglewicz, Danuta

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is an X-linked recessive disease affecting lower motor neurons. In the present case report, we describe morphological changes in a muscle biopsy obtained from a 62-year-old patient with gynecomastia and with the following neurological symptoms: dysphagia, dysarthria, wasting and fasciculation of the tongue, proximal weakness, fasciculations in the limb muscles, and an absence of all tendon reflexes. Neurogenic alternations were predominantly observed using light and electron microscopy. The angulated atrophic muscle fibers formed bundles. The numerous nuclei were pyknotic or pale, some of them were also ubiquitin positive; they were grouped inside so-called "nuclear sacks". At the ultrastructural level, atrophic muscle fibers revealed disruption and loss of sarcomeres, duplication of Z-line, and rod-like structures. The nuclei, often with irregular shapes, revealed varying degrees of chromatin condensation, from dispersed to highly condensed, like pyknotic nuclei. Occasionally electron-dense inclusions in the nuclei were found. Some myogenic features like hypertrophic muscle fibers and proliferation of connective tissue were also visible. The neurogenic and myogenic pathological changes suggested SBMA, which was confirmed with genetic analysis (trinucleotide CAG (glutamie)-repeat expansion in the androgen-receptor gene).

  17. Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy.

    PubMed

    Polanco, Maria Josè; Parodi, Sara; Piol, Diana; Stack, Conor; Chivet, Mathilde; Contestabile, Andrea; Miranda, Helen C; Lievens, Patricia M-J; Espinoza, Stefano; Jochum, Tobias; Rocchi, Anna; Grunseich, Christopher; Gainetdinov, Raul R; Cato, Andrew C B; Lieberman, Andrew P; La Spada, Albert R; Sambataro, Fabio; Fischbeck, Kenneth H; Gozes, Illana; Pennuto, Maria

    2016-12-21

    Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMA belongs to the family of polyQ diseases, which are fatal neurodegenerative disorders mainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the form of aggregates. The neurotoxicity of the polyQ proteins can be modified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments. We sought to identify signaling pathways that modulate polyQ-AR phosphorylation for therapy development. We report that cyclin-dependent kinase 2 (CDK2) phosphorylates polyQ-AR specifically at Ser(96) Phosphorylation of polyQ-AR by CDK2 increased protein stabilization and toxicity and is negatively regulated by the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway. To translate these findings into therapy, we developed an analog of pituitary adenylyl cyclase activating polypeptide (PACAP), a potent activator of the AC/PKA pathway. Chronic intranasal administration of the PACAP analog to knock-in SBMA mice reduced Ser(96) phosphorylation, promoted polyQ-AR degradation, and ameliorated disease outcome. These results provide proof of principle that noninvasive therapy based on the use of PACAP analogs is a therapeutic option for SBMA.

  18. Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

    PubMed Central

    Milioto, Carmelo; Malena, Adriana; Maino, Eleonora; Polanco, Maria J.; Marchioretti, Caterina; Borgia, Doriana; Pereira, Marcelo Gomes; Blaauw, Bert; Lieberman, Andrew P.; Venturini, Roberta; Plebani, Mario; Sambataro, Fabio; Vergani, Lodovica; Pegoraro, Elena; Sorarù, Gianni; Pennuto, Maria

    2017-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA. PMID:28117338

  19. Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes.

    PubMed

    Milioto, Carmelo; Malena, Adriana; Maino, Eleonora; Polanco, Maria J; Marchioretti, Caterina; Borgia, Doriana; Pereira, Marcelo Gomes; Blaauw, Bert; Lieberman, Andrew P; Venturini, Roberta; Plebani, Mario; Sambataro, Fabio; Vergani, Lodovica; Pegoraro, Elena; Sorarù, Gianni; Pennuto, Maria

    2017-01-24

    Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower motor neurons. SBMA is caused by expansions of a polyglutamine tract in the gene coding for androgen receptor (AR). Expression of polyglutamine-expanded AR causes damage to motor neurons and skeletal muscle cells. Here we investigated the effect of β-agonist stimulation in SBMA myotube cells derived from mice and patients, and in knock-in mice. We show that treatment of myotubes expressing polyglutamine-expanded AR with the β-agonist clenbuterol increases their size. Clenbuterol activated the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway and decreased the accumulation of polyglutamine-expanded AR. Treatment of SBMA knock-in mice with clenbuterol, which was started at disease onset, ameliorated motor function and extended survival. Clenbuterol improved muscle pathology, attenuated the glycolytic-to-oxidative metabolic alterations occurring in SBMA muscles and induced hypertrophy of both glycolytic and oxidative fibers. These results indicate that β-agonist stimulation is a novel therapeutic strategy for SBMA.

  20. Characterization of behavioral and neuromuscular junction phenotypes in a novel allelic series of SMA mouse models.

    PubMed

    Osborne, Melissa; Gomez, Daniel; Feng, Zhihua; McEwen, Corissa; Beltran, Jose; Cirillo, Kim; El-Khodor, Bassem; Lin, Ming-Yi; Li, Yun; Knowlton, Wendy M; McKemy, David D; Bogdanik, Laurent; Butts-Dehm, Katherine; Martens, Kimberly; Davis, Crystal; Doty, Rosalinda; Wardwell, Keegan; Ghavami, Afshin; Kobayashi, Dione; Ko, Chien-Ping; Ramboz, Sylvie; Lutz, Cathleen

    2012-10-15

    A number of mouse models for spinal muscular atrophy (SMA) have been genetically engineered to recapitulate the severity of human SMA by using a targeted null mutation at the mouse Smn1 locus coupled with the transgenic addition of varying copy numbers of human SMN2 genes. Although this approach has been useful in modeling severe SMA and very mild SMA, a mouse model of the intermediate form of the disease would provide an additional research tool amenable for drug discovery. In addition, many of the previously engineered SMA strains are multi-allelic by design, containing a combination of transgenes and targeted mutations in the homozygous state, making further genetic manipulation difficult. A new genetic engineering approach was developed whereby variable numbers of SMN2 sequences were incorporated directly into the murine Smn1 locus. Using combinations of these alleles, we generated an allelic series of SMA mouse strains harboring no, one, two, three, four, five, six or eight copies of SMN2. We report here the characterization of SMA mutants in this series that displayed a range in disease severity from embryonic lethal to viable with mild neuromuscular deficits.

  1. Mouse models of SMA: tools for disease characterization and therapeutic development.

    PubMed

    Bebee, Thomas W; Dominguez, Catherine E; Chandler, Dawn S

    2012-08-01

    Mouse models of human disease are an important tool for studying disease mechanism and manifestation in a way that is physiologically relevant. Spinal muscular atrophy (SMA) is a neurodegenerative disease that is caused by deletion or mutation of the survival motor neuron gene (SMN1). The SMA disease is present in a spectrum of disease severities ranging from infant mortality, in the most severe cases, to minor motor impairment, in the mildest cases. The variability of disease severity inversely correlates with the copy number, and thus expression of a second, partially functional survival motor neuron gene, SMN2. Correspondingly, a plethora of mouse models has been developed to mimic these different types of SMA. These models express a range of SMN protein levels and extensively cover the severe and mild types of SMA, with neurological and physiological manifestation of disease supporting the relevance of these models. The SMA models provide a strong background for studying SMA and have already shown to be useful in pre-clinical therapeutic studies. The purpose of this review is to succinctly summarize the genetic and disease characteristic of the SMA mouse models and to highlight their use for therapeutic testing.

  2. Quantitative muscle ultrasound measures rapid declines over time in children with SMA type 1.

    PubMed

    Ng, Kay W; Connolly, Anne M; Zaidman, Craig M

    2015-11-15

    Muscles are small in spinal muscular atrophy (SMA). It is not known if muscle size changes over time in SMA type 1. We quantified changes over time in muscle size and echointensity during two repeated ultrasound examinations of unilateral proximal (biceps brachii/brachialis and quadriceps) and distal (anterior forearm flexors and tibialis anterior) muscles in three children with SMA type 1. We compared muscle thickness (MT) to body weight-dependent normal reference values. Children were 1, 6, and 11months old at baseline and had 2, 2 and 4 months between ultrasound examinations, respectively. At baseline, MT was normal for weight in all muscles except an atrophic quadriceps in the oldest child. MT decreased and echointensity increased (worsened) over time. At follow up, MT was below normal for weight in the quadriceps in all three children, in the biceps/brachioradialis in two, and in the anterior forearm in one. Tibialis anterior MT remained normal for weight in all three children. Muscle echointensity increased over time in all muscles and, on average, more than doubled in two children. In children with SMA type 1, muscle atrophies and becomes hyperechoic over time. Quantitative muscle ultrasound measures disease progression in SMA type 1 that warrants additional study in more children.

  3. Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585.

    PubMed

    Schreml, Julia; Riessland, Markus; Paterno, Mario; Garbes, Lutz; Roßbach, Kristina; Ackermann, Bastian; Krämer, Jan; Somers, Eilidh; Parson, Simon H; Heller, Raoul; Berkessel, Albrecht; Sterner-Kock, Anja; Wirth, Brunhilde

    2013-06-01

    Spinal muscular atrophy (SMA) is the leading genetic cause of early childhood death worldwide and no therapy is available today. Many drugs, especially histone deacetylase inhibitors (HDACi), increase SMN levels. As all HDACi tested so far only mildly ameliorate the SMA phenotype or are unsuitable for use in humans, there is still need to identify more potent drugs. Here, we assessed the therapeutic power of the pan-HDACi JNJ-26481585 for SMA, which is currently used in various clinical cancer trials. When administered for 64 h at 100 nM, JNJ-26481585 upregulated SMN levels in SMA fibroblast cell lines, including those from non-responders to valproic acid. Oral treatment of Taiwanese SMA mice and control littermates starting at P0 showed no overt extension of lifespan, despite mild improvements in motor abilities and weight progression. Many treated and untreated animals showed a very rapid decline or unexpected sudden death. We performed exploratory autopsy and histological assessment at different disease stages and found consistent abnormalities in the intestine, heart and lung and skeletal muscle vasculature of SMA animals, which were not prevented by JNJ-26481585 treatment. Interestingly, some of these features may be only indirectly caused by α-motoneuron function loss but may be major life-limiting factors in the course of disease. A better understanding of - primary or secondary - non-neuromuscular organ involvement in SMA patients may improve standard of care and may lead to reassessment of how to investigate SMA patients clinically.

  4. Association of IgM monoclonal gammopathy with progressive muscular atrophy and multifocal motor neuropathy: a case-control study.

    PubMed

    Vlam, Lotte; Piepers, Sanne; Sutedja, Nadia A; Jacobs, Bart C; Tio-Gillen, Anne P; Stam, Marloes; Franssen, Hessel; Veldink, Jan H; Cats, Elisabeth A; Notermans, Nicolette C; Bloem, Andries C; Wadman, Renske I; van der Pol, W-Ludo; van den Berg, Leonard H

    2015-03-01

    Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN.

  5. Distinct Etiological Roles for Myocytes and Motor Neurons in a Mouse Model of Kennedy's Disease/Spinobulbar Muscular Atrophy.

    PubMed

    Ramzan, Firyal; McPhail, Mike; Rao, Pengcheng; Mo, Kaiguo; Halievski, Katherine; Swift-Gallant, Ashlyn; Mendoza-Viveros, Lucia; Cheng, Hai-Ying M; Monks, D Ashley

    2015-04-22

    Polyglutamine (polyQ) expansion of the androgen receptor (AR) causes Kennedy's disease/spinobulbar muscular atrophy (KD/SBMA) through poorly defined cellular mechanisms. Although KD/SBMA has been thought of as a motor neuron disease, recent evidence indicates a key role for skeletal muscle. To resolve which early aspects of the disease can be caused by neurogenic or myogenic mechanisms, we made use of the tet-On and Cre-loxP genetic systems to selectively and acutely express polyQ AR in either motor neurons (NeuroAR) or myocytes (MyoAR) of transgenic mice. After 4 weeks of transgene induction in adulthood, deficits in gross motor function were seen in NeuroAR mice, but not MyoAR mice. Conversely, reduced size of fast glycolytic fibers and alterations in expression of candidate genes were observed only in MyoAR mice. Both NeuroAR and MyoAR mice exhibited reduced oxidative capacity in skeletal muscles, as well as a shift in fast fibers from oxidative to glycolytic. Markers of oxidative stress were increased in the muscle of NeuroAR mice and were reduced in motor neurons of both NeuroAR and MyoAR mice. Despite secondary pathology in skeletal muscle and behavioral deficits, no pathological signs were observed in motor neurons of NeuroAR mice, possibly due to relatively low levels of polyQ AR expression. These results indicate that polyQ AR in motor neurons can produce secondary pathology in muscle. Results also support both neurogenic and myogenic contributions of polyQ AR to several acute aspects of pathology and provide further evidence for disordered cellular respiration in KD/SBMA skeletal muscle.

  6. Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy.

    PubMed

    Giorgetti, Elisa; Rusmini, Paola; Crippa, Valeria; Cristofani, Riccardo; Boncoraglio, Alessandra; Cicardi, Maria E; Galbiati, Mariarita; Poletti, Angelo

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease due to a CAG triplet-repeat expansion in the androgen receptor (AR) gene, which is translated into an elongated polyglutamine (polyQ) tract in AR protein (ARpolyQ). ARpolyQ toxicity is activated by the AR ligand testosterone (or dihydrotestosterone), and the polyQ triggers ARpolyQ misfolding and aggregation in spinal cord motoneurons and muscle cells. In motoneurons, testosterone triggers nuclear toxicity by inducing AR nuclear translocation. Thus, (i) prevention of ARpolyQ nuclear localization, combined with (ii) an increased ARpolyQ cytoplasmic clearance, should reduce its detrimental activity. Using the antiandrogen Bicalutamide (Casodex(®)), which slows down AR activation and nuclear translocation, and the disaccharide trehalose, an autophagy activator, we found that, in motoneurons, the two compounds together reduced ARpolyQ insoluble forms with higher efficiency than that obtained with single treatments. The ARpolyQ clearance was mediated by trehalose-induced autophagy combined with the longer cytoplasmic retention of ARpolyQ bound to Bicalutamide. This allows an increased recognition of misfolded species by the autophagic system prior to their migration into the nucleus. Interestingly, the combinatory use of trehalose and Bicalutamide was also efficient in the removal of insoluble species of AR with a very long polyQ (Q112) tract, which typically aggregates into the cell nuclei. Collectively, these data suggest that the combinatory use of Bicalutamide and trehalose is a novel approach to facilitate ARpolyQ clearance that has to be tested in other cell types target of SBMA (i.e. muscle cells) and in vivo in animal models of SBMA.

  7. Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy.

    PubMed

    Dossena, Marta; Bedini, Gloria; Rusmini, Paola; Giorgetti, Elisa; Canazza, Alessandra; Tosetti, Valentina; Salsano, Ettore; Sagnelli, Anna; Mariotti, Caterina; Gellera, Cinzia; Navone, Stefania Elena; Marfia, Giovanni; Alessandri, Giulio; Corsi, Fabio; Parati, Eugenio Agostino; Pareyson, Davide; Poletti, Angelo

    2014-01-01

    Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, we propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs) as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage to express only ARpolyQ, and not the wild type AR allele. Therefore, we isolated and characterized adipose-derived MSCs from three SBMA patients (ADSC from Kennedy's patients, ADSCK) and three control volunteers (ADSCs). We found that both ADSCs and ADSCKs express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes), whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on our mesenchymal cultures we found lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA.

  8. ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study.

    PubMed

    Filosto, Massimiliano; Aureli, Massimo; Castellotti, Barbara; Rinaldi, Fabrizio; Schiumarini, Domitilla; Valsecchi, Manuela; Lualdi, Susanna; Mazzotti, Raffaella; Pensato, Viviana; Rota, Silvia; Gellera, Cinzia; Filocamo, Mirella; Padovani, Alessandro

    2016-11-01

    ASAH1 gene encodes for acid ceramidase that is involved in the degradation of ceramide into sphingosine and free fatty acids within lysosomes. ASAH1 variants cause both the severe and early-onset Farber disease and rare cases of spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by childhood onset of proximal muscle weakness and atrophy due to spinal motor neuron degeneration followed by occurrence of severe and intractable myoclonic seizures and death in the teenage years. We studied two subjects, a 30-year-old pregnant woman and her 17-year-old sister, affected with a very slowly progressive non-5q SMA since childhood. No history of seizures or myoclonus has been reported and EEG was unremarkable. The molecular study of ASAH1 gene showed the presence of the homozygote nucleotide variation c.124A>G (r.124a>g) that causes the amino acid substitution p.Thr42Ala. Biochemical evaluation of cultured fibroblasts showed both reduction in ceramidase activity and accumulation of ceramide compared with the normal control. This study describes for the first time the association between ASAH1 variants and an adult SMA phenotype with no myoclonic epilepsy nor death in early age, thus expanding the phenotypic spectrum of ASAH1-related SMA. ASAH1 molecular analysis should be considered in the diagnostic testing of non-5q adult SMA patients.

  9. Transcriptional activator TAp63 is upregulated in muscular atrophy during ALS and induces the pro-atrophic ubiquitin ligase Trim63

    PubMed Central

    von Grabowiecki, Yannick; Abreu, Paula; Blanchard, Orphee; Palamiuc, Lavinia; Benosman, Samir; Mériaux, Sophie; Devignot, Véronique; Gross, Isabelle; Mellitzer, Georg; Gonzalez de Aguilar, José L; Gaiddon, Christian

    2016-01-01

    Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, uncovering a p53 deregulation as common denominator. We then characterized the induction of several p53 family members (p53, p63, p73) and a correlation between the levels of p53 family target genes and the severity of muscle atrophy in ALS patients and mice. In particular, we observed increased p63 protein levels in the fibers of atrophic muscles via denervation-dependent and -independent mechanisms. At a functional level, we demonstrated that TAp63 and p53 transactivate the promoter and increased the expression of Trim63 (MuRF1), an effector of muscle atrophy. Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63. DOI: http://dx.doi.org/10.7554/eLife.10528.001 PMID:26919175

  10. Targeting RNA-splicing for SMA treatment.

    PubMed

    Zhou, Jianhua; Zheng, Xuexiu; Shen, Haihong

    2012-03-01

    The central dogma of DNA-RNA-protein was established more than 40 years ago. However, important biological processes have been identified since the central dogma was developed. For example, methylation is important in the regulation of transcription. In contrast, proteins, are more complex due to modifications such as phosphorylation, glycosylation, ubiquitination, or cleavage. RNA is the mediator between DNA and protein, but it can also be modulated at several levels. Among the most profound discoveries of RNA regulation is RNA splicing. It has been estimated that 80% of pre-mRNA undergo alternative splicing, which exponentially increases biological information flow in cellular processes. However, an increased number of regulated steps inevitably accompanies an increased number of errors. Abnormal splicing is often found in cells, resulting in protein dysfunction that causes disease. Splicing of the survival motor neuron (SMN) gene has been extensively studied during the last two decades. Accumulating knowledge on SMN splicing has led to speculation and search for spinal muscular atrophy (SMA) treatment by stimulating the inclusion of exon 7 into SMN mRNA. This mini-review summaries the latest progress on SMN splicing research as a potential treatment for SMA disease.

  11. Pathological impact of SMN2 mis-splicing in adult SMA mice.

    PubMed

    Sahashi, Kentaro; Ling, Karen K Y; Hua, Yimin; Wilkinson, John Erby; Nomakuchi, Tomoki; Rigo, Frank; Hung, Gene; Xu, David; Jiang, Ya-Ping; Lin, Richard Z; Ko, Chien-Ping; Bennett, C Frank; Krainer, Adrian R

    2013-10-01

    Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. The related SMN2 gene expresses suboptimal levels of functional SMN protein, due to a splicing defect. Many SMA patients reach adulthood, and there is also adult-onset (type IV) SMA. There is currently no animal model for adult-onset SMA, and the tissue-specific pathogenesis of post-developmental SMN deficiency remains elusive. Here, we use an antisense oligonucleotide (ASO) to exacerbate SMN2 mis-splicing. Intracerebroventricular ASO injection in adult SMN2-transgenic mice phenocopies key aspects of adult-onset SMA, including delayed-onset motor dysfunction and relevant histopathological features. SMN2 mis-splicing increases during late-stage disease, likely accelerating disease progression. Systemic ASO injection in adult mice causes peripheral SMN2 mis-splicing and affects prognosis, eliciting marked liver and heart pathologies, with decreased IGF1 levels. ASO dose-response and time-course studies suggest that only moderate SMN levels are required in the adult central nervous system, and treatment with a splicing-correcting ASO shows a broad therapeutic time window. We describe distinctive pathological features of adult-onset and early-onset SMA.

  12. Selective vulnerability of spinal and cortical motor neuron subpopulations in delta7 SMA mice.

    PubMed

    d'Errico, Paolo; Boido, Marina; Piras, Antonio; Valsecchi, Valeria; De Amicis, Elena; Locatelli, Denise; Capra, Silvia; Vagni, Francesco; Vercelli, Alessandro; Battaglia, Giorgio

    2013-01-01

    Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinal motor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of ∆7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the ∆7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping better therapeutic options for affected patients.

  13. Cure SMA

    MedlinePlus

    ... the SMA drug pipeline. Together, we're making real progress toward a treatment and a cure. Latest ... Announce SPINRAZA (nusinersen) Meets Primary Endpoint at Interim Analysis of Phase 3 CHERISH Study Biogen and Ionis ...

  14. Spinal Muscular Atrophy

    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:// ...

  15. Spinal Muscular Atrophy

    MedlinePlus

    ... with symptoms and prevent complications. They may include machines to help with breathing, nutritional support, physical therapy, and medicines. NIH: National Institute of Neurological Disorders and Stroke

  16. Spinal Muscular Atrophy

    MedlinePlus

    ... of several hereditary diseases that progressively destroy lower motor neurons—nerve cells in the brain stem and ... such as speaking, walking, breathing, and swallowing. Lower motor neurons control movement in the arms, legs, chest, ...

  17. Proteasome-mediated Proteolysis of the Polyglutamine-expanded Androgen Receptor Is a Late Event in Spinal and Bulbar Muscular Atrophy (SBMA) Pathogenesis*

    PubMed Central

    Heine, Erin M.; Berger, Tamar R.; Pluciennik, Anna; Orr, Christopher R.; Zboray, Lori; Merry, Diane E.

    2015-01-01

    Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a “toxic fragment” that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, becoming proteolyzed to a smaller fragment through a process requiring the proteasome after it is incorporated into intranuclear inclusions. Moreover, the toxicity-predicting conformational antibody 3B5H10 bound to soluble full-length AR species but not to fragment-containing nuclear inclusions. These data suggest that the AR is toxic as a full-length protein, challenging the notion of polyglutamine protein fragment-associated toxicity by redefining the role of AR proteolysis in spinal and bulbar muscular atrophy pathogenesis. PMID:25795778

  18. Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis.

    PubMed

    Heine, Erin M; Berger, Tamar R; Pluciennik, Anna; Orr, Christopher R; Zboray, Lori; Merry, Diane E

    2015-05-15

    Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a "toxic fragment" that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, becoming proteolyzed to a smaller fragment through a process requiring the proteasome after it is incorporated into intranuclear inclusions. Moreover, the toxicity-predicting conformational antibody 3B5H10 bound to soluble full-length AR species but not to fragment-containing nuclear inclusions. These data suggest that the AR is toxic as a full-length protein, challenging the notion of polyglutamine protein fragment-associated toxicity by redefining the role of AR proteolysis in spinal and bulbar muscular atrophy pathogenesis.

  19. Refinement of the spinal muscular atrophy locus to the interval between D5S435 and MAP1B

    SciTech Connect

    Soares, V.M.; Brzustowicz, L.M.; Kleyn, P.W.; Knowles, J.A.; Palmer, D.A.; Asokan, S.; Penchaszadeh, G.K.; Gilliam, T.C. ); Munsat, T.L. )

    1993-02-01

    The childhood-onset SMA locus has been mapped to chromosome 5q13, in a region bounded by the proximal locus, D5S6, and the closely linked distal loci, D5S112 and MAP1B. We now describe a highly polymorphic, tightly linked microsatellite marker (D5S435) that is very likely the closet proximal marker to the SMA locus. Multipoint linkage analysis firmly establishes the following order of markers at 5q13; centromere-D5S76-D5S6-D5S435-MAP1B/D5S112-D5S39-telomere. The data indicate that SMA resides in an approximately 0.7-cM (range 01.-2.1) region between D5S435 and MAP1B. This finding reduces by approximately fourfold the genetic region that most likely harbors the SMA locus and will facilitate the physical mapping and cloning of the disease gene region. 24 refs., 3 figs., 1 tab.

  20. Increased IGF-1 in muscle modulates the phenotype of severe SMA mice.

    PubMed

    Bosch-Marcé, Marta; Wee, Claribel D; Martinez, Tara L; Lipkes, Celeste E; Choe, Dong W; Kong, Lingling; Van Meerbeke, James P; Musarò, Antonio; Sumner, Charlotte J

    2011-05-01

    Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor function and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myogenic differentiation and generates myocyte hypertrophy in vitro and in vivo. We hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMAΔ7 mice. SMAΔ7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared with mIGF-1-negative SMA littermates (median survival = 14 versus 10 days, respectively, log-rank P = 0.025). Surprisingly, this was not associated with a significant improvement in motor behavior. Treatment of both mIGF-1(NEG) and mIGF-1(POS) SMA mice with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior, but the combination of mIGF-1 and TSA treatment was not synergistic. These results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that therapeutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients.

  1. VPA response in SMA is suppressed by the fatty acid translocase CD36.

    PubMed

    Garbes, Lutz; Heesen, Ludwig; Hölker, Irmgard; Bauer, Tim; Schreml, Julia; Zimmermann, Katharina; Thoenes, Michaela; Walter, Michael; Dimos, John; Peitz, Michael; Brüstle, Oliver; Heller, Raoul; Wirth, Brunhilde

    2013-01-15

    Functional loss of SMN1 causes proximal spinal muscular atrophy (SMA), the most common genetic condition accounting for infant lethality. Hence, the hypomorphic copy gene SMN2 is the only resource of functional SMN protein in SMA patients and influences SMA severity in a dose-dependent manner. Consequently, current therapeutic approaches focus on SMN2. Histone deacetylase inhibitors (HDACi), such as the short chain fatty acid VPA (valproic acid), ameliorate the SMA phenotype by activating the SMN2 expression. By analyzing blood SMN2 expression in 16 VPA-treated SMA patients, about one-third of individuals were identified as positive responders presenting increased SMN2 transcript levels. In 66% of enrolled patients, a concordant response was detected in the respective fibroblasts. Most importantly, by taking the detour of reprograming SMA patients' fibroblasts, we showed that the VPA response was maintained even in GABAergic neurons derived from induced pluripotent stem cells (iPS) cells. Differential expression microarray analysis revealed a complete lack of response to VPA in non-responders, which was associated with an increased expression of the fatty acid translocase CD36. The pivotal role of CD36 as the cause of non-responsiveness was proven in various in vitro approaches. Most importantly, knockdown of CD36 in SMA fibroblasts converted non- into pos-responders. In summary, the concordant response from blood to the central nervous system (CNS) to VPA may allow selection of pos-responders prior to therapy. Increased CD36 expression accounts for VPA non-responsiveness. These findings may be essential not only for SMA but also for other diseases such as epilepsy or migraine frequently treated with VPA.

  2. Increased IGF-1 in muscle modulates the phenotype of severe SMA mice

    PubMed Central

    Bosch-Marcé, Marta; Wee, Claribel D.; Martinez, Tara L.; Lipkes, Celeste E.; Choe, Dong W.; Kong, Lingling; Van Meerbeke, James P.; Musarò, Antonio; Sumner, Charlotte J.

    2011-01-01

    Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor function and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myogenic differentiation and generates myocyte hypertrophy in vitro and in vivo. We hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMAΔ7 mice. SMAΔ7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared with mIGF-1-negative SMA littermates (median survival = 14 versus 10 days, respectively, log-rank P = 0.025). Surprisingly, this was not associated with a significant improvement in motor behavior. Treatment of both mIGF-1NEG and mIGF-1POS SMA mice with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior, but the combination of mIGF-1 and TSA treatment was not synergistic. These results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that therapeutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients. PMID:21325354

  3. [Translation and validation of the Egen Klassifikation scale for the Spanish population: functional assessment for non-ambulatory individuals with Duchenne's muscular dystrophy and spinal muscular atrophy].

    PubMed

    Fagoaga, Joaquín; Girabent-Farrés, Montserrat; Bagur-Calafat, Caritat; Febrer, Anna; Steffensen, Birgit F

    2013-06-01

    Introduccion. La escala Egen Klassifikation (EK) es un cuestionario que valora la capacidad funcional de personas con distrofia muscular de Duchenne y atrofia muscular espinal no ambulantes y que estan en silla de ruedas. Objetivo. Traducir y validar la EK para la poblacion espanola, como instrumento de medicion de la capacidad funcional en dichos pacientes. Pacientes y metodos. Se realiza, en primer lugar, una traduccion-retrotraduccion de la EK en la poblacion espanola y, posteriormente, se practica el estudio de fiabilidad de la version traducida al espanol de dicha escala. Se llevan a cabo tres mediciones a 30 pacientes con edades comprendidas entre 4 y 67 anos. Dos de estas mediciones se realizan por el mismo observador, y la tercera, por un segundo observador, para evaluar la concordancia intra e interobservador. Resultados. Los valores obtenidos referidos a la puntuacion total de los items de la escala, suma EK, reflejan un indice de fiabilidad del 0,995. Tambien muestran una fiabilidad superior a 0,86 en cada uno de los items, tanto en las observaciones intra como interobservador. Conclusiones. La version espanola de la EK es un instrumento valido y fiable para la poblacion espanola, como herramienta de medicion de la capacidad funcional en pacientes con distrofia muscular de Duchenne y atrofia muscular espinal no ambulantes y que estan en silla de ruedas.

  4. Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models.

    PubMed

    Osman, Erkan Y; Miller, Madeline R; Robbins, Kate L; Lombardi, Abby M; Atkinson, Arleigh K; Brehm, Amanda J; Lorson, Christian L

    2014-09-15

    Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the loss of Survival Motor Neuron-1 (SMN1). In all SMA patients, a nearly identical copy gene called SMN2 is present, which produces low levels of functional protein owing to an alternative splicing event. To prevent exon-skipping, we have targeted an intronic repressor, Element1 (E1), located upstream of SMN2 exon 7 using Morpholino-based antisense oligonucleotides (E1(MO)-ASOs). A single intracerebroventricular injection in the relatively severe mouse model of SMA (SMNΔ7 mouse model) elicited a robust induction of SMN protein, and mean life span was extended from an average survival of 13 to 54 days following a single dose, consistent with large weight gains and a correction of the neuronal pathology. Additionally, E1(MO)-ASO treatment in an intermediate SMA mouse (SMN(RT) mouse model) significantly extended life span by ∼700% and weight gain was comparable with the unaffected animals. While a number of experimental therapeutics have targeted the ISS-N1 element of SMN2 pre-mRNA, the development of E1 ASOs provides a new molecular target for SMA therapeutics that dramatically extends survival in two important pre-clinical models of disease.

  5. [Evolution of functional capacity, assessed with the Egen Klassifikation scale, in the Spanish population with spinal muscular atrophy or Duchenne muscular dystrophy. A three year longitudinal study].

    PubMed

    Fagoaga, J; Girabent-Farres, M; Bagur-Calafat, C; Steffensen, B F

    2015-10-16

    Introduccion. La atrofia muscular espinal (AME) y la distrofia muscular de Duchenne (DMD) son dos enfermedades neuromusculares que evolucionan con perdida progresiva de la fuerza muscular y, en consecuencia, perdida de la capacidad funcional. La valoracion con escalas de medicion permite conocer mejor y cuantificar esta involucion, asi como tomar decisiones terapeuticas para anticiparse a los problemas y mejorar la calidad de vida de las personas afectas de estas patologias. Objetivo. Estudiar los cambios de la capacidad funcional de un grupo de pacientes con AME y DMD en un periodo de tres años. Pacientes y metodos. Diecinueve personas de la poblacion española afectas de AME o DMD, a las que se valoro con la escala Egen Klassifikation en dos ocasiones, en un periodo de tres años. Resultados. Los resultados obtenidos reflejan una disminucion de la capacidad funcional de estas personas durante este periodo de tiempo, con una diferencia significativa en la suma total de la escala (p = 0,003). Todos los items de la escala tuvieron valoraciones inferiores despues de tres años, y se llego a la significacion estadistica en la valoracion de la capacidad de mover las manos y de toser. Conclusion. La capacidad funcional de los pacientes con AME y DMD disminuye de forma significativa en tres años.

  6. Fungal Smn and Spf30 homologues are mainly present in filamentous fungi and genomes with many introns: implications for spinal muscular atrophy.

    PubMed

    Mier, Pablo; Pérez-Pulido, Antonio J

    2012-01-10

    Spinal muscular atrophy is an important rare genetic disease characterized by the loss of motor neurons, where the main gene responsible is smn1. Orthologous genes have only been characterized in a single fungal genome: Schizosaccharomyces pombe. We have searched for putative SMN orthologues in publically available fungal genomes, finding that they are predominately present in filamentous fungi. SMN binding partners and the SPF30 SMN paralogue, which are all involved in mRNA splicing, were found to be present in a similar but non-identical subset of fungal genomes. The Saccharomycces cerevisiae yeast genome contains neither smn1 orthologues nor paralogues and it has been suggested that this might be related to the low number of introns in this yeast. Here we have tested this hypothesis by looking at other fungal genomes. Significantly, we find that fungal genomes with high numbers of introns also possess an SMN orthologue or at least its paralogue, SPF30.

  7. Implication of fetal SMN2 expression in type I SMA pathogenesis: protection or pathological gain of function?

    PubMed

    Soler-Botija, Carolina; Cuscó, Ivón; Caselles, Lídia; López, Eva; Baiget, Montserrat; Tizzano, Eduardo F

    2005-03-01

    Spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron gene 1 (SMN1). The SMN2 gene, which is the highly homologous SMN1 copy that is present in all the patients, is unable to prevent the disease. Most of the SMN1 transcript is full-length, whereas a substantial proportion of the SMN2 transcript lacks exon 7 (delta7). We characterized the developmental expression of SMN2 by comparing control and SMA fetuses. The control spinal cord revealed the highest amount of FL SMN, most of which was of SMN1 origin. When analyzing the SMA spinal cord transcripts, we detected a considerable reduction in the FL/delta7 ratios due to a decrease in the FL and an increase in delta7 isoform. After immunoblot and immunohistochemistry analyses, we found that the amount of SMN2 protein in the SMA spinal cord and muscle was lower than in the controls. However, the results of the expression of SMN2 in intestine, lung, adrenal gland, kidney, and eye, which are unaffected by the disease, were the same in controls and SMA samples. In these tissues, SMN2 may compensate for the absence of SMN1, whereas in SMA motor neurons, a cell-specific dysregulation of the SMN2 expression could favor the onset of the acute form of the disease.

  8. The molecular responses of skeletal muscle satellite cells to continuous expression of IGF-1: implications for the rescue of induced muscular atrophy in aged rats

    NASA Technical Reports Server (NTRS)

    Chakravarthy, M. V.; Booth, F. W.; Spangenburg, E. E.

    2001-01-01

    Approximately 50% of humans older than 85 years have physical frailty due to weak skeletal muscles. This indicates a need for determining mechanisms to combat this problem. A critical cellular factor for postnatal muscle growth is a population of myogenic precursor cells called satellite cells. Given the complex process of sarcopenia, it has been postulated that, at some point in this process, a limited satellite cell proliferation potential could become rate-limiting to the regrowth of old muscles. It is conceivable that if satellite cell proliferative capacity can be maintained or enhanced with advanced age, sarcopenia could potentially be delayed or prevented. Therefore, the purposes of this paper are to describe whether IGF-I can prevent muscular atrophy induced by repeated cycles of hindlimb immobilization, increase the in vitro proliferation in satellite cells from these muscles and, if so, the molecular mechanisms by which IGF-I mediates this increased proliferation. Our results provide evidence that IGF-I can enhance aged muscle regrowth possibly through increased satellite cell proliferation. The results also suggest that IGF-I enhances satellite cell proliferation by decreasing the cell cycle inhibitor, p27Kip1, through the PI3'-K/Akt pathway. These data provide molecular evidence for IGF-I's rescue effect upon aging-associated skeletal muscle atrophy.

  9. SMN deficiency does not induce oxidative stress in SMA iPSC-derived astrocytes or motor neurons.

    PubMed

    Patitucci, Teresa N; Ebert, Allison D

    2016-02-01

    Spinal muscular atrophy (SMA) is a genetic disorder characterized by loss of motor neurons in the spinal cord leading to muscle atrophy and death. Although motor neurons (MNs) are the most obviously affected cells in SMA, recent evidence suggest dysfunction in multiple cell types. Astrocytes are a crucial component of the motor circuit and are intimately involved with MN health and maintenance. We have previously shown that SMA astrocytes are altered both morphologically and functionally early in disease progression, though it is unclear what causes astrocytes to become reactive. Oxidative stress is a common feature among neurodegenerative diseases. Oxidative stress can both induce apoptosis in neurons and can cause astrocytes to become reactive, which are features observed in the SMA induced pluripotent stem cell (iPSC) cultures. Therefore, we asked if oxidative stress contributes to SMA astrocyte pathology. We examined mitochondrial bioenergetics, transcript and protein levels of oxidative and anti-oxidant factors, and reactive oxygen species (ROS) production and found little evidence of oxidative stress. We did observe a significant increase in endogenous catalase expression in SMA iPSCs. While catalase knockdown in SMA iPSCs increased ROS production above basal levels, levels of ROS remained lower than in controls, further arguing against robust oxidative stress in this system. Viral delivery of survival motor neuron (SMN) reversed astrocyte activation and restored catalase levels to normal, without changing mitochondrial respiration or expression of oxidative stress markers. Taken together, these data indicate that SMN deficiency induces astrocyte reactivity, but does not do so through an oxidative stress-mediated process.

  10. Expression of Muscle-Specific MiRNA 206 in the Progression of Disease in a Murine SMA Model

    PubMed Central

    Valsecchi, Valeria; Boido, Marina; De Amicis, Elena; Piras, Antonio; Vercelli, Alessandro

    2015-01-01

    Spinal muscular atrophy (SMA) is a severe neuromuscular disease, the most common in infancy, and the third one among young people under 18 years. The major pathological landmark of SMA is a selective degeneration of lower motor neurons, resulting in progressive skeletal muscle denervation, atrophy, and paralysis. Recently, it has been shown that specific or general changes in the activity of ribonucleoprotein containing micro RNAs (miRNAs) play a role in the development of SMA. Additionally miRNA-206 has been shown to be required for efficient regeneration of neuromuscular synapses after acute nerve injury in an ALS mouse model. Therefore, we correlated the morphology and the architecture of the neuromuscular junctions (NMJs) of quadriceps, a muscle affected in the early stage of the disease, with the expression levels of miRNA-206 in a mouse model of intermediate SMA (SMAII), one of the most frequently used experimental model. Our results showed a decrease in the percentage of type II fibers, an increase in atrophic muscle fibers and a remarkable accumulation of neurofilament (NF) in the pre-synaptic terminal of the NMJs in the quadriceps of SMAII mice. Furthermore, molecular investigation showed a direct link between miRNA-206-HDAC4-FGFBP1, and in particular, a strong up-regulation of this pathway in the late phase of the disease. We propose that miRNA-206 is activated as survival endogenous mechanism, although not sufficient to rescue the integrity of motor neurons. We speculate that early modulation of miRNA-206 expression might delay SMA neurodegenerative pathway and that miRNA-206 could be an innovative, still relatively unexplored, therapeutic target for SMA. PMID:26030275

  11. Expression of Muscle-Specific MiRNA 206 in the Progression of Disease in a Murine SMA Model.

    PubMed

    Valsecchi, Valeria; Boido, Marina; De Amicis, Elena; Piras, Antonio; Vercelli, Alessandro

    2015-01-01

    Spinal muscular atrophy (SMA) is a severe neuromuscular disease, the most common in infancy, and the third one among young people under 18 years. The major pathological landmark of SMA is a selective degeneration of lower motor neurons, resulting in progressive skeletal muscle denervation, atrophy, and paralysis. Recently, it has been shown that specific or general changes in the activity of ribonucleoprotein containing micro RNAs (miRNAs) play a role in the development of SMA. Additionally miRNA-206 has been shown to be required for efficient regeneration of neuromuscular synapses after acute nerve injury in an ALS mouse model. Therefore, we correlated the morphology and the architecture of the neuromuscular junctions (NMJs) of quadriceps, a muscle affected in the early stage of the disease, with the expression levels of miRNA-206 in a mouse model of intermediate SMA (SMAII), one of the most frequently used experimental model. Our results showed a decrease in the percentage of type II fibers, an increase in atrophic muscle fibers and a remarkable accumulation of neurofilament (NF) in the pre-synaptic terminal of the NMJs in the quadriceps of SMAII mice. Furthermore, molecular investigation showed a direct link between miRNA-206-HDAC4-FGFBP1, and in particular, a strong up-regulation of this pathway in the late phase of the disease. We propose that miRNA-206 is activated as survival endogenous mechanism, although not sufficient to rescue the integrity of motor neurons. We speculate that early modulation of miRNA-206 expression might delay SMA neurodegenerative pathway and that miRNA-206 could be an innovative, still relatively unexplored, therapeutic target for SMA.

  12. Paternal isodisomy for chromosome 5 in a child with spinal muscular atropy

    SciTech Connect

    Brzustowicz, L.M.; Penchaszadeh, G.K.; Gilliam, T.C.; Allitto, B.A.; Theve, R.; Michaud, L.; Sugarman, E.; Handelin, B.L.; Chatkupt, S.; Koenigsberger, M.R. )

    1994-03-01

    Paternal isodisomy for chromosomes 5 was detected in a 2-year-old boy with type III spinal muscular atrophy (SMA), an autosomal recessive degenerative disorder of alpha motor neurons, known to map to 5q11.2-13.3. Examination of 17 short-sequence repeat polymorphisms spanning 5p15.1-15.3. to 5q33.3-qter produced no evidence of maternally inherited alleles. Cytogenetic analysis revealed a normal male karyotype, and FISH with probes closely flanking the SMA locus confirmed the presence of two copies of chromosome 5. No developmental abnormalities, other than those attributable to classical childhood-onset SMA, were present. While the absence of a maternally derived chromosome 5 could have produced the symptoms of SMA through the mechanism of genomic imprinting, the lack of more global developmental abnormalities would be unusual. Paternal transmission of two copies of a defective gene at the SMA locus seems to be the most likely cause of disease, but proof of this will have to await the identification of the SMA gene. While uniparental isodisomy is a rare event, it must be considered as a possible mechanism involved in SMA when conducting prenatal testing and counseling for this disorder. 37 refs., 2 figs., 1 tab.

  13. A Korean Case of Juvenile Muscular Atrophy of Distal Upper Extremity (Hirayama Disease) with Dynamic Cervical Cord Compression

    PubMed Central

    Kwon, Ohyun; Lee, Kwang-Woo

    2004-01-01

    We present a Korean case of Hirayama disease with its typical neuroradiological findings of forward displacement of cervical dural sac and compression of the lower cervical cord during neck flexion. A 15-yr-old boy was presented with a one-year history of progressive weakness and atrophy affecting bilateral hands and forearms. The electrodiagnostic findings were compatible with the lesion of the anterior horn cells at the C7, C8, and T1 spinal segments. With neck flexion, cervical magnetic resonance imaging (MRI) showed the anterior shifting of the lower cervical dural sac resulting in the cord compression of those segments. Presumably, this disease might have been prevalent in Korea frequently under the diagnosis of "benign focal amyotrophy". In this regard, we discuss the clinical importance of cervical MRI with neck flexion and anticipate the increasing reports of the case substantiated by its characteristic radiological features. PMID:15483361

  14. Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein.

    PubMed

    Adachi, Hiroaki; Katsuno, Masahisa; Minamiyama, Makoto; Sang, Chen; Pagoulatos, Gerassimos; Angelidis, Charalampos; Kusakabe, Moriaki; Yoshiki, Atsushi; Kobayashi, Yasushi; Doyu, Manabu; Sobue, Gen

    2003-03-15

    Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin-proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.

  15. Conservative care of temporomandibular joint disorder in a 35-year-old patient with spinal muscular atrophy type III: a case study☆

    PubMed Central

    Houle, Sébastien; Descarreaux, Martin

    2009-01-01

    Abstract Objective This article describes the chiropractic clinical management and therapeutic benefits accruing to a patient with temporomandibular joint (TMJ) disorder and spinal muscular atrophy type III. Clinical Features A 35-year-old white man presented at the university chiropractic outpatient clinic with a complaint of masseter muscle pain and mouth-opening restriction. Temporomandibular joint range of motion evaluation revealed restricted opening (11 mm interincisival), and pain was rated by the patient at an intensity of 5 on a pain scale of 0 to 10. Intervention and Outcome Chiropractic care was provided and included TMJ mobilization, myofascial therapy, trigger point therapy, and light spinal mobilizations of the upper cervical vertebrae. Final evaluation of TMJ range of motion showed active opening of 12 mm with absence of pain and muscle tenderness of the jaw. Conclusion This case suggests that a patient with musculoskeletal disorders related to underlying neurodegenerative pathologies may benefit from chiropractic management adapted to their condition. In the present case, chiropractic treatment of the TMJ represented a viable, low-cost approach with limited adverse effects compared with surgery. PMID:19948309

  16. The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/CCdh1 ubiquitin ligase complex

    PubMed Central

    Bott, Laura C.; Salomons, Florian A.; Maric, Dragan; Liu, Yuhong; Merry, Diane; Fischbeck, Kenneth H.; Dantuma, Nico P.

    2016-01-01

    Polyglutamine expansion in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA), an X-linked neuromuscular disease that is fully manifest only in males. It has been suggested that proteins with expanded polyglutamine tracts impair ubiquitin-dependent proteolysis due to their propensity to aggregate, but recent studies indicate that the overall activity of the ubiquitin-proteasome system is preserved in SBMA models. Here we report that AR selectively interferes with the function of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which, together with its substrate adaptor Cdh1, is critical for cell cycle arrest and neuronal architecture. We show that both wild-type and mutant AR physically interact with the APC/CCdh1 complex in a ligand-dependent fashion without being targeted for proteasomal degradation. Inhibition of APC/CCdh1 by mutant but not wild-type AR in PC12 cells results in enhanced neurite outgrowth which is typically followed by rapid neurite retraction and mitotic entry. Our data indicate a role of AR in neuronal differentiation through regulation of APC/CCdh1 and suggest abnormal cell cycle reactivation as a pathogenic mechanism in SBMA. PMID:27312068

  17. [Animal models of neurodegenerative diseases on the road to disease-modifying therapy: spinal and bulbar muscular atrophy].

    PubMed

    Sobue, Gen

    2007-11-01

    SBMA is a hereditary neurodegenerative disease caused by expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. The phenotypic difference with gender, which is a specific feature of SBMA, has been recapitulated in a transgenic mouse model of SBMA expressing the full-length human AR containing 97 CAGs under the control of a cytomegalovirus enhancer and a chicken beta-actin promoter (AR-97Q). Affected SBMA mice demonstrate small body size, short life span, progressive muscle atrophy and weakness as well as reduced cage activity, all of which are markedly pronounced and accelerated in the male SBMA mice, but either not observed or far less severe in the female SBMA mice. There is increasing evidence that testosterone, the ligand of AR, plays a pivotal role in the neurodegeneration in SBMA. The striking success of androgen deprivation therapy in SBMA mouse models has been translated into phase 2, and then phase 3, clinical trials. Moreover, animal studies have also been revealing key molecules in the pathogenesis of SBMA such as heat shock proteins, transcriptional co-activators, and axon motors, suggesting additional therapeutic targets.

  18. Muscular reconstruction to improve the deterioration of facial appearance and speech caused by mandibular atrophy: technique and case reports.

    PubMed

    Bosker, H; Wardle, M L

    1999-08-01

    One of the consequences of severe mandibular atrophy is the loss of attachment of the facial muscles that originate from the alveolar process and basal bone. Another is a loss of vestibular depth and reduction in the width of the attached gingiva. The result is reduced ability to chew, a changed and aged appearance, difficulties with pronunciation, and a reduced range of expressions. The traditional goal of treatment has been to improve the ability to chew. We describe a technique by which all these functions can be improved by a combination of insertion of implants and functional reconstruction of the facial muscles and position of the lips. When the muscles are repositioned, the buccal vestibule is deepened, and the incidence of gingival hyperplasia and infrabony pockets along the posts is eliminated. This treatment, which also rejuvenates the face and improves the ability to speak, should help to overcome the loss of self-confidence and self-esteem of these patients by improving their quality of life.

  19. High expression level of Tra2-β1 is responsible for increased SMN2 exon 7 inclusion in the testis of SMA mice.

    PubMed

    Chen, Yu-Chia; Chang, Jan-Gowth; Jong, Yuh-Jyh; Liu, Ting-Yuan; Yuo, Chung-Yee

    2015-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by deletion or mutation of SMN1 gene. All SMA patients carry a nearly identical SMN2 gene, which produces low level of SMN protein due to mRNA exon 7 exclusion. Previously, we found that the testis of SMA mice (smn-/- SMN2) expresses high level of SMN2 full-length mRNA, indicating a testis-specific mechanism for SMN2 exon 7 inclusion. To elucidate the underlying mechanism, we established primary cultures of testis cells from SMA mice and analyzed them for SMN2 exon 7 splicing. We found that primary testis cells after a 2-hour culture still expressed high level of SMN2 full-length mRNA, but the level decreased after longer cultures. We then compared the protein levels of relevant splicing factors, and found that the level of Tra2-β1 also decreased during testis cell culture, correlated with SMN2 full-length mRNA downregulation. In addition, the testis of SMA mice expressed the highest level of Tra2-β1 among the many tissues examined. Furthermore, overexpression of Tra2-β1, but not ASF/SF2, increased SMN2 minigene exon 7 inclusion in primary testis cells and spinal cord neurons, whereas knockdown of Tra2-β1 decreased SMN2 exon 7 inclusion in primary testis cells of SMA mice. Therefore, our results indicate that high expression level of Tra2-β1 is responsible for increased SMN2 exon 7 inclusion in the testis of SMA mice. This study also suggests that the expression level of Tra2-β1 may be a modifying factor of SMA disease and a potential target for SMA treatment.

  20. Homozygous deletion in the SMN1 gene in asymptomatic individual - genetic counselling issues in SMA-risk families.

    PubMed

    Jędrzejowska, Maria; Szczałuba, Krzysztof; Sielska, Danuta

    2011-01-01

    Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders. The mode of inheritance of SMA is what determines the relatively low risk to off spring of affected persons, sibs of carriers of the pathogenic mutation or their more distant relatives. Nonetheless, the risk in question is increased beyond that in the population in general, thereby indicating the need for preventative measures to be taken in respect of SMA families. We present clinical characteristics of such a SMA-risk family. An apparently unaffected brother (patient) of the proband together with his pregnant wife sought genetic counselling about the SMA risk in their off spring. The estimated a priori risk was of about 0.5% (1 in 200). Molecular diagnostic tests performed in the patient indicated the presence of a homozygous deletion of the SMN1 gene identical to the one detected in the affected proband. The patient's wife was identified as a carrier of the deletion. The conditional risk for off spring of the couple was thus recalculated as 50% (1 in 2). Homozygous deletion of the SMN1 gene in unaffected individuals is a relatively rare event, yet one that nevertheless has significant impact on genetic counselling in SMA families. In these circumstances, molecular confirmation of SMA in such families allows for the provision of competent and reliable genetic advice, as well as for the introduction of secondary preventative measures. It also meets inclusion criteria as regards optional invasive prenatal diagnostic testing in families with a high (.25%) risk of the condition being present in the off spring.

  1. SMA Human iPSC-Derived Motor Neurons Show Perturbed Differentiation and Reduced miR-335-5p Expression

    PubMed Central

    Murdocca, Michela; Ciafrè, Silvia Anna; Spitalieri, Paola; Talarico, Rosa Valentina; Sanchez, Massimo; Novelli, Giuseppe; Sangiuolo, Federica

    2016-01-01

    Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. MicroRNAs (miRNAs) are often reported as playing a key role in regulating neuronal differentiation and fate specification. In this study SMA hiPSCs have been differentiated towards early motor neurons and their molecular and immunocytochemical profile were compared to those of wild type cells. Cell cycle proliferation was also evaluated by fluorescence-activated cell sorting (FACS). SMA hiPSCs showed an increased proliferation rate and also higher levels of stem cell markers. Moreover; when differentiated towards early motor neurons they expressed lower levels of NCAM and MN specific markers. The expression of miR-335-5p; already identified to control self-renewal or differentiation of mouse embryonic stem cells (mESCs); resulted to be reduced during the early steps of differentiation of SMA hiPSCs compared to wild type cells. These results suggest that we should speculate a role of this miRNA both in stemness characteristic and in differentiation efficiency of these cells. PMID:27483257

  2. SMA Human iPSC-Derived Motor Neurons Show Perturbed Differentiation and Reduced miR-335-5p Expression.

    PubMed

    Murdocca, Michela; Ciafrè, Silvia Anna; Spitalieri, Paola; Talarico, Rosa Valentina; Sanchez, Massimo; Novelli, Giuseppe; Sangiuolo, Federica

    2016-07-30

    Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. MicroRNAs (miRNAs) are often reported as playing a key role in regulating neuronal differentiation and fate specification. In this study SMA hiPSCs have been differentiated towards early motor neurons and their molecular and immunocytochemical profile were compared to those of wild type cells. Cell cycle proliferation was also evaluated by fluorescence-activated cell sorting (FACS). SMA hiPSCs showed an increased proliferation rate and also higher levels of stem cell markers. Moreover; when differentiated towards early motor neurons they expressed lower levels of NCAM and MN specific markers. The expression of miR-335-5p; already identified to control self-renewal or differentiation of mouse embryonic stem cells (mESCs); resulted to be reduced during the early steps of differentiation of SMA hiPSCs compared to wild type cells. These results suggest that we should speculate a role of this miRNA both in stemness characteristic and in differentiation efficiency of these cells.

  3. The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models.

    PubMed

    Gogliotti, Rocky G; Cardona, Herminio; Singh, Jasbir; Bail, Sophie; Emery, Carina; Kuntz, Nancy; Jorgensen, Michael; Durens, Madel; Xia, Bing; Barlow, Courtenay; Heier, Christopher R; Plasterer, Heather L; Jacques, Vincent; Kiledjian, Megerditch; Jarecki, Jill; Rusche, James; DiDonato, Christine J

    2013-10-15

    Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to the functional loss of the SMN1 gene and the inability of its paralog, SMN2, to fully compensate due to reduced exon 7 splicing efficiency. Since SMA patients have at least one copy of SMN2, drug discovery campaigns have sought to identify SMN2 inducers. C5-substituted quinazolines increase SMN2 promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/- SMA mice), and positively impacts neuromuscular pathologies. In 2B/- SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosing began at P4, highlighting the importance of early intervention. We determined the minimum effective dose and the associated pharmacokinetic (PK) and exposure relationship of RG3039 and DcpS inhibition ex vivo. These data support the long PK half-life with extended pharmacodynamic outcome of RG3039 in 2B/- SMA mice. In motor neurons, RG3039 significantly increased both the average number of cells with gems and average number of gems per cell, which is used as an indirect measure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects.

  4. Vaginal Atrophy

    MedlinePlus

    Vaginal atrophy Overview By Mayo Clinic Staff Vaginal atrophy (atrophic vaginitis) is thinning, drying and inflammation of the vaginal walls due to your body having less estrogen. Vaginal atrophy occurs most ...

  5. SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNΔ7 mouse model of SMA.

    PubMed

    McGovern, Vicki L; Iyer, Chitra C; Arnold, W David; Gombash, Sara E; Zaworski, Phillip G; Blatnik, Anton J; Foust, Kevin D; Burghes, Arthur H M

    2015-10-01

    Proximal spinal muscular atrophy (SMA) is the most frequent cause of hereditary infant mortality. SMA is an autosomal recessive neuromuscular disorder that results from the loss of the Survival Motor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The SMN2 gene produces an insufficient amount of full-length SMN protein that results in loss of motor neurons in the spinal cord and subsequent muscle paralysis. Previously we have shown that overexpression of human SMN in neurons in the SMA mouse ameliorates the SMA phenotype while overexpression of human SMN in skeletal muscle had no effect. Using Cre recombinase, here we show that either deletion or replacement of Smn in motor neurons (ChAT-Cre) significantly alters the functional output of the motor unit as measured with compound muscle action potential and motor unit number estimation. However ChAT-Cre alone did not alter the survival of SMA mice by replacement and did not appreciably affect survival when used to deplete SMN. However replacement of Smn in both neurons and glia in addition to the motor neuron (Nestin-Cre and ChAT-Cre) resulted in the greatest improvement in survival of the mouse and in some instances complete rescue was achieved. These findings demonstrate that high expression of SMN in the motor neuron is both necessary and sufficient for proper function of the motor unit. Furthermore, in the mouse high expression of SMN in neurons and glia, in addition to motor neurons, has a major impact on survival.

  6. Low levels of Survival Motor Neuron protein are sufficient for normal muscle function in the SMNΔ7 mouse model of SMA.

    PubMed

    Iyer, Chitra C; McGovern, Vicki L; Murray, Jason D; Gombash, Sara E; Zaworski, Phillip G; Foust, Kevin D; Janssen, Paul M L; Burghes, Arthur H M

    2015-11-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder characterized by loss of lower motor neurons. SMA is caused by deletion or mutation of the Survival Motor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The loss of SMN1 results in reduced levels of the SMN protein. SMN levels appear to be particularly important in motor neurons; however SMN levels above that produced by two copies of SMN2 have been suggested to be important in muscle. Studying the spatial requirement of SMN is important in both understanding how SMN deficiency causes SMA and in the development of effective therapies. Using Myf5-Cre, a muscle-specific Cre driver, and the Cre-loxP recombination system, we deleted mouse Smn in the muscle of mice with SMN2 and SMNΔ7 transgenes in the background, thus providing low level of SMN in the muscle. As a reciprocal experiment, we restored normal levels of SMN in the muscle with low SMN levels in all other tissues. We observed that decreasing SMN in the muscle has no phenotypic effect. This was corroborated by muscle physiology studies with twitch force, tetanic and eccentric contraction all being normal. In addition, electrocardiogram and muscle fiber size distribution were also normal. Replacement of Smn in muscle did not rescue SMA mice. Thus the muscle does not appear to require high levels of SMN above what is produced by two copies of SMN2 (and SMNΔ7).

  7. Splicing changes in SMA mouse motoneurons and SMN-depleted neuroblastoma cells: Evidence for involvement of splicing regulatory proteins

    PubMed Central

    Huo, Qing; Kayikci, Melis; Odermatt, Philipp; Meyer, Kathrin; Michels, Olivia; Saxena, Smita; Ule, Jernej; Schümperli, Daniel

    2014-01-01

    Spinal Muscular Atrophy (SMA) is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. The second gene copy, SMN2, produces some, but not enough, functional SMN protein. SMN is essential to assemble small nuclear ribonucleoproteins (snRNPs) that form the spliceosome. However, it is not clear whether SMA is caused by defects in this function that could lead to splicing changes in all tissues, or by the impairment of an additional, less well characterized, but motoneuron-specific SMN function. We addressed the first possibility by exon junction microarray analysis of motoneurons (MNs) isolated by laser capture microdissection from a severe SMA mouse model. This revealed changes in multiple U2-dependent splicing events. Moreover, splicing appeared to be more strongly affected in MNs than in other cells. By testing mutiple genes in a model of progressive SMN depletion in NB2a neuroblastoma cells, we obtained evidence that U2-dependent splicing changes occur earlier than U12-dependent ones. As several of these changes affect genes coding for splicing regulators, this may acerbate the splicing response induced by low SMN levels and induce secondary waves of splicing alterations. PMID:25692239

  8. Implementation of SMA carrier testing in genetic laboratories: comparison of two methods for quantifying the SMN1 gene.

    PubMed

    Cuscó, Ivon; Barceló, María J; Baiget, Montserrat; Tizzano, Eduardo F

    2002-12-01

    The degeneration and loss of motor neurons of the anterior horn characterize children affected with spinal muscular atrophy (SMA). Mutations in the survival motor neuron gene (SMN1) are determinant for the development of the disease whereas the number of copies of SMN2, the highly homologous copy of SMN1, plays a role as a phenotypic modifier factor. The detection of SMN1 homozygous deletions is the typical test for SMA diagnosis. Owing to the limitation of this test for carrier and heterozygous deletion analysis, the demand of SMN1 quantitative tests is permanently growing. The high incidence of SMA, the notable carrier frequency, the severity of the disease, and the lack of effective treatment may justify the implementation of such an analysis in DNA diagnostic labs. The advantages and disadvantages of two reliable quantitative methods were evaluated. One of these is a competitive PCR protocol using internal standards and a genomic sequence as a reference. The other method is a real-time PCR employing an external standard as a reference. Both methods present sufficient advantages for incorporation into molecular genetic diagnostic labs. The possibility of studying samples from different labs, the versatility and reproducibility of the analysis, and cost-benefit calculations must be considered in the final choice.

  9. Choline acetyltransferase expression does not identify early pathogenic events in fetal SMA spinal cord.

    PubMed

    Soler-Botija, Carolina; Cuscó, Ivón; López, Eva; Clua, Agustín; Gich, Ignasi; Baiget, Montserrat; Ferrer, Isidre; Tizzano, Eduardo F

    2005-03-01

    We investigated the expression of choline acetyltransferase, a specific marker for cholinergic neurons, in control and spinal muscular atrophy fetuses and newborns. By immunoblot we observed at 12 and 15 weeks a similar pattern of choline acetyltransferase expression in spinal muscular atrophy with respect to controls, although at 22 weeks this expression was reduced, probably due to a smaller number of motor neurons in the spinal muscular atrophy spinal cord. By immunohistochemistry, the counting of positive and negative motor neurons for choline acetyltransferase immunostaining in control and spinal muscular atrophy fetuses showed a similar proportion at all stages analyzed. The choline acetyltransferase-negative motor neurons were of similar appearance in both groups. After birth, chromatolytic motor neurons were detected in spinal muscular atrophy, all of which were choline acetyltransferase-negative. Our results in spinal muscular atrophy fetuses indicate that choline acetyltransferase immunostaining does not identify early events in neuronal pathogenesis and suggest that the spinal muscular atrophy surviving motor neurons may not be dysfunctional during this period. Furthermore, spinal muscular atrophy choline acetyltransferase-negative motor neurons showed detectable pathological changes only after birth, indicating that choline acetyltransferase is a late marker for motor neuron degeneration and not a primary contributing factor in this process.

  10. Characterisation of SMN hybrid genes in Spanish SMA patients: de novo, homozygous and compound heterozygous cases.

    PubMed

    Cuscó, I; Barceló, M J; del Rio, E; Martín, Y; Hernández-Chico, C; Bussaglia, E; Baiget, M; Tizzano, E F

    2001-03-01

    Autosomal recessive spinal muscular atrophy (SMA) is classified, by age of onset and maximal motor milestones achieved, into type I (severe form), type II (intermediate form) and type III (mild/moderate form). SMA is caused by mutations in the survival motor neuron telomeric gene (SMN1) and a centromeric functional copy of this gene (SMN2) exists, both genes being located at 5q13. Homozygous deletion of exons 7 and 8 of SMN1 has been detected in approx 85% of Spanish SMA patients regardless of their phenotype. Nineteen cases with the sole deletion of exon 7 but not exon 8 (2 cases of type I, 13 cases of type II, four cases of type III) were further analysed for the presence of SMN2-SMN1 hybrid genes. We detected four different hybrid structures. Most of the patients were carriers of a hybrid structure: centromeric intron 6- centromeric exon 7- telomeric exon 8 (CCT), with or without neuronal apoptosis-inhibitor protein (NAIP). In two patients, a different hybrid structure, viz. telomeric intron 6- centromeric exon 7- telomeric exon 8 (TCT), was detected with or without NAIP. A phenotype-genotype correlation comparing the different structures of the hybrid alleles was delineated. Type I cases in our series are attributable to intrachromosomal deletion with a smaller number of SMN2 copies. Most cases with hybrid genes are type II occurring by a combination of a classical deletion in one chromosome and a hybrid gene in the other. Type III cases are closely associated with homozygozity or compound heterozygozity for hybrid genes resulting from two conversion events and have more copies of hybrid genes and SMN2 than type I or II cases.

  11. YAC contigs of the Rab1 and wobbler (wr) spinal muscular atrophy gene region on proximal mouse chromosome 11 and of the homologous region on human chromosome 2p

    SciTech Connect

    Wedemeyer, N.; Lengeling, A.; Ronsiek, M.

    1996-03-05

    Despite rapid progress in the physical characterization of murine and human genomes, little molecular information is available on certain regions, e.g., proximal mouse chromosome 11 (Chr 11) and human chromosome 2p (Chr2p). We have localized the wobbler spinal atrophy gene wr to proximal mouse Chr 11, tightly linked to Rab1, a gene coding for a small GTP-binding protein, and Glns-ps1, an intronless pseudogene of the glutamine synthetase gene. We have not used these markers to construct a 1.3-Mb yeast artificial chromosome (YAC) contig of the Rab1 region on mouse Chr 11. Four YAC clones isolated from two independent YAC libraries were characterized by rare-cutting analysis, fluorescence in situ hybridization (FISH), and sequence-tagged site (STS) isolation and mapping. Rab1 and Glns-ps1 were found to be only 200 kb apart. A potential CpG island near a methylated NarI site and a trapped exon, ETG1.1, were found over 250 kb from Rab1. Two overlapping YACs were identified that contained a 150-kb region of human Chr 2p, comprising the RAB1 locus, AHY1.1, and the human homologue of ETG1.1, indicating a high degree of conservation of this region in the two species. We mapped AHY1.1 and thus human RAB1 on Chr 2p13.4-p14 using somatic cell hybrids and a radiation hybrid panel, thus extending a known region of conserved synteny between mouse Chr 11 and human Chr 2p. Recently, the gene LMGMD2B for a human recessive neuromuscular disease, limb girdle muscular dystrophy type 2B, has been mapped to 2p13-p16. The conservation between the mouse Rab1 and human RAB1 regions will be helpful in identifying candidate genes for the wobbler spinal muscular atrophy and in clarifying a possible relationship between wr and LMGMD2B. 33 refs., 7 figs., 3 tabs.

  12. Isolation of SMA candidate genes from a YAC contig by direct selection of cDNA clones from normalized cDNA libraries

    SciTech Connect

    Ross, B.M.; Bonaldo, M.F.; Vitale, E.

    1994-09-01

    A YAC contig has been constructed across the spinal muscular atrophy (SMA) region of chromosome 5 (5q11-13). Further definition by pedigree analysis has yielded a minimal genetic region of 400 kb. For isolation of candidate genes in this region, the following cDNA selection method was hybridized to directionally cloned normalized (Cot 1 DNA-preannealed) cDNA libraries in the form of single-stranded circles. The libraries used were constructed from SMA infant brain and normal fetal liver+spleen. Hybridizing circles were eluted off the filter, partially converted into duplexes and electroporated into bacteria. The selected clones were then sequentially hybridized with a human Cot 1 DNA probe (BRL), and a probe made from the corresponding YAC DNA. Clones that hybridized only to the YAC DNA probe were verified to map to the critical region by genomic Southern analyses. Ten different cDNA clones have been isolated by this procedure so far. Three of them have been definitively mapped back to the region. Four of the ten clones are now completely sequenced. One clone shows sequence homology to a transcriptional initiation factor; another has homology to a prokaryotic attachment site sequence for the lipid moiety of membrane lipoproteins. Two clones show no homology to sequences represented in the public databases. We are continuing the full characterization of the cDNA clones as candidates for the SMA gene.

  13. [Functional assessment for people unable to walk due to spinal muscular atrophy and Duchenne muscular dystrophy. Translation and validation of the Egen Klassifikation 2 scale for the Spanish population].

    PubMed

    Fagoaga, Joaquín; Girabent-Farrés, Montserrat; Bagur-Calafat, Caritat; Febrer, Anna; Steffensen, Birgit F

    2015-05-16

    Introduccion. La escala Egen Klassifikation 2 (EK2), ampliacion de la escala EK, evalua la capacidad funcional de personas con atrofia muscular espinal (AME) y distrofia muscular de Duchenne (DMD) que estan en fase de silla de ruedas. Esta version es mas especifica para la AME que su antecesora. Objetivo. Analizar la validez y fiabilidad de la version española de dicha escala como instrumento de medicion de la capacidad funcional en pacientes afectos de AME y DMD que estan en silla de ruedas. Pacientes y metodos. Primeramente se realizo una traduccion-retrotraduccion al español de la version en ingles de la EK2 y, posteriormente, se estudio la fiabilidad de la version traducida. Para ello, se seleccionaron 39 pacientes, de edades comprendidas entre 4 y 60 años, que fueron valorados por dos observadores. Para evaluar la concordancia intraobservador se realizaron dos evaluaciones por un mismo observador, y para la interobservador, se realizo una tercera evaluacion por un segundo observador. Resultados. Los valores obtenidos referidos a la puntuacion total de los items de la escala (suma EK2) reflejan una fiabilidad intra e interobservador excelente, de 0,993 y 0,988, respectivamente. Asimismo, para cada uno de los items, la fiabilidad fue excelente, a excepcion de un item, en el que fue buena. Conclusiones. La version española de la escala EK2 es un instrumento valido y fiable para la poblacion española como herramienta de medicion de la capacidad funcional en pacientes con AME y DMD que estan en silla de ruedas.

  14. Muscular Dystrophy

    MedlinePlus

    ... depending on the type of muscular dystrophy. Duchenne muscular dystrophy About half of people with muscular dystrophy have ... muscles Muscle pain and stiffness Learning disabilities Becker muscular dystrophy Signs and symptoms are similar to those of ...

  15. Novel dynein DYNC1H1 neck and motor domain mutations link distal SMA and abnormal cortical development

    PubMed Central

    Fiorillo, Chiara; Moro, Francesca; Yi, Julie; Weil, Sarah; Brisca, Giacomo; Astrea, Guja; Severino, Mariasavina; Romano, Alessandro; Battini, Roberta; Rossi, Andrea; Minetti, Carlo; Bruno, Claudio; Santorelli, Filippo M.; Vallee, Richard

    2014-01-01

    DYNC1H1 encodes the heavy chain of cytoplasmic dynein 1, a motor protein complex implicated in retrograde axonal transport, neuronal migration, and other intracellular motility functions. Mutations in DYNC1H1 have been described in autosomal dominant Charcot-Marie-Tooth type 2 and in families with distal spinal muscular atrophy (SMA) predominantly affecting the legs (SMA-LED). Recently, defects of cytoplasmic dynein 1 were also associated with a form of mental retardation and neuronal migration disorders. Here we describe two unrelated patients presenting a combined phenotype of congenital motor neuron disease associated with focal areas of cortical malformation. In each patient we identified a novel de novo mutation in DYNC1H1: c.3581A>G (p.Gln1194Arg) in one case and c.9142G>A (p.Glu3048Lys) in the other. The mutations lie in different domains of the dynein heavy chain, and are deleterious to protein function as indicated by assays for Golgi recovery after nocodazole washout in patient fibroblasts. Our results expand the set of pathological mutations in DYNC1H1, reinforce the role of cytoplasmic dynein in disorders of neuronal migration and provide evidence for a syndrome including spinal nerve degeneration and brain developmental problems. PMID:24307404

  16. SMN transcript levels in leukocytes of SMA patients determined by absolute real-time PCR

    PubMed Central

    Tiziano, Francesco Danilo; Pinto, Anna Maria; Fiori, Stefania; Lomastro, Rosa; Messina, Sonia; Bruno, Claudio; Pini, Antonella; Pane, Marika; D'Amico, Adele; Ghezzo, Alessandro; Bertini, Enrico; Mercuri, Eugenio; Neri, Giovanni; Brahe, Christina

    2010-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous mutations of the SMN1 gene. Three forms of SMA are recognized (type I–III) on the basis of clinical severity. All patients have at least one or more (usually 2–4) copies of a highly homologous gene (SMN2), which produces insufficient levels of functional SMN protein, because of alternative splicing of exon 7. Recently, evidence has been provided that SMN2 expression can be enhanced by pharmacological treatment. However, no reliable biomarkers are available to test the molecular efficacy of the treatments. At present, the only potential biomarker is the dosage of SMN products in peripheral blood. However, the demonstration that SMN full-length (SMN-fl) transcript levels are reduced in leukocytes of patients compared with controls remains elusive (except for type I). We have developed a novel assay based on absolute real-time PCR, which allows the quantification of SMN1-fl/SMN2-fl transcripts. For the first time, we have shown that SMN-fl levels are reduced in leukocytes of type II–III patients compared with controls. We also found that transcript levels are related to clinical severity as in type III patients SMN2-fl levels are significantly higher compared with type II and directly correlated with functional ability in type II patients and with age of onset in type III patients. Moreover, in haploidentical siblings with discordant phenotype, the less severely affected individuals showed significantly higher transcript levels. Our study shows that SMN2-fl dosage in leukocytes can be considered a reliable biomarker and can provide the rationale for SMN dosage in clinical trials. PMID:19603064

  17. Muscular Dystrophy

    MedlinePlus

    ... Devices The Search for a Cure en español Distrofia muscular About MD Muscular dystrophy (MD) is a ... muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the ...

  18. Muscle atrophy

    MedlinePlus

    ... damage caused by injury, diabetes, toxins, or alcohol Polio ( poliomyelitis ) Spinal cord injury Although people can adapt to ... Guillain-Barré syndrome Hypotonia Muscle cramps Muscular dystrophy Polio Review Date 1/5/2016 Updated by: Joseph ...

  19. Muscular Dystrophy

    MedlinePlus

    ... It Like for Teens With MD? en español Distrofia muscular Aside from seeing the telethon on Labor ... which weakens different muscle groups in various ways: Duchenne (pronounced: due-SHEN) muscular dystrophy (DMD) , the most ...

  20. Muscular Dystrophy

    MedlinePlus

    Muscular dystrophy (MD) is a group of more than 30 inherited diseases. They all cause muscle weakness and ... ability to walk. There is no cure for muscular dystrophy. Treatments can help with the symptoms and prevent ...

  1. Muscular dystrophy

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001190.htm Muscular dystrophy To use the sharing features on this page, please enable JavaScript. Muscular dystrophy is a group of inherited disorders that cause ...

  2. Facioscapulohumeral muscular dystrophy.

    PubMed

    Tawil, Rabi

    2008-10-01

    Facioscapulohumeral muscular dystrophy (FSHD), a dominantly inherited disorder, is the third most common dystrophy after Duchenne and myotonic muscular dystrophy. No known effective treatments exist for FSHD. The lack of an understanding of the underlying pathophysiology remains an obstacle in the development of targeted therapeutic interventions. The genetic defect is a loss of a critical number of a repetitive element (D4Z4) in the 4q subtelomeric region. The loss of the repeats results in specific changes in chromatin structure, although neither the molecular nor the cellular consequences of this change are known. Nevertheless, these epigenetic changes in chromatin structure offer a potential therapeutic target. This review discusses current management strategies in FSHD as well as potential therapeutic interventions to slow down or reverse the progressive muscle atrophy and weakness.

  3. SMA DOE Student Fellowship Initiative

    SciTech Connect

    Steel Manufacturers Association

    2004-12-24

    Steel companies in many areas of the country have found it increasingly difficult to attract talented recent graduates of college and university engineering and applied science programs to the Electric Arc Furnace iron & steel industry. College student involvement in co-operative programs at steel companies can attract needed talent to the industry. Additionally, certain R & D needs identified in the Steel Industry Technology Roadmap are addressed as co-operative program activities. The Steel Manufacturers Association (''SMA'') therefore established a co-operative education program for selected college students who have completed the first or second year of a four or five-year college program, to be recognized as SMA Co-Operative Fellows, in regard to their summer and fall semester projects with SMA's member companies.

  4. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid

    PubMed Central

    2011-01-01

    Background Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1) and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor. Methods Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC), the Hammersmith Functional Motor Scale (HFMS), and the Barthel Index. Results After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period. Conclusion Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease. Trial Registration ClinicalTrials.gov: NCT01033331 PMID:21435220

  5. SMA actuators for morphing wings

    NASA Astrophysics Data System (ADS)

    Brailovski, V.; Terriault, P.; Georges, T.; Coutu, D.

    An experimental morphing laminar wing was developed to prove the feasibility of aircraft fuel consumption reduction through enhancement of the laminar flow regime over the wing extrados. The morphing wing prototype designed for subsonic cruise flight conditions (Mach 0.2 … 0.3; angle of attack - 1 … +2∘), combines three principal subsystems: (1) flexible extrados, (2) rigid intrados and (3) an actuator group located inside the wing box. The morphing capability of the wing relies on controlled deformation of the wing extrados under the action of shape memory alloys (SMA) actuators. A coupled fluid-structure model of the morphing wing was used to evaluate its mechanical and aerodynamic performances in different flight conditions. A 0.5 m chord and 1 m span prototype of the morphing wing was tested in a subsonic wind tunnel. In this work, SMA actuators for morphing wings were modeled using a coupled thermo-mechanical finite element model and they were windtunnel validated. If the thermo-mechanical model of SMA actuators presented in this work is coupled with the previously developed structureaerodynamic model of the morphing wing, it could serve for the optimization of the entire morphing wing system.

  6. Muscular Dystrophy

    MedlinePlus

    ... in Duchenne muscular dystrophy. Dev. Med. Child Neurol. Mar 1995;37(3):260-269. 4. Centers for ... DM1) . The International Myotonic Dystrophy Consortium (IDMC). Neurology. Mar 28 2000;54(6):1218-1221. 5. Harper ...

  7. Muscular Dystrophy

    MedlinePlus

    ... affects about 1 out of every 3,500 boys. (Girls can carry the gene that causes the disease, ... and heart problems. Limb-girdle muscular dystrophy affects boys and girls equally. Symptoms usually start when kids are between ...

  8. Muscular Dystrophy

    MedlinePlus

    ... be affected. Limb-girdle muscular dystrophy (LGMD) affects boys and girls equally, weakening muscles in the shoulders and upper ... weakness and poor muscle tone. Occurring in both girls and boys, it can have different symptoms. It varies in ...

  9. Optic nerve atrophy

    MedlinePlus

    Optic atrophy; Optic neuropathy ... There are many causes of optic atrophy. The most common is poor blood flow. This is called ischemic optic neuropathy. The problem most often affects older adults. ...

  10. Two SMA-Actuated Miniature Mechanisms

    NASA Technical Reports Server (NTRS)

    Willey, Cliff E.

    2005-01-01

    The figures depict two miniature mechanisms actuated by strips made of shape-memory alloy (SMA). A typical SMA is a nickel-titanium alloy known by the trade name "Flexinol" or "Nitinol." In preparation for a typical application, a suitably sized and shaped piece of an SMA is deformed by a predetermined amount at the lower of two operating temperatures, then mounted in a mechanism. When stroking of the mechanism in one direction is desired, the piece of SMA is heated above a transition temperature to make it return to the "remembered" undeformed state. When stroking of the mechanism in the opposite direction is desired, the SMA is cooled below the transition temperature to make it return to the deformed state. Also, the SMA alloy chosen for a specific application is one that has a transition temperature somewhat above the ambient temperature, so that stroking in one direction or the opposite direction can be achieved by heating the SMA, or refraining from heating the SMA, respectively, above the transition temperature. In the present mechanisms as in typical other SMA mechanisms, the heating is effected by electric currents applied via electrical contacts at the ends of the SMA strips. The purpose served by the mechanism of Figure 1 is to lock or release a flexible latch attachment. In preparation for use in this mechanism, two initially straight SMA strips are deformed into curved springs that, when mounted in the mechanism at ambient temperature, clamp the knob at the lower end of the flexible latch attachment. When heated above their transition temperature by an electric current, the SMA strips return to their original straight configuration, thereby releasing the knob. This mechanism is redundant in the sense that as long as at least one of the two SMA strips straightens when commanded to do so, the knob is released. The mechanism of Figure 2 is suited to any of a variety of applications in which there are requirements for a small mechanism that affords

  11. SMA Syndrome Treated by Single Incision Laparoscopic Duodenojejunostomy.

    PubMed

    Kim, Sungsoo; Kim, Yoo Seok; Min, Young-Don

    2014-01-01

    Superior mesenteric artery (SMA) syndrome is a mechanical duodenal obstruction by the SMA. The traditional approach to SMA syndrome was open bypass surgery. Nowadays, a conventional approach has been replaced by laparoscopic surgery. But single incision laparoscopic approach for SMA syndrome is rare. Herein, we report the first case of SMA syndrome patient who was treated by single incision laparoscopic duodenojejunostomy.

  12. SMA microactuators for microvalve applications

    NASA Astrophysics Data System (ADS)

    Kohl, M.; Liu, Y.; Krevet, B.; Dürr, S.; Ohtsuka, M.

    2004-06-01

    This paper presents a study of the mechanical and thermal properties of SMA microvalves, which are driven by a microactuator of a NiTi foil or a Ni2MnGa thin film. By coupled finite element simulations, von Mises stress profiles and resulting actuation forces are determined, which are compared with experimental force-displacement characteristics. The relatively high phase transformation temperatures of the used Ni2MnGa specimens Mf / Af of 92 / 125 circC, give rise to cooling times of about 25 ms compared to 90 ms for NiTi. Thus, Ni2MnGa microvalves show a superior switching performance. However, due to brittleness and buckling instability, Ni2MnGa microvalves only allow a maximum controllable pressure difference of 70 kPa, which is more than a factor of 7 smaller compared to NiTi microvalves.

  13. Functional dissociation of pre-SMA and SMA-proper in temporal processing.

    PubMed

    Schwartze, Michael; Rothermich, Kathrin; Kotz, Sonja A

    2012-03-01

    The ability to assess temporal structure is crucial in order to adapt to an ever-changing environment. Increasing evidence suggests that the supplementary motor area (SMA) is involved in both sensory and sensorimotor processing of temporal structure. However, it is not entirely clear whether the structural differentiation of the SMA translates into functional specialization, and how the SMA relates to other systems that engage in temporal processing, namely the cerebellum and cortico-striatal circuits. Anatomically, the SMA comprises at least two subareas, the rostral pre-SMA and the caudal SMA-proper. Each displays a characteristic pattern of connections to motor and non-motor structures. Crucially, these connections establish a potential hub among cerebellar and cortico-striatal systems, possibly forming a dedicated subcortico-cortical temporal processing network. To further explore the functional role of each SMA subarea, we performed a meta-analysis of functional neuroimaging studies by contrasting activations according to whether they linked with either sensory, sensorimotor, sequential, non-sequential, explicit, non-explicit, subsecond, or suprasecond temporal processing. This procedure yielded a set of functional differences, which mirror the rostro-caudal anatomical dimension. Activations associated with sensory, non-sequential, and suprasecond temporal processing tend to locate to the rostral SMA, while the opposite is true for the caudal SMA. These findings confirm a functional dissociation of pre-SMA and SMA-proper in temporal processing.

  14. Drug Might Help Some Babies with Rare, Fatal Disease

    MedlinePlus

    ... Might Help Some Babies With Rare, Fatal Disease Spinal muscular atrophy is typically lethal within 2 years, but new ... promise, researchers report. There is no treatment for spinal muscular atrophy type 1 (SMA-1), a degenerative neuromuscular disease ...

  15. The paradox of muscle hypertrophy in muscular dystrophy.

    PubMed

    Kornegay, Joe N; Childers, Martin K; Bogan, Daniel J; Bogan, Janet R; Nghiem, Peter; Wang, Jiahui; Fan, Zheng; Howard, James F; Schatzberg, Scott J; Dow, Jennifer L; Grange, Robert W; Styner, Martin A; Hoffman, Eric P; Wagner, Kathryn R

    2012-02-01

    Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans and syndromes in mice, dogs, and cats. Affected humans and dogs have progressive disease that leads primarily to muscle atrophy. Mdx mice progress through an initial phase of muscle hypertrophy followed by atrophy. Cats have persistent muscle hypertrophy. Hypertrophy in humans has been attributed to deposition of fat and connective tissue (pseudohypertrophy). Increased muscle mass (true hypertrophy) has been documented in animal models. Muscle hypertrophy can exaggerate postural instability and joint contractures. Deleterious consequences of muscle hypertrophy should be considered when developing treatments for muscular dystrophy.

  16. The combined influence of stretch, mobility and electrical stimulation in the prevention of muscle fiber atrophy caused hypokinesia and hypodynamia

    NASA Technical Reports Server (NTRS)

    Goldspink, G.; Goldspink, D.; Loughna, P.

    1984-01-01

    The morphological and biochemical changes which occur in the hind limb muscles of the rat in response to hypokinesia and hypodynamia were investigated. Hind limb cast fixation and suspension techniques were employed to study the musclar atrophy after five days of hypokinesia and hypodynamia induced by suspension, appreciable muscular atrophy was apparent, particularly in the anti-gravity muscles. The effect of passive stretching and electrical stimulation on muscle atrophy was studied. Changes in muscle protein mass were assessed with spectrophotometric and radioactive techniques. Passive stretch is shown to counteract muscle disuse atrophy. The change in the numbers of specific muscle fibers in atrophied muscles is discussed.

  17. S&MA Requirements Tool (SMART)

    NASA Technical Reports Server (NTRS)

    Kulpa, Vyga

    2004-01-01

    In FY03 QS10 began building an S&MA web based data management tool,"Safety & Mission Assurance Requirements Tool" (SMART) that identifies S&MA requirements, tailors requirements to IAW project/program categories, tracks implementation, and provides a template for developing requirements and tracking waivers. This report provides a SMART process flow, typical application, typical data requirement deliverables, progress in 03, and FY04 activities.

  18. Transcriptional profile of a myotube starvation model of atrophy

    NASA Technical Reports Server (NTRS)

    Stevenson, Eric J.; Koncarevic, Alan; Giresi, Paul G.; Jackman, Robert W.; Kandarian, Susan C.

    2005-01-01

    Skeletal muscle wasting is a pervasive phenomenon that can result from a wide range of pathological conditions as well as from habitual muscular inactivity. The present work describes a cell-culture condition that induces significant atrophy in skeletal muscle C2C12 myotubes. The failure to replenish differentiation media in mature myotubes leads to rapid atrophy (53% in diameter), which is referred to here as starvation. Affymetrix microarrays were used to develop a transcriptional profile of control (fed) vs. atrophied (nonfed) myotubes. Myotube starvation was characterized by an upregulation of genes involved in translational inhibition, amino acid biosynthesis and transport, and cell cycle arrest/apoptosis, among others. Downregulated genes included several structural and regulatory elements of the extracellular matrix as well as several elements of Wnt/frizzled and TGF-beta signaling pathways. Interestingly, the characteristic transcriptional upregulation of the ubiquitin-proteasome system, calpains, and cathepsins known to occur in multiple in vivo models of atrophy were not seen during myotube starvation. With the exception of the downregulation of extracellular matrix genes, serine protease inhibitor genes, and the upregulation of the translation initiation factor PHAS-I, this model of atrophy in cell culture has a transcriptional profile quite distinct from any study published to date with atrophy in whole muscle. These data show that, although the gross morphology of atrophied muscle fibers may be similar in whole muscle vs. myotube culture, the processes by which this phenotype is achieved differ markedly.

  19. Muscular dystrophy - resources

    MedlinePlus

    Resources - muscular dystrophy ... The following organizations are good resources for information on muscular dystrophy : Muscular Dystrophy Association -- www.mdausa.org National Institute of Neurological Disorders and Stroke -- www.ninds.nih. ...

  20. Somatic Therapy of a Mouse SMA Model with a U7 snRNA Gene Correcting SMN2 Splicing

    PubMed Central

    Odermatt, Philipp; Trüb, Judith; Furrer, Lavinia; Fricker, Roger; Marti, Andreas; Schümperli, Daniel

    2016-01-01

    Spinal Muscular Atrophy is due to the loss of SMN1 gene function. The duplicate gene SMN2 produces some, but not enough, SMN protein because most transcripts lack exon 7. Thus, promoting the inclusion of this exon is a therapeutic option. We show that a somatic gene therapy using the gene for a modified U7 RNA which stimulates this splicing has a profound and persistent therapeutic effect on the phenotype of a severe Spinal Muscular Atrophy mouse model. To this end, the U7 gene and vector and the production of pure, highly concentrated self-complementary (sc) adenovirus-associated virus 9 vector particles were optimized. Introduction of the functional vector into motoneurons of newborn Spinal Muscular Atrophy mice by intracerebroventricular injection led to a highly significant, dose-dependent increase in life span and improvement of muscle functions. Besides the central nervous system, the therapeutic U7 RNA was expressed in the heart and liver which may additionally have contributed to the observed therapeutic efficacy. This approach provides an additional therapeutic option for Spinal Muscular Atrophy and could also be adapted to treat other diseases of the central nervous system with regulatory small RNA genes. PMID:27456062

  1. Progressive hemifacial atrophy

    PubMed Central

    Sande, Abhijeet; Risbud, Mukund; Kshar, Avinash; Paranjpe, Arati Oka

    2013-01-01

    Progressive hemifacial atrophy, also known as Parry-Romberg Syndrome, is an uncommon degenerative and poorly understood condition. It is characterized by a slow and progressive but self-limited atrophy affecting one side of the face. The incidence and the cause of this alteration are unknown. A cerebral disturbance of fat metabolism has been proposed as a primary cause. Possible factors that are involved in the pathogenesis include trauma, viral infections, heredity, endocrine disturbances and auto-immunity. The most common complications that appear in association to this disorder are: trigeminal neuralgia, facial paresthesia, severe headache and epilepsy. Characteristically, the atrophy progresses slowly for several years and, it becomes stable. The objective of this work is, through the presentation of a clinical case, to accomplish a literature review concerning general characteristics, etiology, physiopathology and treatment of progressive hemifacial atrophy. PMID:23878573

  2. Meaning of Muscular Dystrophy

    MedlinePlus

    ... Video: Getting an X-ray The Meaning of Muscular Dystrophy KidsHealth > For Kids > The Meaning of Muscular Dystrophy ... you know someone who has MD. What Is Muscular Dystrophy? Muscular dystrophy (say: MUS-kyoo-lur DIS-troh- ...

  3. TMS of supplementary motor area (SMA) facilitates mental rotation performance: Evidence for sequence processing in SMA.

    PubMed

    Cona, G; Marino, G; Semenza, C

    2017-02-01

    In the present study we applied online transcranial magnetic stimulation (TMS) bursts at 10Hz to the supplementary motor area (SMA) and primary motor cortex to test whether these regions are causally involved in mental rotation. Furthermore, in order to investigate what is the specific role played by SMA and primary motor cortex, two mental rotation tasks were used, which included pictures of hands and abstract objects, respectively. While primary motor cortex stimulation did not affect mental rotation performance, SMA stimulation improved the performance in the task with object stimuli, and only for the pairs of stimuli that had higher angular disparity between each other (i.e., 100° and 150°). The finding that the effect of SMA stimulation was modulated by the amount of spatial orientation information indicates that SMA is causally involved in the very act of mental rotation. More specifically, we propose that SMA mediates domain-general sequence processes, likely required to accumulate and integrate information that are, in this context, spatial. The possible physiological mechanisms underlying the facilitation of performance due to SMA stimulation are discussed.

  4. Osteoprotegerin protects against muscular dystrophy.

    PubMed

    Dufresne, Sébastien S; Dumont, Nicolas A; Bouchard, Patrice; Lavergne, Éliane; Penninger, Josef M; Frenette, Jérôme

    2015-04-01

    Receptor-activator of NF-κB, its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology still is elusive. Here, we show that muscle cells can produce and secrete osteoprotegerin and pharmacologic treatment of dystrophic mdx mice with recombinant osteoprotegerin muscles. (Recombinant osteoprotegerin-Fc mitigates the loss of muscle force in a dose-dependent manner and preserves muscle integrity, particularly in fast-twitch extensor digitorum longus.) Our data identify osteoprotegerin as a novel protector of muscle integrity, and it potentially represents a new therapeutic avenue for both muscular diseases and osteoporosis.

  5. Genetics Home Reference: spinal and bulbar muscular atrophy

    MedlinePlus

    ... chromosomes. In males (who have only one X chromosome ), a mutation in the only copy of the gene in ... the disorder than females (who have two X chromosomes). Females with a mutation in one copy of the AR gene in ...

  6. Genetics Home Reference: spinal muscular atrophy with progressive myoclonic epilepsy

    MedlinePlus

    ... Sell E, Vanstone MR, Smith AC, Garandeau D, Garcia V, Carpentier S, Le Trionnaire E, Sabourdy F, Beaulieu ... Tiziano FD, Veillet J, Bayes M, Nolent F, Garcia V, Servidei S, Bertini E, Castro-Giner F, Renda ...

  7. [An autopsy case of segmental mediolytic arteritis (SMA) accompanied with microscopic polyarteritis nodosa].

    PubMed

    Ito, M R; Ohtani, H; Nakamura, Y; Abe, T; Nose, M

    1995-08-01

    Segmental Mediolytic Arteritis (SMA) is a very rare arterial lesion which is limited in adults to the involvement of the intra-abdominal muscular arteries. The pathology is characterized by segmental disruption of the arterial media which leads segmental mediolysis, with subsequent dissecting aneurysm or rupture. A 73-year-old man was admitted to a hospital because of high fever, general fatigue and weight loss. These symptoms were resistant to antibiotic therapy, and soon after, renal insufficiency developed. Three months after the onset of symptoms, he died suddenly of hemorrhagic shock. Autopsy revealed rupture of the splenic artery and systemic necrotizing arteritis in the small-sized arteries of liver, pancreas and kidneys, as well as in the connective tissues around the adrenal glands. Histopathology of the splenic artery was consistent with SMA, and that of the systemic vascular lesions, with microscopic polyarteritis nodosa. Focal glomerular lesions characteristic of crescentic and/or granulomatous glomerulonephritis were present. A developmental mechanism for SMA is discussed with respect to this case together with a review of previous reports of this disease.

  8. Muscle Atrophy Reversed by Growth Factor Activation of Satellite Cells in a Mouse Muscle Atrophy Model

    PubMed Central

    Hauerslev, Simon; Vissing, John; Krag, Thomas O.

    2014-01-01

    Muscular dystrophies comprise a large group of inherited disorders that lead to progressive muscle wasting. We wanted to investigate if targeting satellite cells can enhance muscle regeneration and thus increase muscle mass. We treated mice with hepatocyte growth factor and leukemia inhibitory factor under three conditions: normoxia, hypoxia and during myostatin deficiency. We found that hepatocyte growth factor treatment led to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myognic transcription factors MyoD and myogenin, and subsequently the negative growth control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we demonstrated that myostatin regulates satellite cell activation and myogenesis in vivo following treatment, consistent with previous findings in vitro. Our results suggest, not only a novel in vivo pharmacological treatment directed specifically at activating the satellite cells, but also a myostatin dependent mechanism that may contribute to the progressive muscle wasting seen in severely affected patients with muscular dystrophy and significant on-going regeneration. This treatment could potentially be applied to many conditions that feature muscle wasting to increase muscle bulk and strength. PMID:24963862

  9. Muscle atrophy reversed by growth factor activation of satellite cells in a mouse muscle atrophy model.

    PubMed

    Hauerslev, Simon; Vissing, John; Krag, Thomas O

    2014-01-01

    Muscular dystrophies comprise a large group of inherited disorders that lead to progressive muscle wasting. We wanted to investigate if targeting satellite cells can enhance muscle regeneration and thus increase muscle mass. We treated mice with hepatocyte growth factor and leukemia inhibitory factor under three conditions: normoxia, hypoxia and during myostatin deficiency. We found that hepatocyte growth factor treatment led to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myognic transcription factors MyoD and myogenin, and subsequently the negative growth control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we demonstrated that myostatin regulates satellite cell activation and myogenesis in vivo following treatment, consistent with previous findings in vitro. Our results suggest, not only a novel in vivo pharmacological treatment directed specifically at activating the satellite cells, but also a myostatin dependent mechanism that may contribute to the progressive muscle wasting seen in severely affected patients with muscular dystrophy and significant on-going regeneration. This treatment could potentially be applied to many conditions that feature muscle wasting to increase muscle bulk and strength.

  10. Flexibility and Muscular Strength.

    ERIC Educational Resources Information Center

    Liemohn, Wendell

    1988-01-01

    This definition of flexibility and muscular strength also explores their roles in overall physical fitness and focuses on how increased flexibility and muscular strength can help decrease or eliminate lower back pain. (CB)

  11. Research opportunities in muscle atrophy

    NASA Technical Reports Server (NTRS)

    Herbison, G. J. (Editor); Talbot, J. M. (Editor)

    1984-01-01

    Muscle atrophy in a weightless environment is studied. Topics of investigation include physiological factors of muscle atrophy in space flight, biochemistry, countermeasures, modelling of atrophied muscle tissue, and various methods of measurement of muscle strength and endurance. A review of the current literature and suggestions for future research are included.

  12. Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy

    PubMed Central

    Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

    2015-01-01

    Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy. PMID:25945103

  13. Dynamic response of a frame with SMA bracing

    NASA Astrophysics Data System (ADS)

    Sun, Shuangshuang; Rajapakse, R. K. N. D.

    2003-08-01

    This paper investigates the dynamic response of a frame structure with pre-strained SMA bracing elements. The constitutive model proposed by Brinson is used to simulate the axial response of SMA bracing elements. A non-linear transient finite element model incorporated with Newmark's time integration scheme is used to analyze the dynamic response of a structure. The time histories of displacements and hysteresis loops of SMA tendons are computed under harmonic loading. The effect of forcing amplitude and initial pre-strains of SMA tendons on transient dynamic response of a structure is discussed. The suitability of pseudoelastic SMA for energy dissipation is briefly discussed.

  14. Perspectives of stem cell therapy in Duchenne muscular dystrophy.

    PubMed

    Meregalli, Mirella; Farini, Andrea; Belicchi, Marzia; Parolini, Daniele; Cassinelli, Letizia; Razini, Paola; Sitzia, Clementina; Torrente, Yvan

    2013-09-01

    Muscular dystrophies are heritable and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle, usually caused by mutations in the proteins forming the link between the cytoskeleton and the basal lamina. As a result of mutations in the dystrophin gene, Duchenne muscular dystrophy patients suffer from progressive muscle atrophy and an exhaustion of muscular regenerative capacity. No efficient therapies are available. The evidence that adult stem cells were capable of participating in the regeneration of more than their resident organ led to the development of potential stem cell treatments for degenerative disorder. In the present review, we describe the different types of myogenic stem cells and their possible use for the progression of cell therapy in Duchenne muscular dystrophy.

  15. Anthropomorphic finger antagonistically actuated by SMA plates.

    PubMed

    Engeberg, Erik D; Dilibal, Savas; Vatani, Morteza; Choi, Jae-Won; Lavery, John

    2015-08-20

    Most robotic applications that contain shape memory alloy (SMA) actuators use the SMA in a linear or spring shape. In contrast, a novel robotic finger was designed in this paper using SMA plates that were thermomechanically trained to take the shape of a flexed human finger when Joule heated. This flexor actuator was placed in parallel with an extensor actuator that was designed to straighten when Joule heated. Thus, alternately heating and cooling the flexor and extensor actuators caused the finger to flex and extend. Three different NiTi based SMA plates were evaluated for their ability to apply forces to a rigid and compliant object. The best of these three SMAs was able to apply a maximum fingertip force of 9.01N on average. A 3D CAD model of a human finger was used to create a solid model for the mold of the finger covering skin. Using a 3D printer, inner and outer molds were fabricated to house the actuators and a position sensor, which were assembled using a multi-stage casting process. Next, a nonlinear antagonistic controller was developed using an outer position control loop with two inner MOSFET current control loops. Sine and square wave tracking experiments demonstrated minimal errors within the operational bounds of the finger. The ability of the finger to recover from unexpected disturbances was also shown along with the frequency response up to 7 rad s(-1). The closed loop bandwidth of the system was 6.4 rad s(-1) when operated intermittently and 1.8 rad s(-1) when operated continuously.

  16. Detection of novel mutations in the SMN Tudor domain in type I SMA patients.

    PubMed

    Cuscó, I; Barceló, M Jesus; del Río, E; Baiget, M; Tizzano, E F

    2004-07-13

    The authors present a complete SMN gene analysis in four type I unrelated spinal muscular atrophy patients who retained one copy of the SMN1 gene. Two intragenic point mutations were identified in exon 3 (I116F, Q136E), affecting a very conserved region with the Tudor domain of SMN1. The remaining two patients showed no alterations in the SMN1 coding sequences although a transcription defect was detected in one of them, corroborating the existence of non-functional SMN1 genes.

  17. The link between stress disorders and autonomic dysfunction in muscular dystrophy

    PubMed Central

    Sabharwal, Rasna

    2014-01-01

    Muscular dystrophy is a progressive disease of muscle weakness, muscle atrophy and cardiac dysfunction. Patients afflicted with muscular dystrophy exhibit autonomic dysfunction along with cognitive impairment, severe depression, sadness, and anxiety. Although the psychological aspects of cardiovascular disorders and stress disorders are well known, the physiological mechanism underlying this relationship is not well understood, particularly in muscular dystrophy. Therefore, the goal of this perspective is to highlight the importance of autonomic dysfunction and psychological stress disorders in the pathogenesis of muscular dystrophy. This article will for the first time—(i) outline autonomic mechanisms that are common to both psychological stress and cardiovascular disorders in muscular dystrophy; (ii) propose therapies that would improve behavioral and autonomic functions in muscular dystrophy. PMID:24523698

  18. Correlating interfacial properties with stress transfer in SMA composites

    SciTech Connect

    Kline, G.E.; Jonnalagadda, K.; Sottos, N.R.

    1995-12-31

    Shape memory alloy (SMA) wires have been proposed as large strain actuators for use in smart structures. SMA wires can be embedded in a host material to alter the stiffness or modal response and provide vibration control. The interaction between the embedded SMA and the host material is critical to applications requiring transfer of loads or strain from the wire to the host. Paine, Jones and Rogers have asserted the importance of interfacial adhesion between embedded SMA wires and the host material. When the SMA wires are actuated, large shear strains are generated at the SMA/host interface. The stronger the interface, the greater the transfer of strain from the actuator to the host material. Although there has been a significant amount of research dedicated to characterizing and modeling the response of SMA alone, little work has been done to understand the behavior of embedded SMA wires. Maximum displacement, load transfer and repeatability of actuation of the embedded wire are particularly critical in assessing the effects of the host material. This work continues to investigate the interaction between SMA wires and a host polymer matrix. High resolution photoelasticity was utilized to study the internal stresses induced during actuation of an embedded shape memory alloy wire in a polymer matrix. The influence of several wire surface treatments on the resulting stresses and load transfer was investigated. Four different surface treatments were considered: untreated, acid etched, hand sanded and sandblasted. Pull-out data indicated that sandblasting of wires increased the SMA/polymer interfacial bond strength while hand sanding and acid cleaning actually decreased the bond strength. Wires with greater adhesion (sandblasted) resulted in higher stresses induced in the polymer while those with lower adhesion transferred less load. Overall, properties of the SMA/polymer interface were shown to significantly affect the performance of the embedded SMA actuator.

  19. Fabrication and Characterization of SMA Hybrid Composites

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.; Lach, Cynthia L.; Cano, Robert J.

    2001-01-01

    Results from an effort to fabrication shape memory alloy hybrid composite (SMAHC) test specimens and characterize the material system are presented in this study. The SMAHC specimens are conventional composite structures with an embedded SMA constituent. The fabrication and characterization work was undertaken to better understand the mechanics of the material system, address fabrication issues cited in the literature, and provide specimens for experimental validation of a recently developed thermomechanical model for SMAHC structures. Processes and hardware developed for fabrication of the SMAHC specimens are described. Fabrication of a SMA14C laminate with quasi-isotropic lamination and ribbon-type Nitinol actuators embedded in the 0' layers is presented. Beam specimens are machined from the laminate and are the focus of recent work, but the processes and hardware are readily extensible to more practical structures. Results of thermomechanical property testing on the composite matrix and Nitinol ribbon are presented. Test results from the Nitinol include stress-strain behavior, modulus versus temperature. and constrained recovery stress versus temperature and thermal cycle. Complex thermomechanical behaviors of the Nitinol and composite matrix are demonstrated, which have significant implications for modeling of SMAHC structures.

  20. Treatment of vaginal atrophy.

    PubMed

    Domoney, Claudine

    2014-03-01

    Vaginal or vulvovaginal atrophy is a widespread but poorly recognized condition of peri- and post-menopausal women. It causes urogenital symptoms of dryness, reduced lubrication, itching, burning, irritable bladder symptoms and painful intercourse. This impacts quality of life and sexual health, but increases with time rather than reduces, as with most other menopausal symptoms. With early identification, treatments can improve these symptoms and reverse the physical changes. However, when embedded, bladder and sexual changes have occurred and these may be more difficult to remedy. Therefore, it is important to educate both healthcare professionals and women about these symptoms and advise on the range of interventions available.

  1. 3-D diffusion tensor axonal tracking shows distinct SMA and pre-SMA projections to the human striatum.

    PubMed

    Lehéricy, Stéphane; Ducros, Mathieu; Krainik, Alexandre; Francois, Chantal; Van de Moortele, Pierre-François; Ugurbil, Kamil; Kim, Dae-Shik

    2004-12-01

    Studies in non-human primates have shown that medial premotor projections to the striatum are characterized as a set of distinct circuits conveying different type of information. This study assesses the anatomical projections from the supplementary motor area (SMA), pre-SMA and motor cortex (MC) to the human striatum using diffusion tensor imaging (DTI) axonal tracking. Eight right-handed volunteers were studied at 1.5 T using DTI axonal tracking. A connectivity matrix was computed, which tested for connections between cortical areas (MC, SMA and pre-SMA) and subcortical areas (posterior, middle and anterior putamen and the head of the caudate nucleus) in each hemisphere. Pre-SMA projections to the striatum were located rostral to SMA projections to the striatum. The SMA and the MC were similarly connected to the posterior and middle putamen and not to the anterior striatum. These data show that the MC and SMA have connections with similar parts of the sensorimotor compartment of the human striatum, whereas the pre-SMA sends connections to more rostral parts of the striatum, including the associative compartment.

  2. Posterior Cortical Atrophy

    PubMed Central

    Crutch, Sebastian J; Lehmann, Manja; Schott, Jonathan M; Rabinovici, Gil D; Rossor, Martin N; Fox, Nick C

    2013-01-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterized by a progressive decline in visuospatial, visuoperceptual, literacy and praxic skills. The progressive neurodegeneration affecting parietal, occipital and occipito-temporal cortices which underlies PCA is attributable to Alzheimer's disease (AD) in the majority of patients. However, alternative underlying aetiologies including Dementia with Lewy Bodies (DLB), corticobasal degeneration (CBD) and prion disease have also been identified, and not all PCA patients have atrophy on clinical imaging. This heterogeneity has led to diagnostic and terminological inconsistencies, caused difficulty comparing studies from different centres, and limited the generalizability of clinical trials and investigations of factors driving phenotypic variability. Significant challenges remain in identifying the factors associated with both the selective vulnerability of posterior cortical regions and the young age of onset seen in PCA. Greater awareness of the syndrome and agreement over the correspondence between syndrome-and disease-level classifications are required in order to improve diagnostic accuracy, research study design and clinical management. PMID:22265212

  3. Familial bulbospinal neuronopathy with optic atrophy: a distinct entity.

    PubMed Central

    Paradiso, G; Micheli, F; Taratuto, A L; Parera, I C

    1996-01-01

    A 61 year old woman and her 58 year old brother presented with the clinical picture of late onset progressive bulbar and spinal muscular atrophy with family history of involvement in successive generations. The sister also had optic neuropathy and the brother developed diabetes mellitus and sex hormone abnormalities. Neurophysiological and histopathological studies showed a pattern of motor and sensory neuronopathy. There was no abnormal expansion of CAG repeats in the androgen receptor gene. This family seems to have a previously unrecognised entity with the bulbospinal neuronopathy phenotype. Images PMID:8708690

  4. Switchable Shape Memory Alloys (SMA) Thermal Materials Project

    NASA Technical Reports Server (NTRS)

    Falker, John; Zeitlin, Nancy; Williams, Martha; Fesmire, James

    2014-01-01

    Develop 2-way switchable thermal systems for use in systems that function in cold to hot temperature ranges using different alloy designs for SMA system concepts. In this project, KSC will specifically address designs of two proof of concept SMA systems with transition temperatures in the 65-95 C range and investigate cycle fatigue and "memory loss" due to thermal cycling.

  5. SMA actuators: a viable practical technology (Presentation Video)

    NASA Astrophysics Data System (ADS)

    Browne, Alan L.; Brown, Jeffrey; Hodgson, Darel E.

    2015-04-01

    Diverse products either based solely on or incorporating Shape Memory Alloys (SMA) have and are being made in a wide range of industries, and IP is being captured. Why then compared to SE (superelastic) Nitinol, and especially conventional technology, do so few ideas reach production? This presentation delves deeply into this topic in reaching the final assessment that SMA actuators are indeed now a viable practical technology. The presentation begins with an introduction to and description of the fundamental basis of SMA actuator technology. Examples of multiple commercially available geometric forms of SMA actuators are given and the functionalities that they provide are described. This is followed by examples of multiple commercial products incorporating such SMA actuators. Given that there are literally millions of commercial products incorporating conventional actuator technologies, indications are given as to why there are their less than 1000 that utilize SMA. Experience based challenges to the commercial use of SMA actuators are described. Besides having to compete with existing non-SMA technology which is quite mature additional challenges that are unique to SM actuators are indicated these including a wider than expected set of technical engineering problems and challenges and that a broader scope of dynamics is required.

  6. Investigation on low velocity impact resistance of SMA composite material

    NASA Astrophysics Data System (ADS)

    Hu, Dianyin; Zhang, Long; Wang, Rongqiao; Zhang, Xiaoyong

    2016-04-01

    A method to improve low velocity impact resistance of aeroengine composite casing using shape memory alloy's properties of shape memory(SM) and super-elasticity(SE) is proposed in this study. Firstly, a numerical modeling of SMA reinforced composite laminate under low velocity impact load with impact velocity of 10 m/s is established based on its constitutive model implemented by the VUMAT subroutine of commercial software ABAQUS. Secondly, the responses of SMA composite laminate including stress and deflection distributions were achieved through transient analysis under low velocity impact load. Numerical results show that both peak stress and deflection values of SMA composite laminate are less than that without SMA, which proves that embedding SMA into the composite structure can effectively improve the low velocity impact performance of composite structure. Finally, the influence of SM and SE on low velocity impact resistance is quantitatively investigated. The values of peak stress and deflection of SMA composite based on SM property decrease by 18.28% and 9.43% respectively, compared with those without SMA, instead of 12.87% and 5.19% based on SE. In conclusion, this proposed model described the impact damage of SMA composite structure and turned to be a more beneficial method to enhance the impact resistance by utilizing SM effect.

  7. Effect of Electroacupuncture on the Expression of Glycyl-tRNA Synthetase and Ultrastructure Changes in Atrophied Rat Peroneus Longus Muscle Induced by Sciatic Nerve Injection Injury.

    PubMed

    Wang, Meng; Zhang, Xiao Ming; Yang, Sheng Bo

    2016-01-01

    Glycyl-tRNA synthetase (GlyRS) is one of the key enzymes involved in protein synthesis. Its mutations have been reported to cause Charcot-Marie-Tooth disease which demonstrates muscular atrophy in distal extremities, particularly manifested in peroneus muscles. In this situation, the dysfunctions of mitochondria and sarcoplasmic reticulum (SR) affect energy supply and excitation-contraction coupling of muscle fibers, therefore resulting in muscular atrophy. Although the treatment of muscular atrophy is a global urgent problem, it can be improved by electroacupuncture (EA) treatment. To investigate the mechanism underlying EA treatment improving muscular atrophy, we focused on the perspective of protein synthesis by establishing a penicillin injection-induced sciatic nerve injury model. In our model, injured rats without treatment showed decreased sciatic functional index (SFI), decreased peroneus longus muscle weight and muscle fiber cross-sectional area, aggregated mitochondria with vacuoles appearing, swollen SR, and downregulated mRNA and protein expression levels of GlyRS and myosin heavy chain IIb (MHC-IIb). The injured rats with EA treatment showed significant recovery. These results indicated that EA stimulation can alleviate peroneus longus muscular atrophy induced by iatrogenic sciatic nerve injury through promoting the recovery of GlyRS and muscle ultrastructure and increasing muscle protein synthesis.

  8. Preliminary characterization and modeling of SMA-based textile composites

    NASA Astrophysics Data System (ADS)

    Masuda, Arata; Ni, Qing-Qing; Sone, Akira; Zhang, Run-Xin; Yamamura, Takahiko

    2004-07-01

    In this paper, we conduct a feasibility study to investigate the future potential of textile composites with shape memory alloys. Two different types of SMA-based textile composites are presented. First, a composite plate with embedded woven SMA layer is fabricated, and the stiffness tuning capability is evaluated by impact vibration tests. The results are not favorable, but may be improved by increasing the volume fraction of SMA, and by controlling the prestrain more accurately during the lamination process. The modeling and analysis methodology for woven SMA-based composites are briefly discussed. Then, the possibility of textile composites with SMA stitching is discussed, that is expected to give the composites multi-functions such as tunable stiffness, shape control and sensing capability, selectively distributed on demand.

  9. Dominant optic atrophy

    PubMed Central

    2012-01-01

    Definition of the disease Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. Epidemiology The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. Clinical description DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Aetiology Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Diagnosis Patients are usually diagnosed during their early childhood, because of bilateral, mild

  10. [Scleroderma with progressive facial hemiatrophy and atrophy of the other side of the body].

    PubMed

    Lapresle, J; Desi, M

    1982-01-01

    The authors report the case of a 28 year old woman suffering from a chronic polyarthritis with a linear sclerodermia and presenting a crossed atrophy involving the left side of the body and the right side of the face and neck. The polyarthritis began at age 6, with signs of systemic illness, resulting early in important joint disability and proceeding with exacerbations and remissions. From the onset of this polyarthritis the patient experienced in the left side of the body highly painful and frequent muscular cramps which became rarer with the occurrence and progression of atrophy on the same side. At age 15, the patient experienced similar cramps in the right face, followed by progressive right hemiatrophy. At age 28, examination showed crossed atrophy involving the left side of the body and the right side of the face, tongue and neck, associated in these territories with several atrophic plaques on the skin, circumscribed alopecia, as well as numerous joint sequella. The laboratory date yielded immunologic abnormalities. On the CT scan the brain was normal but the right facial hemiatrophy involving orbital region and pharynx was visible. On the muscular biopsy there were inflammatory changes in the atrophic territory. Skin biopsies were consistent with sclerodermia. Two clinical points should be emphasized. Firstly, the remarkably crossed topography of the atrophy: the upper limit of the left body atrophy corresponded with the lower limit of the right face and neck atrophy; secondly, the unusual features of the muscular cramps. The relationship between sclerodermic facial hemiatrophy and Parry Romberg syndrome are then discussed: the study of this case and the literature do not provide sufficient criteria to allow description of two separate entities. Finally, the pathogenesis of localized sclerodermia is considered; in this case the association with the immunologic abnormalities and chronic polyarthritis is in favor of the hypothesis of a systemic disorder.

  11. Brain atrophy in frontotemporal dementia.

    PubMed Central

    Frisoni, G B; Beltramello, A; Geroldi, C; Weiss, C; Bianchetti, A; Trabucchi, M

    1996-01-01

    OBJECTIVES--To evaluate the pattern of regional brain atrophy in patients with frontotemporal dementia by comparing it with that in patients with Alzheimer's disease and normal controls. METHODS--Fourteen patients with frontotemporal dementia, 13 with moderate, and 33 with mild Alzheimer's disease, and 31 controls were studied. Atrophy was evaluated with linear measures in the anterior brain, medial temporal lobe, and hippocampal formation regions using MRI. RESULTS--Patients with frontotemporal dementia had greater atrophy in the anterior brain regions than patients with Alzheimer's disease or controls. Atrophy of the hippocampal formation, which best discriminates Alzheimer's disease from controls, was present also in patients with frontotemporal dementia. By contrast, atrophy of the medial temporal lobe, which is also present in Alzheimer's disease, was absent in frontotemporal dementia. CONCLUSION--A pattern of atrophy in the frontal lobes and hippocampal formation with sparing of the medial temporal lobe might be distinctive of frontotemporal dementia. Hippocampal involvement might not be specific for Alzheimer's disease and specific patterns of atrophy might be distinctive of some forms of degenerative dementia. Images PMID:8708683

  12. The Significance of Bronchial Atrophy

    PubMed Central

    Maisel, John C.; Silvers, G. Wayne; George, Marlyce S.; Dart, Gladys A.; Petty, Thomas L.; Mitchell, Roger S.

    1972-01-01

    In a 4-year period, 196 lungs from patients with and without chronic obstructive pulmonary disease were examined postmortem for the presence of atrophy in segmental and subsegmental bronchi. As a result of simultaneous postmortem spirometry, cinefluorobronchography and partitioning of airways resistance, plus later assessment of anatomic emphysema, bronchial atrophy emerges as only one of at least three factors usually cooperating in production of abnormal expiratory airway collapse. In selected cases, bronchial atrophy appears to be an important contributor to expiratory airways obstruction. ImagesFig 1 PMID:5021107

  13. Relationship between input power and power density of SMA spring

    NASA Astrophysics Data System (ADS)

    Park, Cheol Hoon; Ham, Sang Yong; Son, Young Su

    2016-04-01

    The important required characteristics of an artificial muscle for a human arm-like manipulator are high strain and high power density. From this viewpoint, an SMA (shape memory alloy) spring is a good candidate for the actuator of a robotic manipulator that utilizes an artificial muscle. In this study, the maximum power density of an SMA spring was evaluated with respect to the input power. The spring samples were fabricated from SMA wires of different diameters ranging between 0.1 and 0.3 mm. For each diameter, two types of wires with different transition temperatures were used. The relationship between the transition temperature and maximum power density was also evaluated. Each SMA spring was stretched downward by an attached weight and the temperature was increased through the application of an electric current. The displacement, velocity, and temperature of the SMA spring were measured by laser displacement sensors and a thermocouple. Based on the experimental data, it was determined that the maximum power densities of the different SMA springs ranged between 1,300 and 5,500 W/kg. This confirmed the applicability of an SMA spring to human arm-like robotic manipulators. The results of this study can be used as reference for design.

  14. Becker muscular dystrophy

    MedlinePlus

    ... and wheelchairs may improve movement and self-care. Genetic counseling may be recommended. Daughters of a man with ... Genetic counseling may be advised if there is a family history of Becker muscular dystrophy.

  15. Research opportunities in muscle atrophy

    NASA Technical Reports Server (NTRS)

    Herbison, G. J.; Talbot, J. M.

    1984-01-01

    A trophy of skeletal muscle; muscle a trophy associated with manned space flight; the nature, causes, and mechanisms of muscle atrophy associated with space flight, selected physiological factors, biochemical aspects, and countermeasures are addressed.

  16. Miniature High-Force, Long-Stroke SMA Linear Actuators

    NASA Technical Reports Server (NTRS)

    Cummin, Mark A.; Donakowski, William; Cohen, Howard

    2008-01-01

    Improved long-stroke shape-memory-alloy (SMA) linear actuators are being developed to exert significantly higher forces and operate at higher activation temperatures than do prior SMA actuators. In these actuators, long linear strokes are achieved through the principle of displacement multiplication, according to which there are multiple stages, each intermediate stage being connected by straight SMA wire segments to the next stage so that relative motions of stages are additive toward the final stage, which is the output stage. Prior SMA actuators typically include polymer housings or shells, steel or aluminum stages, and polymer pads between successive stages of displacement-multiplication assemblies. Typical output forces of prior SMA actuators range from 10 to 20 N, and typical strokes range from 0.5 to 1.5 cm. An important disadvantage of prior SMA wire actuators is relatively low cycle speed, which is related to actuation temperature as follows: The SMA wires in prior SMA actuators are typically made of a durable nickel/titanium alloy that has a shape-memory activation temperature of 80 C. An SMA wire can be heated quickly from below to above its activation temperature to obtain a stroke in one direction, but must then be allowed to cool to somewhat below its activation temperature (typically, less than or equal to 60 C in the case of an activation temperature of 80 C) to obtain a stroke in the opposite direction (return stroke). At typical ambient temperatures, cooling times are of the order of several seconds. Cooling times thus limit cycle speeds. Wires made of SMA alloys having significantly higher activation temperatures [denoted ultra-high-temperature (UHT) SMA alloys] cool to the required lower return-stroke temperatures more rapidly, making it possible to increase cycle speeds. The present development is motivated by a need, in some applications (especially aeronautical and space-flight applications) for SMA actuators that exert higher forces, operate

  17. Highly-Compact SMA Actuators A Feasibiltiy Study of Fuel-Powered and Thermoelectric SMA Actuators

    DTIC Science & Technology

    2003-12-01

    TEM top surface TEM DC Power source Finned Heat Sink (FHS) DAQ Thermocouple(s) TEM bottom surface Config 1: single TEM ( Melcor ) Config 2: stacked TEM...strained to 3% before testing. A PWM based actuation control scheme was used to resistively heat the SMA actuator. TEMs were acquired from Melcor and...Output 1.70W 2.06W Avg. Energy Output 0.17J 0.103J Stacked (2) TEMs Energy Input 72J 36J Power Input 1.6W Power Input 501.6W 501.6W Weight 2.2gr

  18. Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry

    ClinicalTrials.gov

    2016-08-26

    Myotonic Dystrophy; Facioscapulohumeral Muscular Dystrophy; Muscular Dystrophy; Myotonic Dystrophy Type 1; Myotonic Dystrophy Type 2; Congenital Myotonic Dystrophy; PROMM (Proximal Myotonic Myopathy); Steinert's Disease; Myotonic Muscular Dystrophy

  19. Seismic Protection of an Ancient Aqueduct Using SMA Devices

    SciTech Connect

    Chrysostomou, Christis Z.; Demetriou, Themos; Stassis, Andreas; Hamdaoui, Karim

    2008-07-08

    The effectiveness of the use of Cu-based shape memory alloy (SMA) prestressing devices on an ancient aqueduct is examined in this paper. The dynamic characteristics of the aqueduct were measured within the span of three years and computational models were developed that matched very closely its dynamic behaviour. Using this as a bench mark, SMA prestressing devices were applied on the structure and the effects on its dynamic characteristics were assessed. It was noted that the SMA prestressing devices have a significant effect on the dynamic response of the structure. This is attributed to the stiffening of the structure due to the increase in contact between the masonry units and hence the increase of its stiffness through the increase of the modulus of elasticity of the masonry matrix. It can be concluded that the SMA prestressing devices can provide an inconspicuous means of stiffening masonry structures and increase their resistance to earthquake loads.

  20. Seismic Protection of an Ancient Aqueduct Using SMA Devices

    NASA Astrophysics Data System (ADS)

    Chrysostomou, Christis Z.; Demetriou, Themos; Stassis, Andreas; Hamdaoui, Karim

    2008-07-01

    The effectiveness of the use of Cu-based shape memory alloy (SMA) prestressing devices on an ancient aqueduct is examined in this paper. The dynamic characteristics of the aqueduct were measured within the span of three years and computational models were developed that matched very closely its dynamic behaviour. Using this as a bench mark, SMA prestressing devices were applied on the structure and the effects on its dynamic characteristics were assessed. It was noted that the SMA prestressing devices have a significant effect on the dynamic response of the structure. This is attributed to the stiffening of the structure due to the increase in contact between the masonry units and hence the increase of its stiffness through the increase of the modulus of elasticity of the masonry matrix. It can be concluded that the SMA prestressing devices can provide an inconspicuous means of stiffening masonry structures and increase their resistance to earthquake loads.

  1. Shape correction of composite beams with SMA wires

    NASA Astrophysics Data System (ADS)

    Maji, Arup K.; Rochin, Refugio

    2001-07-01

    Shape Memory Alloys (SMA) are increasingly used as smart devices ina erospace applicatons.Their priry advnatage over other smart materials z9piezo-ceramics adnpiezo-polymers) is in their ability to undergo large strains and dispalcements that enables the devlopment of smart mechanissm. The specific objective of this research was toinvestigate the use of embedded SMA for active shape correctionof flexibl emirror substrates.Active shape correction is a possiblemeans of mitigating thrmally induced distortions in space based optical iaging systems inorder to understand and quantify the designvalraibles that lead to that goal, embedded SMA wires we used toa cctuate a series of composite bmeasm.Themoemvent induced byactutionw as monitored with theMoire inteferietery method,and the rsutls wer compared witha n anlaytical model.The repeatabiltya nd rlaibltiyof a possible acutation systmeand the propertis of the SMa wires was also studied by testing the stress-strian anthe stress reo ery behavior under controlled conditons.110

  2. CUG-BP1 regulates RyR1 ASI alternative splicing in skeletal muscle atrophy.

    PubMed

    Tang, Yinglong; Wang, Huiwen; Wei, Bin; Guo, Yuting; Gu, Lei; Yang, Zhiguang; Zhang, Qing; Wu, Yanyun; Yuan, Qi; Zhao, Gang; Ji, Guangju

    2015-11-04

    RNA binding protein is identified as an important mediator of aberrant alternative splicing in muscle atrophy. The altered splicing of calcium channels, such as ryanodine receptors (RyRs), plays an important role in impaired excitation-contraction (E-C) coupling in muscle atrophy; however, the regulatory mechanisms of ryanodine receptor 1 (RyR1) alternative splicing leading to skeletal muscle atrophy remains to be investigated. In this study we demonstrated that CUG binding protein 1 (CUG-BP1) was up-regulated and the alternative splicing of RyR1 ASI (exon70) was aberrant during the process of neurogenic muscle atrophy both in human patients and mouse models. The gain and loss of function experiments in vivo demonstrated that altered splicing pattern of RyR1 ASI was directly mediated by an up-regulated CUG-BP1 function. Furthermore, we found that CUG-BP1 affected the calcium release activity in single myofibers and the extent of atrophy was significantly reduced upon gene silencing of CUG-BP1 in atrophic muscle. These findings improve our understanding of calcium signaling related biological function of CUG-BP1 in muscle atrophy. Thus, we provide an intriguing perspective of involvement of mis-regulated RyR1 splicing in muscular disease.

  3. Damper-controlled switch for SMA motion smoothing

    NASA Astrophysics Data System (ADS)

    Aguayo, Clover; Utter, Brent; Luntz, Jonathan; Gonzalez, Richard; Brei, Diann; Johnson, Nancy L.; Alexander, Paul W.

    2014-04-01

    While the use of SMA-actuated devices continues to grow in many industries, current device limitations pose a challenge to successful adoption for certain classes of applications. SMA-actuated devices typically demonstrate motion with non-constant velocity due to the non-linear thermo-mechanically coupled behavior of SMA material transformation, and motion sensitivity to external factors such as voltage and load. This variation in motion can lead to the perception of poor device quality, limiting SMA-actuated devices to applications hidden from the sight of the product user, or requiring them to be augmented with higher cost controls to improve the motion quality. Therefore, a need exists for simple, passive, low-cost device technologies that enable the designer to prescribe desired motion characteristics with relative insensitivity to fluctuation in operating conditions. This paper presents a Damper Controlled Switch (DCS) mechanism that delivers constant velocity and relative insensitivity to operating conditions when combined with a standard SMA wire actuator. The DCS includes a damper that acts against a spring to open a switch when the velocity exceeds a tunable threshold. To validate the ability of the DCS to provide the desired motion quality, experiments were conducted comparing the normal motion of the SMA actuator to the motion produced when the same actuator was fitted with a DCS prototype. The addition of the DCS produced nearly constant actuator velocity, performing significantly better than the SMA actuator alone. The tunability of the DCS was demonstrated producing a wide range of attainable constant velocities. Finally, a set of experiments explored the DCS's sensitivity to voltage and load, indicating a low sensitivity to a wide range of operating parameters for which the operating limits were identified. The DCS represents a simple, compact technology based on passive, low-cost components, providing a very practical solution that will enable

  4. MicroRNA in skeletal muscle development, growth, atrophy, and disease.

    PubMed

    Kovanda, Anja; Režen, Tadeja; Rogelj, Boris

    2014-01-01

    MicroRNAs (miRNAs) are short noncoding RNAs that are important global- as well as tissue- and cell-type-specific regulators of gene expression. Muscle-specific miRNAs or myomirs have been shown to control various processes in skeletal muscles, from myogenesis and muscle homeostasis to different responses to environmental stimuli, such as exercise. Importantly, myomirs are also involved in the development of muscle atrophy arising from aging, immobility, prolonged exposure to microgravity, or muscular and neuromuscular disorders. Additionally, muscle atrophy is both induced by and exacerbates many important chronic and infectious diseases. As global yet specific muscle regulators, myomirs are also good candidates for therapeutic use. Understanding the dynamics of myomirs expression and their role in the development of disease is necessary to determine their potential for muscle atrophy prevention.

  5. Idiopathic atrophie blanche.

    PubMed

    Amato, Lauretta; Chiarini, Caterina; Berti, Samantha; Massi, Daniela; Fabbri, Paolo

    2006-01-01

    clinical, serologic, histopathologic, and immunopathologic findings, a diagnosis of idiopathic atrophie blanche was made. The patient was treated with dapsone (50 mg p.o. q.d.) and pentoxifylline (400 mg p.o. t.i.d.) with pain relief and complete resolution of the ulcerations after 6 weeks of therapy.

  6. Evaluation of Limb-Girdle Muscular Dystrophy

    ClinicalTrials.gov

    2014-03-06

    Becker Muscular Dystrophy; Limb-Girdle Muscular Dystrophy, Type 2A (Calpain-3 Deficiency); Limb-Girdle Muscular Dystrophy, Type 2B (Miyoshi Myopathy, Dysferlin Deficiency); Limb-Girdle Muscular Dystrophy, Type 2I (FKRP-deficiency)

  7. Regulation of muscle atrophy in aging and disease.

    PubMed

    Vinciguerra, Manlio; Musaro, Antonio; Rosenthal, Nadia

    2010-01-01

    Muscle aging is characterized by a decline in functional performance and restriction of adaptability, due to progressive loss of muscle tissue coupled with a decrease in strength and force output. Together with selective activation ofapoptotic pathways, a hallmark of age-related muscle loss or sarcopenia is the progressive incapacity of regeneration machinery to replace damaged muscle. These characteristics are shared by pathologies involving muscle wasting, such as muscular dystrophies or amyotrophic lateral sclerosis, cancer and AIDS, all characterized by alterations in metabolic and physiological parameters, progressive weakness in specific muscle groups. Modulation ofextracellular agonists, receptors, protein kinases, intermediate molecules, transcription factors and tissue-specific gene expression collectively compromise the functionality of skeletal muscle tissue, leading to muscle degeneration and persistent protein degradation through activation ofproteolytic systems, such as calpain, ubiquitin-proteasome and caspase. Additional decrements in muscle growth factors compromise skeletal muscle growth, differentiation, survival and regeneration. A better understanding of the mechanisms underlying the pathogenesis of muscle atrophy and wasting associated with different diseases has been the objective of numerous studies and represents an important first step for the development of therapeutic approaches. Among these, insulin-like growth factor-1 (IGF-1) has emerged as a growth factor with a remarkably wide range of actions and a tremendous potential as a therapeutic in attenuating the atrophy and frailty associated with muscle aging and diseases. In this chapter we provide an overview of current concepts in muscle atrophy, focusing specifically on the molecular basis of IGF-1 action and survey current gene and cell therapeutic approaches to rescue muscle atrophy in aging and disease.

  8. Learning about Duchenne Muscular Dystrophy

    MedlinePlus

    ... form of muscular dystrophy that occurs primarily in boys. It is caused by an alteration (mutation) in ... to date, which encodes the muscle protein, dystrophin. Boys with Duchenne muscular dystrophy do not make the ...

  9. Simulation-Based Design of a Rotatory SMA Drive

    NASA Astrophysics Data System (ADS)

    Dilthey, Sascha; Meier, Horst

    2009-08-01

    The design and optimization of a rotatory drive powered by shape memory alloy (SMA) actuators is described in this paper. SMA actuators used in technical applications are parameterized by the use of trial-and-error methods, because there is a lack of computer-aided design tools for this active material. A numerical modeling approach was developed to design and optimize the geometry and the load and heating conditions of SMA actuators in a technical system to achieve a good dynamic and a high reliability. The shape memory effect used in most technical systems is the extrinsic two way effect (2WE). This effect can be simulated with the numerical model which was implemented in MATLAB/SIMULINK. The focus of the model is on the activation behavior of the SMA actuator, which defines its rate of heating and cooling. Different load conditions and various actuator geometries and shapes, e.g. wire or spring actuator, are simulated by the calculation of the energetic balance of the whole system. The numerical model can be used to simulate time variant heating currents in order to obtain an optimal system performance. The model was used to design a rotatory SMA-drive system, which is based on the moving concept of a wave drive gear set. In contrast to the conventional system, which is driven by an electric motor, the SMA drive consists of a strain wave gear and SMA wire actuators that are applied circularly to generate a rotatory movement. Special characteristics of this drive system are a high torque density and a high positioning accuracy.

  10. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components.

    PubMed Central

    Savage, C; Das, P; Finelli, A L; Townsend, S R; Sun, C Y; Baird, S E; Padgett, R W

    1996-01-01

    Although transforming growth factor beta (TGF-beta) superfamily ligands play critical roles in diverse developmental processes, how cells transduce signals from these ligands is still poorly understood. Cell surface receptors for these ligands have been identified, but their cytoplasmic targets are unknown. We have identified three Caenorhabditis elegans genes, sma-2, sma-3, and sma-4, that have mutant phenotypes similar to those of the TGF-beta-like receptor gene daf-4, indicating that they are required for daf-4-mediated developmental processes. We show that sma-2 functions in the same cells as daf-4, consistent with a role in transducing signals from the receptor. These three genes define a protein family, the dwarfins, that includes the Mad gene product, which participates in the decapentaplegic TGF-beta-like pathway in Drosophila [Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H. & Gelbart, W. M. (1995) Genetics 139, 1347-1358]. The identification of homologous components of these pathways in distantly related organisms suggests that dwarfins may be universally required for TGF-beta-like signal transduction. In fact, we have isolated highly conserved dwarfins from vertebrates, indicating that these components are not idiosyncratic to invertebrates. These analyses suggest that dwarfins are conserved cytoplasmic signal transducers. Images Fig. 1 PMID:8570636

  11. Duchenne muscular dystrophy.

    PubMed

    Yiu, Eppie M; Kornberg, Andrew J

    2015-08-01

    Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies.

  12. Facioscapulohumeral muscular dystrophy.

    PubMed

    Statland, Jeffrey; Tawil, Rabi

    2014-08-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a common type of adult muscular dystrophy and is divided into types 1 and 2 based on genetic mutation. Clinically, both FSHD types often show asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms followed by the distal then proximal lower extremities. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both types share a common downstream mechanism, making it possible for future disease-directed therapies to be effective for both FSHD types.

  13. Optic atrophy and glaucomatous cupping.

    PubMed

    Radius, R L; Maumenee, A E

    1978-02-01

    We reviewed 170 eyes of 112 patients with optic atrophy from various causes. Special attention was directed towards measured cup:disk ratios as well as presence of glaucomatous-like cupping of the optic nerve head. We observed a small but significant increase in nerve head cupping in eyes with optic atrophy when compared to contralateral eyes, as well as to eyes of 50 diabetic patients. No characteristic glaucomatous disk changes were documented. We evaluated these findings with respect to possible causes of glaucomatous disk and field changes.

  14. Clinical and Laboratory Features Distinguishing Juvenile Polymyositis and Muscular Dystrophy

    PubMed Central

    MAMYROVA, GULNARA; KATZ, JAMES D.; JONES, ROBERT V.; TARGOFF, IRA N.; LACHENBRUCH, PETER A.; JONES, OLCAY Y.; MILLER, FREDERICK W.; RIDER, LISA G.

    2016-01-01

    Objective To differentiate juvenile polymyositis (PM) and muscular dystrophy, both of which may present with chronic muscle weakness and inflammation. Methods We studied 39 patients with probable or definite juvenile PM and 9 patients with muscular dystrophies who were initially misdiagnosed as having juvenile PM. Differences in demographic, clinical, and laboratory results; outcomes; and treatment responses were evaluated by Fisher’s exact and rank sum tests. Random forests classification analysis and logistic regression were performed to examine significant differences in multivariable models. Results Clinical features and serum muscle enzyme levels were similar between juvenile PM and dystrophy patients, except 89% of dystrophy patients had muscle atrophy compared with 46% of juvenile PM patients. Dystrophy patients had a longer delay to diagnosis (median 12 versus 4 months) and were less frequently hospitalized than juvenile PM patients (22% versus 74%). No dystrophy patients, but 54% of juvenile PM patients, had a myositis autoantibody. Dystrophy patients more frequently had myopathic features on muscle biopsy, including diffuse variation of myofiber size, fiber hypertrophy, and myofiber fibrosis (44–100% versus 8–53%). Juvenile PM patients more frequently had complex repetitive discharges on electromyography and a complete response to treatment with prednisone or other immunosuppressive agents than dystrophy patients (44% versus 0%). Random forests analysis revealed that the most important features in distinguishing juvenile PM from dystrophies were myositis autoantibodies, clinical muscle atrophy, and myofiber size variation on biopsy. Logistic regression confirmed muscle atrophy, myofiber fibrosis, and hospitalization as significant predictors. Conclusion Muscular dystrophy can present similarly to juvenile PM. Selected clinical and laboratory features are helpful in combination in distinguishing these conditions. PMID:23925923

  15. Prosthetic leg powered by MR brake and SMA wires

    NASA Astrophysics Data System (ADS)

    Nguyen, The; Munguia, Vicente; Calderon, Jose

    2014-04-01

    Current knee designs for prosthetic legs rely on electric motors for both moving and stationary states. The electric motors draw an especially high level of current to sustain a fixed position. The advantage of using magnetorheological (MR) fluid is that it requires less current and can have a variable braking torque. Besides, the proposed prosthetic leg is actuated by NiTinol wire, a popular shape memory alloy (SMA). The incorporation of NiTinol gives the leg more realistic weight distribution with appropriate arrangement of the batteries and wires. The prosthesis in this research was designed with MR brake as stopping component and SMA wire network as actuating component at the knee. The MR brake was designed with novel non-circular shape for the rotor that improved the braking torque while minimizing the power consumption. The design also helped simplify the control of braking process. The SMA wire network was design so that the knee motion was actively rotated in both directions. The SMA wires were arranged and played very similar role as the leg's muscles. The study started with the overall solid design of the knee including both MR and SMA parts. Theoretical models were derived and programmed in Simulink for both components. The simulation was capable of predicting the power required for moving the leg or hold it in a fixed position for a certain amount of time. Subsequently, the design was prototyped and tested to validate the theoretical prediction. The theoretical models were updated accordingly to correlate with the experimental data.

  16. Seismic response control of frame structure braced with SMA tendons

    NASA Astrophysics Data System (ADS)

    Yan, Shi; Song, Gangbing; Huo, Linsheng; Gu, Haichang

    2007-04-01

    This paper presents studies of seismic response control of a frame structure braced with SMA (Shape Memory Alloy) tendons through both numerical and experimental approaches. Based on the Brinson one-dimensional constitutive law for SMAs, a two-story frame structure braced diagonally with SMA tendons is used as an example to simulate numerically the vibration control process. By considering the temperature, different initial states and thermal properties of the SMA tendon, and the variable intensity and frequency of earthquake input, the parameters of the system were analyzed during the numerically simulation. The time histories of the displacement and hysteretic loops of the SMA tendons were simulated under earthquake ground motion by using finite element method (FEM). To validate the efficiency of the simulation, a shaking table test for the frame structure was conducted. Both numerical simulation and experimental results show that the actively controlled martensite SMA tendons can effectively suppress the vibration of the multi-story frame structure during an earthquake.

  17. Meaning of Muscular Dystrophy

    MedlinePlus

    ... MD Living With MD en español Qué significa distrofia muscular Over Labor Day, just as you're ... grown-up. This article talks about two types: Duchenne and Becker MD. Generally, only boys get Duchenne ...

  18. Finite element simulation of adaptive aerospace structures with SMA actuators

    NASA Astrophysics Data System (ADS)

    Frautschi, Jason; Seelecke, Stefan

    2003-07-01

    The particular demands of aerospace engineering have spawned many of the developments in the field of adaptive structures. Shape memory alloys are particularly attractive as actuators in these types of structures due to their large strains, high specific work output and potential for structural integration. However, the requisite extensive physical testing has slowed development of potential applications and highlighted the need for a simulation tool for feasibility studies. In this paper we present an implementation of an extended version of the M'ller-Achenbach SMA model into a commercial finite element code suitable for such studies. Interaction between the SMA model and the solution algorithm for the global FE equations is thoroughly investigated with respect to the effect of tolerances and time step size on convergence, computational cost and accuracy. Finally, a simulation of a SMA-actuated flexible trailing edge of an aircraft wing modeled with beam elements is presented.

  19. FE Simulation of SMA Seal for Mars Sample Return

    NASA Technical Reports Server (NTRS)

    Bao, Xiaoqi; Younse, Paulo; Bhandari, Pradeep

    2013-01-01

    Several NASA rovers and landers have been on Mars and performed successful in-situ exploration. Returning Martian samples to Earth for extensive analysis is of great interest to the planetary science community. Current Mars sample return architecture would require leaving the acquired samples on Mars for years before being retrieved by subsequent mission. Each sample would be sealed securely to keep its integrity. A reliable seal technique that does not affect the integrity of the samples and uses a simple low-mass tool is required. The shape memory alloy (SMA) seal technique is a promising candidate. A study of the thermal performances of several primary designs of a SMA seal for sample tubes by finite element (FE) simulation are presented in this paper. The results show sealing the sample tube by SMA plugs and controlling the sample temperature below the allowed temperature level are feasible.

  20. Graphical design for thin-film SMA microactuators

    NASA Astrophysics Data System (ADS)

    Ishida, A.; Sato, M.; Yoshikawa, W.; Tabata, O.

    2007-10-01

    Simple graphical designs for bridge- and diaphragm-type actuators using shape-memory alloy (SMA) thin films are proposed. The performance (force and displacement) of these actuators is predicted on the basis of the stress-strain curves of an SMA film by introducing the material parameter K that represents the mechanical properties of both the austenite and martensite films. The methods of designing actuators are presented along with numerical examples and their validity is discussed, referring to some actual devices such as a microvalve and a micropump. A comparison of theory and actual device performance shows that the proposed design gives a useful approximation for practical applications. The advantage of the proposed design method is that, once the value of K is obtained for a given SMA film, one can design various actuators with various dimensions without detailed information about its mechanical properties.

  1. Adaptive and energy efficient SMA-based handling systems

    NASA Astrophysics Data System (ADS)

    Motzki, P.; Kunze, J.; Holz, B.; York, A.; Seelecke, S.

    2015-04-01

    Shape Memory Alloys (SMA's) are known as actuators with very high energy density. This fact allows for the construction of very light weight and energy-efficient systems. In the field of material handling and automated assembly process, the avoidance of big moments of inertia in robots and kinematic units is essential. High inertial forces require bigger and stronger robot actuators and thus higher energy consumption and costs. For material handling in assembly processes, many different individual grippers for various work piece geometries are used. If one robot has to handle different work pieces, the gripper has to be exchanged and the assembly process is interrupted, which results in higher costs. In this paper, the advantages of using high energy density Shape Memory Alloy actuators in applications of material-handling and gripping-technology are explored. In particular, light-weight SMA actuated prototypes of an adaptive end-effector and a vacuum-gripper are constructed via rapid-prototyping and evaluated. The adaptive end-effector can change its configuration according to the work piece geometry and allows the handling of multiple different shaped objects without exchanging gripper tooling. SMA wires are used to move four independent arms, each arm adds one degree of freedom to the kinematic unit. At the tips of these end-effector arms, SMA-activated suction cups can be installed. The suction cup prototypes are developed separately. The flexible membranes of these suction cups are pulled up by SMA wires and thus a vacuum is created between the membrane and the work piece surface. The self-sensing ability of the SMA wires are used in both prototypes for monitoring their actuation.

  2. Emerging roles for histone deacetylases in age-related muscle atrophy

    PubMed Central

    Walsh, Michael E.; Van Remmen, Holly

    2016-01-01

    BACKGROUND: Skeletal muscle atrophy during aging, a process known as sarcopenia, is associated with muscle weakness, frailty, and the loss of independence in older adults. The mechanisms contributing to sarcopenia are not totally understood, but muscle fiber loss due to apoptosis, reduced stimulation of anabolic pathways, activation of catabolic pathways, denervation, and altered metabolism have been observed in muscle from old rodents and humans. OBJECTIVE: Recently, histone deacetylases (HDACs) have been implicated in muscle atrophy and dysfunction due to denervation, muscular dystrophy, and disuse, and HDACs play key roles in regulating metabolism in skeletal muscle. In this review, we will discuss the role of HDACs in muscle atrophy and the potential of HDAC inhibitors for the treatment of sarcopenia. CONCLUSIONS: Several HDAC isoforms are potential targets for intervention in sarcopenia. Inhibition of HDAC1 prevents muscle atrophy due to nutrient deprivation. HDAC3 regulates metabolism in skeletal muscle and may inhibit oxidative metabolism during aging. HDAC4 and HDAC5 have been implicated in muscle atrophy due to denervation, a process implicated in sarcopenia. HDAC inhibitors are already in use in the clinic, and there is promise in targeting HDACs for the treatment of sarcopenia. PMID:28035339

  3. [Two boys with non-progressive unilateral atrophy of the calf muscles].

    PubMed

    Sasaki, Masayuki; Oomi, Tsuyoshi; Segawa, Masami; Komaki, Hirofumi; Sugai, Kenji

    2006-11-01

    We report here two boys who presented with atrophy of the right calf muscle. The onset was insidious and the symptom was found in infancy in case 2. They were followed for more than 5 years and no progression was seen. No sensory disturbances or autonomic nervous system symptoms were observed. Although needle electric myograph and muscle biopsy findings showed a neurogenic pattern, no cause was confirmed. Recently, a new disease concept of "benign monomelic amyotrophy of lower limb" was established and this could be applied to these patients. This disorder is rare and it is seen in young adults. It is characterized by non-progressive unilateral calf muscle atrophy. There is almost no possibility that this disorder is a variant of spinal muscular atrophy. When a patient presents with unilateral calf muscle atrophy, the treatable causes of the atrophy, including spinal cord disorders or peripheral nerve disorders, should be excluded first. If a confirmed cause cannot be found, then there should be a careful follow-up of the patient, even if the symptoms are stable.

  4. Micro-Ball-Lens Optical Switch Driven by SMA Actuator

    NASA Technical Reports Server (NTRS)

    Yang, Eui-Hyeok

    2003-01-01

    The figure is a simplified cross section of a microscopic optical switch that was partially developed at the time of reporting the information for this article. In a fully developed version, light would be coupled from an input optical fiber to one of two side-by-side output optical fibers. The optical connection between the input and the selected output fiber would be made via a microscopic ball lens. Switching of the optical connection from one output fiber to another would be effected by using a pair of thin-film shape-memory-alloy (SMA) actuators to toggle the lens between two resting switch positions. There are many optical switches some made of macroscopic parts by conventional fabrication techniques and some that are microfabricated and, hence, belong to the class of microelectromechanical systems (MEMS). Conventionally fabricated optical switches tend to be expensive. MEMS switches can be mass-produced at relatively low cost, but their attractiveness has been diminished by the fact that, heretofore, MEMS switches have usually been found to exhibit high insertion losses. The present switch is intended to serve as a prototype of low-loss MEMS switches. In addition, this is the first reported SMA-based optical switch. The optical fibers would be held in V grooves in a silicon frame. The lens would have a diameter of 1 m; it would be held by, and positioned between, the SMA actuators, which would be made of thin films of TiNi alloy. Although the SMA actuators are depicted here as having simple shapes for the sake of clarity of illustration, the real actuators would have complex, partly net-like shapes. With the exception of the lens and the optical fibers, the SMA actuators and other components of the switch would be made by microfabrication techniques. The components would be assembled into a sandwich structure to complete the fabrication of the switch. To effect switching, an electric current would be passed through one of the SMA actuators to heat it above

  5. Modeling of piezo-SMA composites for thermal energy harvester

    NASA Astrophysics Data System (ADS)

    Namli, Onur Cem; Lee, Jae-Kon; Taya, Minoru

    2007-04-01

    A hydrid composite comprised of shape memory alloy (SMA) fibers with piezoelectric ceramic is designed to transform thermomechanical energy into electrical energy that can be stored or used to power other devices. SMA fiber, after its shape is memorized and prestrained at martensitic phase, extends to its original length upon heating to austenitic finish temperature. The compressive residual stress of the composite is induced at austenitic phase, and then by cooling to martensitic finish temperature, SMA will shrink and the residual stress will reduce. By direct effect of the piezoelectric matrix material the mechanical energy which was induced by temperature change can be converted to electrical energy. 1-D and 3-D models for the energy harvesting mechanism of the composite have been proposed. Eshelby formulation with Mori-Tanaka mean field theory modification is used to determine the effective thermo-electro-mechanical properties of the composite. Attention is focused on the constrained recovery behavior of SMA phase in this study. Electrical model is examined and the electrical energy stored in the piezoelectric matrix as a result of stress fluctuation is estimated. Numerical example is given that illustrate the ability of the composite to convert the thermomechanical energy into electrical energy.

  6. Fabricating Composite-Material Structures Containing SMA Ribbons

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.; Cano, Roberto J.; Lach, Cynthia L.

    2003-01-01

    An improved method of designing and fabricating laminated composite-material (matrix/fiber) structures containing embedded shape-memory-alloy (SMA) actuators has been devised. Structures made by this method have repeatable, predictable properties, and fabrication processes can readily be automated. Such structures, denoted as shape-memory-alloy hybrid composite (SMAHC) structures, have been investigated for their potential to satisfy requirements to control the shapes or thermoelastic responses of themselves or of other structures into which they might be incorporated, or to control noise and vibrations. Much of the prior work on SMAHC structures has involved the use SMA wires embedded within matrices or within sleeves through parent structures. The disadvantages of using SMA wires as the embedded actuators include (1) complexity of fabrication procedures because of the relatively large numbers of actuators usually needed; (2) sensitivity to actuator/ matrix interface flaws because voids can be of significant size, relative to wires; (3) relatively high rates of breakage of actuators during curing of matrix materials because of sensitivity to stress concentrations at mechanical restraints; and (4) difficulty of achieving desirable overall volume fractions of SMA wires when trying to optimize the integration of the wires by placing them in selected layers only.

  7. Soft and smart modular structures actuated by shape memory alloy (SMA) wires as tentacles of soft robots

    NASA Astrophysics Data System (ADS)

    Jin, Hu; Dong, Erbao; Xu, Min; Liu, Chunshan; Alici, Gursel; Jie, Yang

    2016-08-01

    This paper introduces the design and fabrication of a multi-layered smart modular structure (SMS) that has been inspired by the muscular organs and modularity in soft animals. The SMS is capable of planar reciprocal motion of bending in heating process and recovering in cooling process when SMA wires carry out phase transformation. An adaptive regulation heating strategy is applied to avoid overheating and achieve bending range control of the SMS based on the resistance feedback of the SMA wires which as actuator of the SMS. The SMS can modular assemble soft robots with multiple morphologies such as lateral robots, bilateral robots and actinomorphic robots. A five-armed actinomorphic soft robot is conducted to crawling in terrestrial ground (max speed: 140 mm s-1, 0.7 body s-1), swimming in underwater environment (max speed: 67 mm s-1, 2.5 height s-1) and griping fragile objects (max object weight: 0.91 kg, 15 times the weight of itself). Those demonstrate that the performance of the SMS is good enough to be modular units to establish soft robots which possess a high speed of response, good adaptability and a safe interaction with their environments.

  8. Translational Research for Muscular Dystrophy

    DTIC Science & Technology

    2012-05-01

    REPORT TYPE Annual 3. DATES COVERED 1 MAR 2011 - 30 APR 2012 4. TITLE AND SUBTITLE Translational Research for Muscular Dystrophy 5a. CONTRACT...SUPPLEMENTARY NOTES 14. ABSTRACT The goal of this work is to increase the availability of critical mouse models of human muscular dystrophy (MD...3 W81XWH-11-1-0330 Cox, Gregory A 4 4 11 11 12 Translational Research for Muscular Dystrophy W81XWH-11-1-0330 Gregory A

  9. Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner

    PubMed Central

    Randolph, Matthew E; Luo, Qingwei; Ho, Justin; Vest, Katherine E; Sokoloff, Alan J; Pavlath, Grace K

    2014-01-01

    The inability to swallow, or dysphagia, is a debilitating and life-threatening condition that arises with ageing or disease. Dysphagia results from neurological or muscular impairment of one or more pharyngeal muscles, which function together to ensure proper swallowing and prevent the aspiration of food or liquid into the lungs. Little is known about the effects of age or disease on pharyngeal muscles as a group. Here we show ageing affected pharyngeal muscle growth and atrophy in wild-type mice depending on the particular muscle analysed. Furthermore, wild-type mice also developed dysphagia with ageing. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, PABPN1. We examined pharyngeal muscles of mice overexpressing either wild-type A10 or mutant A17 PABPN1. Overexpression of mutant A17 PABPN1 differentially affected growth of the palatopharyngeus muscle dependent on its location within the pharynx. Interestingly, overexpression of wild-type A10 PABPN1 was protective against age-related muscle atrophy in the laryngopharynx and prevented the development of age-related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both ageing and muscular dystrophy in a region-dependent manner. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle growth and atrophy, which may lead to novel therapies for individuals with dysphagia. PMID:25326455

  10. The Role of the Supplementary Motor Region in Overt Reading: Evidence for Differential Processing in SMA-Proper and Pre-SMA as a Function of Task Demands.

    PubMed

    Cummine, Jacqueline; Hanif, Wahab; Dymouriak-Tymashov, Inna; Anchuri, Kavya; Chiu, Stephanie; Boliek, Carol A

    2017-03-04

    A differentiation in function between the pre-SMA (i.e., cognitive load) and the SMA-proper (i.e., motor execution) has been described (Zhang et al., Cereb Cortex 22:99-111, 2012). These differential SMA functions may be influential in overt reading tasks. The present study examined the relationships between various segments of the SMA and overt reading through the modulation of task demands in an effort to explore the complexity of the print-to-speech network. Skilled reading adults (N = 15) took part in five overt reading tasks: pure regular word reading, pure exception word reading, mixed regular word and exception word reading, go/no-go reading with nonword foils and go/no-go reading with pseudohomophone foils. Five regions of interest that spanned the pre-SMA to the SMA-proper were isolated. Behaviour-function relationships were tested to examine the associations between performance (response time) and brain activity (percent signal change). Further, the coherence between feedforward (SMA) and feedback (supramarginal gyrus) regions were explored to further refine the print-to-speech network. We found that the pre-SMA was related to cognitively demanding tasks (go/no-go with pseudohomophones), whereas the SMA-proper was related to an automatized task (pure regular words). Notably, only those tasks that required information from the feedback system (i.e., mixed word lists, go/no-go tasks) showed connections between SMA regions and the supramarginal gyrus, which is in line with the role of feedback and feedforward systems in the print-to-speech network. Together, these results support the notion that the pre-SMA and SMA-proper are sensitive to reading tasks that differentially invoke higher cognitive resources (mixed word lists, go/no-go) versus automatized articulation (pure lists), respectively. We discuss our findings in the context of print-to-speech neural networks.

  11. Cardio-Muscular Conditioner

    NASA Technical Reports Server (NTRS)

    1993-01-01

    In the mid-sixties, Gary Graham, a Boeing designer, developed a cardiovascular conditioner for a planned Air Force orbiting laboratory. After the project was cancelled, Graham participated in space station conditioning studies for the Skylab program. Twenty years later, he used this expertise to develop the Shuttle 2000-1, a physical therapy and athletic development conditioner, available through Contemporary Designs. The machine is used by football teams, sports clinics and medical rehabilitation centers. Cardiovascular fitness and muscular strength development are promoted through both kinetic and plyometric exercises.

  12. [Posterior cortical atrophy (Benson-syndrome)].

    PubMed

    Rózsa, Anikó; Szilvássy, Ildikó; Kovács, Krisztina; Boór, Krisztina; Gács, Gyula

    2010-01-30

    We present the characteristics of posterior cortical atrophy--a very rare cortical dementia--in a 69 year old woman's case. Our patient's symptoms began with a visual problem which was initially explained by ophthalmological disorder. After neurological exam visual agnosia was diagnosed apart from other cognitive disorder (alexia without agraphia, acalculia, prosopagnosia, constructional disorder, clock-time recognition disorder, dressing apraxia, visuospatial disorientation). The brain MRI showed bilateral asymmetric parieto-occipital atrophy which is characteristic of posterior cortical atrophy.

  13. Iris atrophy in sickle cell disease.

    PubMed Central

    Acheson, R W; Ford, S M; Maude, G H; Lyness, R W; Serjeant, G R

    1986-01-01

    Iris atrophy, of unknown origin and believed to be secondary to the vaso-occlusive process of sickle cell disease, has been observed in 25 eyes of 22 patients (two SS disease, 20 SC disease). The crude prevalence was highest in males with SC disease, in whom 14.7% of patients were affected. Iris atrophy was closely associated with proliferative sickle retinopathy in the same eye. Analysis of haematological indices failed to reveal any significant differences between patients with and without iris atrophy. The characteristics and distribution of iris atrophy are described as well as the histopathology in one 68-year-old male patient with SS disease. Images PMID:3718915

  14. Connective tissue growth factor is overexpressed in muscles of human muscular dystrophy.

    PubMed

    Sun, Guilian; Haginoya, Kazuhiro; Wu, Yanling; Chiba, Yoko; Nakanishi, Tohru; Onuma, Akira; Sato, Yuko; Takigawa, Masaharu; Iinuma, Kazuie; Tsuchiya, Shigeru

    2008-04-15

    The detailed process of how dystrophic muscles are replaced by fibrotic tissues is unknown. In the present study, the immunolocalization and mRNA expression of connective tissue growth factor (CTGF) in muscles from normal and dystrophic human muscles were examined with the goal of elucidating the pathophysiological function of CTGF in muscular dystrophy. Biopsies of frozen muscle from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, congenital muscular dystrophy, spinal muscular atrophy, congenital myopathy were analyzed using anti-CTGF polyclonal antibody. Reverse transcription-polymerase chain reaction (RT-PCR) was also performed to evaluate the expression of CTGF mRNA in dystrophic muscles. In normal muscle, neuromuscular junctions and vessels were CTGF-immunopositive, which suggests a physiological role for CTGF in these sites. In dystrophic muscle, CTGF immunoreactivity was localized to muscle fiber basal lamina, regenerating fibers, and the interstitium. Triple immunolabeling revealed that activated fibroblasts were immunopositive for CTGF and transforming growth factor-beta1 (TGF-beta1). RT-PCR analysis revealed increased levels of CTGF mRNA in the muscles of DMD patients. Co-localization of TGF-beta1 and CTGF in activated fibroblasts suggests that CTGF expression is regulated by TGF-beta1 through a paracrine/autocrine mechanism. In conclusion, TGF-beta1-CTGF pathway may play a role in the fibrosis that is commonly observed in muscular dystrophy.

  15. SMA Hybrid Composites for Dynamic Response Abatement Applications

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.

    2000-01-01

    A recently developed constitutive model and a finite element formulation for predicting the thermomechanical response of Shape Memory Alloy (SMA) hybrid composite (SMAHC) structures is briefly described. Attention is focused on constrained recovery behavior in this study, but the constitutive formulation is also capable of modeling restrained or free recovery. Numerical results are shown for glass/epoxy panel specimens with embedded Nitinol actuators subjected to thermal and acoustic loads. Control of thermal buckling, random response, sonic fatigue, and transmission loss are demonstrated and compared to conventional approaches including addition of conventional composite layers and a constrained layer damping treatment. Embedded SMA actuators are shown to be significantly more effective in dynamic response abatement applications than the conventional approaches and are attractive for combination with other passive and/or active approaches.

  16. Enhanced autophagy as a potential mechanism for the improved physiological function by simvastatin in muscular dystrophy.

    PubMed

    Whitehead, Nicholas P

    2016-01-01

    Autophagy has recently emerged as an important cellular process for the maintenance of skeletal muscle health and function. Excessive autophagy can trigger muscle catabolism, leading to atrophy. In contrast, reduced autophagic flux is a characteristic of several muscle diseases, including Duchenne muscular dystrophy, the most common and severe inherited muscle disorder. Recent evidence demonstrates that enhanced reactive oxygen species (ROS) production by CYBB/NOX2 impairs autophagy in muscles from the dmd/mdx mouse, a genetic model of Duchenne muscular dystrophy. Statins decrease CYBB/NOX2 expression and activity and stimulate autophagy in skeletal muscle. Therefore, we treated dmd/mdx mice with simvastatin and showed decreased CYBB/NOX2-mediated oxidative stress and enhanced autophagy induction. This was accompanied by reduced muscle damage, inflammation and fibrosis, and increased muscle force production. Our data suggest that increased autophagy may be a potential mechanism by which simvastatin improves skeletal muscle health and function in muscular dystrophy.

  17. Therapeutic advances in muscular dystrophy

    PubMed Central

    Leung, Doris G; Wagner, Kathryn R

    2013-01-01

    The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy. PMID:23939629

  18. Optimization of SMA layers in composite structures to enhance damping

    NASA Astrophysics Data System (ADS)

    Haghdoust, P.; Cinquemani, S.; Lecis, N.; Bassani, P.

    2016-04-01

    The performance of lightweight structures can be severely affected by vibration. New design concepts leading to lightweight, slender structural components can increase the vulnerability of the components to failure due to excessive vibration. The intelligent approach to address the problem would be the use of materials which are more capable in dissipating the energy due to their high value of loss factor. Among the different materials available to achieve damping, much attention has been attached to the use of shape memory alloys (SMAs) because of their unique microstructure, leading to good damping capacity. This work describes the design and optimization of a hybrid layered composite structure for the passive suppression of flexural vibrations in slender and light structures. Embedding the SMA layers in composite structure allows to combine different properties: the lightness of the base composite (e.g. fiber glass), the mechanical strength of the insert of metallic material and the relevant damping properties of SMA, in the martensitic phase. In particular, we put our attention on embedding the CuZnAl in the form of thin sheet in a layered composite made by glass fiber reinforced epoxy. By appropriately positioning of the SMA sheets so that they are subjected to the maximum curvature, the damping of the hybrid system can be considerably enhanced. Accordingly analytical method for evaluating the energy dissipation of the thin sheets with different shapes and patterns is developed and is followed by a shape optimization based on genetic algorithm. Eventually different configurations of the hybrid beam structure with different patterns of SMA layer are proposed and compared in the term of damping capacity.

  19. Development of a Simple Structured Artificial Muscle Using SMA Wire

    SciTech Connect

    Ibuki, Ryuta; Maruyama, Shigenao; Komiya, Atsuki

    2006-05-05

    Artificial heart muscle using SMA wire is developed to assist weaken heartbeat. Simple structure design was adopted for large output force, large displacement and rapid cyclic motion of the actuator. The actuator was designed and fabricated from the viewpoint of heat transfer. Moving performance of the actuator was experimentally measured under 10N of loading condition. Under the maximum efficiency condition, the actuator shows cyclic motion with 1mm of displacement and time period of about 2 seconds in one cycle.

  20. Analysis of SMA Hybrid Composite Structures using Commercial Codes

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.; Patel, Hemant D.

    2004-01-01

    A thermomechanical model for shape memory alloy (SMA) actuators and SMA hybrid composite (SMAHC) structures has been recently implemented in the commercial finite element codes MSC.Nastran and ABAQUS. The model may be easily implemented in any code that has the capability for analysis of laminated composite structures with temperature dependent material properties. The model is also relatively easy to use and requires input of only fundamental engineering properties. A brief description of the model is presented, followed by discussion of implementation and usage in the commercial codes. Results are presented from static and dynamic analysis of SMAHC beams of two types; a beam clamped at each end and a cantilevered beam. Nonlinear static (post-buckling) and random response analyses are demonstrated for the first specimen. Static deflection (shape) control is demonstrated for the cantilevered beam. Approaches for modeling SMAHC material systems with embedded SMA in ribbon and small round wire product forms are demonstrated and compared. The results from the commercial codes are compared to those from a research code as validation of the commercial implementations; excellent correlation is achieved in all cases.

  1. STUDY OF THE RHIC BPM SMA CONNECTOR FAILURE PROBLEM

    SciTech Connect

    LIAW,C.; SIKORA, R.; SCHROEDER, R.

    2007-06-25

    About 730 BPMs are mounted on the RHIC CQS and Triplet super-conducting magnets. Semi-rigid coaxial cables are used to bring the electrical signal from the BPM feedthroughs to the outside flanges. at the ambient temperature. Every year around 10 cables will lose their signals during the operation. The connection usually failed at the warm end of the cable. The problems were either the solder joint failed or the center conductor retracted out of the SMA connector. Finite element analyses were performed to understand the failure mechanism of the solder joint. The results showed that (1) The SMA center conductor can separate from the mating connector due to the thermal retraction. (2) The maximum thermal stress at the warm end solder joint can exceed the material strength of the Pb37/Sn63 solder material and (3) The magnet ramping frequency (-10 Hz), during the machine startup, can possibly resonant the coaxial cable and damage the solder joints, especially when a fracture is initiated. Test results confirmed that by using the silver bearing solder material (a higher strength material) and by crimping the cable at the locations close to the SMA connector (to prevent the center conductor from retracting) can effectively resolve the connector failure problem.

  2. Passive base isolation with superelastic nitinol SMA helical springs

    NASA Astrophysics Data System (ADS)

    Huang, Bin; Zhang, Haiyang; Wang, Han; Song, Gangbing

    2014-06-01

    Seismic isolation of structures such as multi-story buildings, nuclear reactors, bridges, and liquid storage tanks should be designed to preserve structural integrity. By implementing seismic isolation technology, the deformation of superstructures can be dramatically reduced, consequently helping to protect their safety as well. In this paper, an innovative type of passive base isolation system, which is mainly composed of superelastic nitinol SMA helical springs, is developed. In order to verify the effectiveness of the proposed system, a two-story experimental steel frame model is constructed, and two superelastic SMA helical springs are thermo-mechanically built in the laboratory. To describe the nonlinear mechanical properties of the superelastic SMA helical springs under reciprocating load, a phenomenological model is presented in terms of a series of tensile tests. Afterwards, a numerical model of the two-story frame with the suggested isolation system is set up to simulate the response of the isolated frame subjected to an earthquake. Both the experimental and the numerical simulation results indicate that the proposed base isolation system can remarkably suppress structural vibrations and has improved isolation effects when compared with a steel spring isolation system. Due to the capabilities of energy dissipation as well as fully re-centering, it is very applicable to utilize the suggested isolation system in base isolated structures to resist earthquakes.

  3. Crustacean muscles: atrophy and regeneration during molting

    SciTech Connect

    Mykles, D.L.; Skinner, D.M.

    1981-01-01

    The ultrastructural basis of atrophy of claw closer muscle of the land crab and the organization of myofibrils and sacroplasmic reticulum during the hydrolysis of protein that occurs during proecdysis was examined. The changes that occur in contractile proteins during claw muscle atrophy and the involvement of Ca/sup 2 +/-dependent proteinases (CDP) in myofilament degradation were investigated. (ACR)

  4. Seronegative Intestinal Villous Atrophy: A Diagnostic Challenge

    PubMed Central

    Teixeira, Cristina; Ribeiro, Suzane; Trabulo, Daniel; Cardoso, Cláudia; Mangualde, João; Freire, Ricardo; Alves, Ana Luísa; Gamito, Élia; Cremers, Isabelle; Oliveira, Ana Paula

    2016-01-01

    Celiac disease is the most important cause of intestinal villous atrophy. Seronegative intestinal villous atrophy, including those that are nonresponsive to a gluten-free diet, is a diagnostic challenge. In these cases, before establishing the diagnosis of seronegative celiac disease, alternative etiologies of atrophic enteropathy should be considered. Recently, a new clinical entity responsible for seronegative villous atrophy was described—olmesartan-induced sprue-like enteropathy. Herein, we report two uncommon cases of atrophic enteropathy in patients with arterial hypertension under olmesartan, who presented with severe chronic diarrhea and significant involuntary weight loss. Further investigation revealed intestinal villous atrophy and intraepithelial lymphocytosis. Celiac disease and other causes of villous atrophy were ruled out. Drug-induced enteropathy was suspected and clinical improvement and histologic recovery were verified after olmesartan withdrawal. These cases highlight the importance for clinicians to maintain a high index of suspicion for olmesartan as a precipitant of sprue-like enteropathy. PMID:27803820

  5. Proteomics profiling of urine reveals specific titin fragments as biomarkers of Duchenne muscular dystrophy.

    PubMed

    Rouillon, Jeremy; Zocevic, Aleksandar; Leger, Thibaut; Garcia, Camille; Camadro, Jean-Michel; Udd, Bjarne; Wong, Brenda; Servais, Laurent; Voit, Thomas; Svinartchouk, Fedor

    2014-07-01

    Diagnosis of muscular dystrophies is currently based on invasive methods requiring muscle biopsies or blood tests. The aim of the present study was to identify urinary biomarkers as a diagnostic tool for muscular dystrophies. Here, the urinary proteomes of Duchenne muscular dystrophy (DMD) patients and healthy donors were compared with a bottom-up proteomic approach. Label-free analysis of more than 1100 identified proteins revealed that 32 of them were differentially expressed between healthy controls and DMD patients. Among these 32 proteins, titin showed the highest fold change between healthy subjects and DMD patients. Interestingly, most of the sequenced peptides belong to the N-terminal and C-terminal parts of titin, and the presence of the corresponding fragments in the urine of DMD patients was confirmed by Western blot analysis. Analysis of a large cohort of DMD patients and age-matched controls (a total of 104 individuals aged from 3 to 20 years) confirmed presence of the N-ter fragment in all but two patients. In two DMD patients aged 16 and 20 years this fragment was undetectable and two healthy controls of 16 and 19 years with serum CK >800 IU/L demonstrated a low level of the fragment. N- and C-terminal titin fragments were also detected in urine from patients with other muscular dystrophies such as Becker muscular dystrophy and Limb-girdle muscular dystrophy (type 1D, 2D and 2J) but not in neurogenic spinal muscular atrophy. They were also present in urine of dystrophin-deficient animal models (GRMD dogs and mdx mice). Titin is the first urinary biomarker that offers the possibility to develop a simple, non-invasive and easy-to-use test for pre-screening of muscular dystrophies, and may also prove to be useful for the non-invasive follow up of DMD patients under treatment.

  6. Fatigue of NiTi SMA-pulley system using Taguchi and ANOVA

    NASA Astrophysics Data System (ADS)

    Mohd Jani, Jaronie; Leary, Martin; Subic, Aleksandar

    2016-05-01

    Shape memory alloy (SMA) actuators can be integrated with a pulley system to provide mechanical advantage and to reduce packaging space; however, there appears to be no formal investigation of the effect of a pulley system on SMA structural or functional fatigue. In this work, cyclic testing was conducted on nickel-titanium (NiTi) SMA actuators on a pulley system and a control experiment (without pulley). Both structural and functional fatigues were monitored until fracture, or a maximum of 1E5 cycles were achieved for each experimental condition. The Taguchi method and analysis of the variance (ANOVA) were used to optimise the SMA-pulley system configurations. In general, one-way ANOVA at the 95% confidence level showed no significant difference between the structural or functional fatigue of SMA-pulley actuators and SMA actuators without pulley. Within the sample of SMA-pulley actuators, the effect of activation duration had the greatest significance for both structural and functional fatigue, and the pulley configuration (angle of wrap and sheave diameter) had a greater statistical significance than load magnitude for functional fatigue. This work identified that structural and functional fatigue performance of SMA-pulley systems is optimised by maximising sheave diameter and using an intermediate wrap-angle, with minimal load and activation duration. However, these parameters may not be compatible with commercial imperatives. A test was completed for a commercially optimal SMA-pulley configuration. This novel observation will be applicable to many areas of SMA-pulley system applications development.

  7. Caenorhabditis elegans SMA-10/LRIG is a conserved transmembrane protein that enhances bone morphogenetic protein signaling.

    PubMed

    Gumienny, Tina L; Macneil, Lesley; Zimmerman, Cole M; Wang, Huang; Chin, Lena; Wrana, Jeffrey L; Padgett, Richard W

    2010-05-20

    Bone morphogenetic protein (BMP) pathways control an array of developmental and homeostatic events, and must themselves be exquisitely controlled. Here, we identify Caenorhabditis elegans SMA-10 as a positive extracellular regulator of BMP-like receptor signaling. SMA-10 acts genetically in a BMP-like (Sma/Mab) pathway between the ligand DBL-1 and its receptors SMA-6 and DAF-4. We cloned sma-10 and show that it has fifteen leucine-rich repeats and three immunoglobulin-like domains, hallmarks of an LRIG subfamily of transmembrane proteins. SMA-10 is required in the hypodermis, where the core Sma/Mab signaling components function. We demonstrate functional conservation of LRIGs by rescuing sma-10(lf) animals with the Drosophila ortholog lambik, showing that SMA-10 physically binds the DBL-1 receptors SMA-6 and DAF-4 and enhances signaling in vitro. This interaction is evolutionarily conserved, evidenced by LRIG1 binding to vertebrate receptors. We propose a new role for LRIG family members: the positive regulation of BMP signaling by binding both Type I and Type II receptors.

  8. Inflammation, atrophy, and gastric cancer

    PubMed Central

    Fox, James G.; Wang, Timothy C.

    2006-01-01

    The association between chronic inflammation and cancer is now well established. This association has recently received renewed interest with the recognition that microbial pathogens can be responsible for the chronic inflammation observed in many cancers, particularly those originating in the gastrointestinal system. A prime example is Helicobacter pylori, which infects 50% of the world’s population and is now known to be responsible for inducing chronic gastric inflammation that progresses to atrophy, metaplasia, dysplasia, and gastric cancer. This Review provides an overview of recent progress in elucidating the bacterial properties responsible for colonization of the stomach, persistence in the stomach, and triggering of inflammation, as well as the host factors that have a role in determining whether gastritis progresses to gastric cancer. We also discuss how the increased understanding of the relationship between inflammation and gastric cancer still leaves many questions unanswered regarding recommendations for prevention and treatment. PMID:17200707

  9. Is hippocampal atrophy a future drug target?

    PubMed

    Dhikav, Vikas; Anand, Kuljeet Singh

    2007-01-01

    Hippocampus is the brain structure, vital for episodic and declarative memory. Atrophy of the human hippocampus is seen in a variety of psychiatric and neurological disorders e.g. recurrent depression, schizophrenia, bipolar disorder, post-traumatic stress disorder, epilepsy, head injury, and Alzheimer's disease (AD). Importantly, aging hippocampus also undergoes atrophy. In many instances, for example, AD, the atrophy precedes the development of symptoms while in others, there is a temporal relationship between atrophy and symptomatology. The presence of atrophied hippocampus is one of the most consistent features of many common psychiatric disorders. Several factors contribute to this atrophy. Stress is one of the most profound factors implicated and the mechanisms involve glucocorticoids, serotonin, excitatory amino acids etc. Hippocampal formation as a whole can undergo atrophy or its individual structural components e.g. apical dendrities can exhibit atrophy. Several drugs of unrelated classes have been shown to prevent atrophy indicating heterogenous manner in which hippocampal atrophy is produced. These include, tianeptine (affects structural plasticity in hippocampus and is an effective antidepressant); phenytoin (antiseizure and neuroprotective); fluoxetine (downregulates neurodegenerative enzyme and increases neuroprotective hippocampal S100 beta); lithium (neuroprotective and antiapoptotic); tricyclic antidepressants (increase hippocampal neurogenesis); antipsychotics (reduce hippocampal neuronal suppression); sodium valproate (increases neurogenesis) and mifepristone (antioxidant, neuroprotective and anti-glucocorticoid). Now the most important question is: to what extent does the hippocampal atrophy play a role in the genesis of symptoms of diseases or their progression? And if it does, can we achieve the same degree of prevention or reversal seen in experimental animals, in humans also. An even more important question is: whether the prevention of

  10. Wasting Mechanisms in Muscular Dystrophy

    PubMed Central

    Shin, Jonghyun; Tajrishi, Marjan M.; Ogura, Yuji; Kumar, Ashok

    2013-01-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. PMID:23669245

  11. NASA Keynote at the 2015 Trilateral SMA Conference, Frascati, Italy

    NASA Technical Reports Server (NTRS)

    Groen, Frank

    2015-01-01

    The purpose of this presentation is to illustrate some new directions within NASA's safety and mission function in response to changes in missions, technology, and practices. The presentation lists last year's highlights from NASA's human and robotic spaceflight missions, and discusses anticipated highlights for the coming year taken from existing Agency presentations. It will highlight changes to NASA's mission and the way NASA does business, as described in the 2014 strategic plan. It will then discuss how these changes pose challenges to trusted SMA practices, and provide some examples of initiatives NASA is taking action to address these challenges.

  12. Ageing with Muscular Disease

    PubMed Central

    Martinsen, Bente; Dreyer, Pia

    2016-01-01

    Background: The demographic development with an ageing population is predicted to be the next global public health challenge. Advances in medicine and the socioeconomic development have reduced mortality and morbidity due to infectious conditions and non-communicable diseases. The increase in longevity will not be restricted to healthy people. Objective: To understand how people with muscular diseases experience ageing. Method: A literature review was conducted using the Matrix Method developed by Garrard (2007). This systematic method was used to identify, describe and interpret studies, irrespective of the methods applied. To avoid the exclusion of important sources, experiences and topics, we chose an integrative approach that accommodates the inclusion of studies with different methodologies. People with MD have gradually extended their life expectancy during the last 30 years. Thus, we reviewed the literature regarding MD and ageing without time limit. Results: We identified three themes: 1) Slowing down early 2) Accepting lifelong deterioration and 3) Striving for normality. Conclusion: People with MD live in a field of tension between a feeling of autonomy and normality and difficulties coping with reduced physical abilities. Getting older accentuates this tension since the physical strength diminishes and it is harder to maintain autonomy. The bodily challenges may coincide with the end of the rehabilitation people living with MD have received. Seemingly, no age-related rehabilitation is offered, and people living with MD are thus at risk of an unnecessarily passive life. PMID:28144383

  13. Superior mesenteric artery (SMA) syndrome: an unusual cause of intestinal obstruction in palliative care.

    PubMed

    So, Chun-Yan; Chan, Kwok-Ying; Au, Ho-Yan; Chan, Man-Lui; Lai, Theresa

    2017-01-01

    Superior mesenteric artery (SMA) syndrome is an uncommon cause of intestinal obstruction and seldom been mentioned in palliative care. Hereby, we reported a case of SMA syndrome who presented with symptoms of upper intestinal obstruction in a 68-year-old patient; subsequent CT findings were classical of SMA syndrome. The patient's history of poliomyelitis and recent significant weight loss were the predisposing factors for SMA syndrome. It also highlights the importance of monitoring signs and symptoms of intestinal obstruction in such patients before considering switching to oral feeding.

  14. Shape Memory Alloy (SMA)-Based Launch Lock

    NASA Technical Reports Server (NTRS)

    Badescu, Mircea; Bao, Xiaoqi; Bar-Cohen, Yoseph

    2014-01-01

    Most NASA missions require the use of a launch lock for securing moving components during the launch or securing the payload before release. A launch lock is a device used to prevent unwanted motion and secure the controlled components. The current launch locks are based on pyrotechnic, electro mechanically or NiTi driven pin pullers and they are mostly one time use mechanisms that are usually bulky and involve a relatively high mass. Generally, the use of piezoelectric actuation provides high precession nanometer accuracy but it relies on friction to generate displacement. During launch, the generated vibrations can release the normal force between the actuator components allowing shaft's free motion which could result in damage to the actuated structures or instruments. This problem is common to other linear actuators that consist of a ball screw mechanism. The authors are exploring the development of a novel launch lock mechanism that is activated by a shape memory alloy (SMA) material ring, a rigid element and an SMA ring holding flexure. The proposed design and analytical model will be described and discussed in this paper.

  15. Structural design of morphing trailing edge actuated by SMA

    NASA Astrophysics Data System (ADS)

    Wang, Qi; Xu, Zhiwei; Zhu, Qian

    2013-09-01

    In this paper, the morphing trailing edge is designed to achieve the up and down deflection under the aerodynamic load. After a detailed and accurate computational analysis to determine the SMA specifications and layout programs, a solid model is created in CATIA and the structures of the morphing wing trailing edge are produced by CNC machining. A set of DSP measurement and control system is designed to accomplish the controlling experiment of the morphing wing trailing edge. At last, via the force analysis, the trailing edge is fabricated with four sections of aluminum alloy, and the arrangement scheme of SMA wires is determined. Experiment of precise control integral has been performed to survey the control effect. The experiment consists of deflection angle tests of the third joint and the integral structure. Primarily, the ultimate deflection angle is tested in these two experiments. Therefore, the controlling experiment of different angles could be performed within this range. The results show that the deflection error is less than 4%and response time is less than 6.7 s, the precise controlling of the morphing trailing edge is preliminary realized.

  16. A Novel SMA-based Concept for Airfoil Structural Morphing

    NASA Astrophysics Data System (ADS)

    Barbarino, S.; Pecora, R.; Lecce, L.; Concilio, A.; Ameduri, S.; Calvi, E.

    2009-08-01

    The adaptive structures concept is of great interest in the aerospace field because of the several benefits which can be accomplished in the fields including noise reduction, load alleviation, weight reduction, etc., at a level in which they can be considered as compulsory in the design of future aircraft. Improvements in terms of the aerodynamic efficiency, aeroelastic behavior, stability, and manoeuvrability performance have already been proved through many international studies in the past. In the family of the Smart Materials, Shape Memory Alloys (SMA) seem to be a suitable solution for many static applications. Their high structural integrability in conjunction with actuation capabilities and a favorable performance per weight ratio, allows the development of original architectures. In this study, a morphing wing trailing edge concept is presented; morphing ability was introduced with the aim of replacing a conventional flap device. A compliant rib structure was designed, based on SMA actuators exhibiting structural potential (bearing external aerodynamic loads). Numerical results, achieved through a FE approach, are presented in terms of trailing edge induced displacement and morphed shape.

  17. Genetics Home Reference: dentatorubral-pallidoluysian atrophy

    MedlinePlus

    ... trinucleotide repeat often increases in size. Larger repeat expansions are usually associated with an earlier onset of ... pallidoluysian atrophy (DRPLA): close correlation of CAG repeat expansions with the wide spectrum of clinical presentations and ...

  18. Infraspinatus muscle atrophy from suprascapular nerve compression.

    PubMed

    Cordova, Christopher B; Owens, Brett D

    2014-02-01

    Muscle weakness without pain may signal a nerve compression injury. Because these injuries should be identified and treated early to prevent permanent muscle weakness and atrophy, providers should consider suprascapular nerve compression in patients with shoulder muscle weakness.

  19. Hippocampal atrophy rates in Alzheimer disease

    PubMed Central

    Henneman, W J.P.; Sluimer, J D.; Barnes, J; van der Flier, W M.; Sluimer, I C.; Fox, N C.; Scheltens, P; Vrenken, H; Barkhof, F

    2009-01-01

    Objective: To investigate the added value of hippocampal atrophy rates over whole brain volume measurements on MRI in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls. Methods: We included 64 patients with AD (67 ± 9 years; F/M 38/26), 44 patients with MCI (71 ± 6 years; 21/23), and 34 controls (67 ± 9 years; 16/18). Two MR scans were performed (scan interval: 1.8 ± 0.7 years; 1.0 T), using a coronal three-dimensional T1-weighted gradient echo sequence. At follow-up, 3 controls and 23 patients with MCI had progressed to AD. Hippocampi were manually delineated at baseline. Hippocampal atrophy rates were calculated using regional, nonlinear fluid registration. Whole brain baseline volumes and atrophy rates were determined using automated segmentation and registration tools. Results: All MRI measures differed between groups (p < 0.005). For the distinction of MCI from controls, larger effect sizes of hippocampal measures were found compared to whole brain measures. Between MCI and AD, only whole brain atrophy rate differed significantly. Cox proportional hazards models (variables dichotomized by median) showed that within all patients without dementia, hippocampal baseline volume (hazard ratio [HR]: 5.7 [95% confidence interval: 1.5–22.2]), hippocampal atrophy rate (5.2 [1.9–14.3]), and whole brain atrophy rate (2.8 [1.1–7.2]) independently predicted progression to AD; the combination of low hippocampal volume and high atrophy rate yielded a HR of 61.1 (6.1–606.8). Within patients with MCI, only hippocampal baseline volume and atrophy rate predicted progression. Conclusion: Hippocampal measures, especially hippocampal atrophy rate, best discriminate mild cognitive impairment (MCI) from controls. Whole brain atrophy rate discriminates Alzheimer disease (AD) from MCI. Regional measures of hippocampal atrophy are the strongest predictors of progression to AD. GLOSSARY AD = Alzheimer disease; BET = brain

  20. Zika virus causes testicular atrophy

    PubMed Central

    Uraki, Ryuta; Hwang, Jesse; Jurado, Kellie Ann; Householder, Sarah; Yockey, Laura J.; Hastings, Andrew K.; Homer, Robert J.; Iwasaki, Akiko; Fikrig, Erol

    2017-01-01

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has recently been found to cause fetal infection and neonatal abnormalities, including microcephaly and neurological dysfunction. ZIKV persists in the semen months after the acute viremic phase in humans. To further understand the consequences of ZIKV persistence in males, we infected Ifnar1−/− mice via subcutaneous injection of a pathogenic but nonlethal ZIKV strain. ZIKV replication persists within the testes even after clearance from the blood, with interstitial, testosterone-producing Leydig cells supporting virus replication. We found high levels of viral RNA and antigen within the epididymal lumen, where sperm is stored, and within surrounding epithelial cells. Unexpectedly, at 21 days post-infection, the testes of the ZIKV-infected mice were significantly smaller compared to those of mock-infected mice, indicating progressive testicular atrophy. ZIKV infection caused a reduction in serum testosterone, suggesting that male fertility can be affected. Our findings have important implications for nonvector-borne vertical transmission, as well as long-term potential reproductive deficiencies, in ZIKV-infected males. PMID:28261663

  1. Models of Multiple System Atrophy

    PubMed Central

    Fellner, Lisa; Wenning, Gregor K.; Stefanova, Nadia

    2016-01-01

    Multiple system atrophy (MSA) is a predominantly sporadic, adult-onset, fatal neurodegenerative disease of unknown etiology. MSA is characterized by autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs in any combination. MSA belongs to a group of neurodegenerative disorders termed α-synucleinopathies, which also include Parkinson’s disease and dementia with Lewy bodies. Their common pathological feature is the occurrence of abnormal α-synuclein positive inclusions in neurons or glial cells. In MSA, the main cell type presenting aggregates composed of α-synuclein are oligodendroglial cells. This pathological hallmark, also called glial cytoplasmic inclusions (GCIs), is associated with progressive and profound neuronal loss in various regions of the brain. The development of animal models of MSA is justified by the limited understanding of the mechanisms of neurodegeneration and GCIs formation, which is paralleled by a lack of therapeutic strategies. Two main types of rodent models have been generated to replicate different features of MSA neuropathology. On one hand, neurotoxin-based models have been produced to reproduce neuronal loss in substantia nigra pars compacta and striatum. On the other hand, transgenic mouse models with overexpression of α-synuclein in oligodendroglia have been used to reproduce GCIs-related pathology. This chapter gives an overview of the atypical Parkinson’s syndrome MSA and summarizes the currently available MSA animal models and their relevance for pre-clinical testing of disease-modifying therapies. PMID:24338664

  2. Zika virus causes testicular atrophy.

    PubMed

    Uraki, Ryuta; Hwang, Jesse; Jurado, Kellie Ann; Householder, Sarah; Yockey, Laura J; Hastings, Andrew K; Homer, Robert J; Iwasaki, Akiko; Fikrig, Erol

    2017-02-01

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has recently been found to cause fetal infection and neonatal abnormalities, including microcephaly and neurological dysfunction. ZIKV persists in the semen months after the acute viremic phase in humans. To further understand the consequences of ZIKV persistence in males, we infected Ifnar1(-/-) mice via subcutaneous injection of a pathogenic but nonlethal ZIKV strain. ZIKV replication persists within the testes even after clearance from the blood, with interstitial, testosterone-producing Leydig cells supporting virus replication. We found high levels of viral RNA and antigen within the epididymal lumen, where sperm is stored, and within surrounding epithelial cells. Unexpectedly, at 21 days post-infection, the testes of the ZIKV-infected mice were significantly smaller compared to those of mock-infected mice, indicating progressive testicular atrophy. ZIKV infection caused a reduction in serum testosterone, suggesting that male fertility can be affected. Our findings have important implications for nonvector-borne vertical transmission, as well as long-term potential reproductive deficiencies, in ZIKV-infected males.

  3. Muscular dystrophy in a dog resembling human becker muscular dystrophy.

    PubMed

    Baroncelli, A B; Abellonio, F; Pagano, T B; Esposito, I; Peirone, B; Papparella, S; Paciello, O

    2014-05-01

    A 3-year-old, male Labrador retriever dog was presented with clinical signs of progressive exercise intolerance, bilateral elbow extension, rigidity of the forelimbs, hindlimb flexion and kyphosis. Microscopical examination of muscle tissue showed marked variability in myofibre size, replacement of muscle with mature adipose tissue and degeneration/regeneration of muscle fibres, consistent with muscular dystrophy. Immunohistochemical examination for dystrophin showed markedly reduced labelling with monoclonal antibodies specific for the rod domain and the carboxy-terminal of dystrophin, while expression of β-sarcoglycan, γ-sarcoglycan and β-dystroglycan was normal. Immunoblotting revealed a truncated dystrophin protein of approximately 135 kDa. These findings supported a diagnosis of congenital canine muscular dystrophy resembling Becker muscular dystrophy in man.

  4. Heuristics for connectivity-based brain parcellation of SMA/pre-SMA through force-directed graph layout.

    PubMed

    Crippa, Alessandro; Cerliani, Leonardo; Nanetti, Luca; Roerdink, Jos B T M

    2011-02-01

    We propose the use of force-directed graph layout as an explorative tool for connectivity-based brain parcellation studies. The method can be used as a heuristic to find the number of clusters intrinsically present in the data (if any) and to investigate their organisation. It provides an intuitive representation of the structure of the data and facilitates interactive exploration of properties of single seed voxels as well as relations among (groups of) voxels. We validate the method on synthetic data sets and we investigate the changes in connectivity in the supplementary motor cortex, a brain region whose parcellation has been previously investigated via connectivity studies. This region is supposed to present two easily distinguishable connectivity patterns, putatively denoted by SMA (supplementary motor area) and pre-SMA. Our method provides insights with respect to the connectivity patterns of the premotor cortex. These present a substantial variation among subjects, and their subdivision into two well-separated clusters is not always straightforward.

  5. Calpain 3 Expression Pattern during Gastrocnemius Muscle Atrophy and Regeneration Following Sciatic Nerve Injury in Rats

    PubMed Central

    Wu, Ronghua; Yan, Yingying; Yao, Jian; Liu, Yan; Zhao, Jianmei; Liu, Mei

    2015-01-01

    Calpain 3 (CAPN3), also known as p94, is a skeletal muscle-specific member of the calpain family that is involved in muscular dystrophy; however, the roles of CAPN3 in muscular atrophy and regeneration are yet to be understood. In the present study, we attempted to explain the effect of CAPN3 in muscle atrophy by evaluating CAPN3 expression in rat gastrocnemius muscle following reversible sciatic nerve injury. After nerve injury, the wet weight ratio and cross sectional area (CSA) of gastrocnemius muscle were decreased gradually from 1–14 days and then recovery from 14–28 days. The active form of CAPN3 (~62 kDa) protein decreased slightly on day 3 and then increased from day 7 to 14 before a decrease from day 14 to 28. The result of linear correlation analysis showed that expression of the active CAPN3 protein level was negatively correlated with muscle wet weight ratio. CAPN3 knockdown by short interfering RNA (siRNA) injection improved muscle recovery on days 7 and 14 after injury as compared to that observed with control siRNA treatment. Depletion of CAPN3 gene expression could promote myoblast differentiation in L6 cells. Based on these findings, we conclude that the expression pattern of the active CAPN3 protein is linked to muscle atrophy and regeneration following denervation: its upregulation during early stages may promote satellite cell renewal by inhibiting differentiation, whereas in later stages, CAPN3 expression may be downregulated to stimulate myogenic differentiation and enhance recovery. These results provide a novel mechanistic insight into the role of CAPN3 protein in muscle regeneration after peripheral nerve injury. PMID:26569227

  6. Immunoproteasome in animal models of Duchenne muscular dystrophy.

    PubMed

    Chen, Chiao-Nan Joyce; Graber, Ted G; Bratten, Wendy M; Ferrington, Deborah A; Thompson, LaDora V

    2014-04-01

    Increased proteasome activity has been implicated in the atrophy and deterioration associated with dystrophic muscles of Duchenne muscular dystrophy (DMD). While proteasome inhibitors show promise in the attenuation of muscle degeneration, proteasome inhibition-induced toxicity was a major drawback of this therapeutic strategy. Inhibitors that selectively target the proteasome subtype that is responsible for the loss in muscle mass and quality would reduce side effects and be less toxic. This study examined proteasome activity and subtype populations, along with muscle function, morphology and damage in wild-type (WT) mice and two murine models of DMD, dystrophin-deficient (MDX) and dystrophin- and utrophin-double-knockout (DKO) mice. We found that immunoproteasome content was increased in dystrophic muscles while the total proteasome content was unchanged among the three genotypes of mice. Proteasome proteolytic activity was elevated in dystrophic muscles, especially in DKO mice. These mice also exhibited more severe muscle atrophy than either WT or MDX mice. Muscle damage and regeneration, characterized by the activity of muscle creatine kinase in the blood and the percentage of central nuclei were equally increased in dystrophic mice. Accordingly, the overall muscle function was similarly reduced in both dystrophic mice compared with WT. These data demonstrated that there was transformation of standard proteasomes to immunoproteasomes in dystrophic muscles. In addition, DKO that showed greatest increase in proteasome activities also demonstrated more severe atrophy compared with MDX and WT. These results suggest a putative role for the immunoproteasome in muscle deterioration associated with DMD and provide a potential target for therapeutic intervention.

  7. Dystrophin-deficient muscular dystrophy in a Norfolk terrier.

    PubMed

    Beltran, E; Shelton, G D; Guo, L T; Dennis, R; Sanchez-Masian, D; Robinson, D; De Risio, L

    2015-05-01

    A six-month-old male entire Norfolk terrier was presented with a 3-month history of poor development, reluctance to exercise and progressive and diffuse muscle atrophy. Serum creatine kinase concentration was markedly elevated. Magnetic resonance imaging of the epaxial muscles revealed asymmetrical streaky signal changes aligned within the muscle fibres (hyperintense on T2-weighted images and short-tau inversion recovery with moderate contrast enhancement on T1-weighted images). Electromyography revealed pseudomyotonic discharges and fibrillation potentials localised at the level of the supraspinatus, epaxial muscles and tibial cranialis muscles. Muscle biopsy results were consistent with dystrophin-deficient muscular dystrophy. The dog remained stable 7 months after diagnosis with coenzyme Q10 and l-carnitine; however after that time, there was a marked deterioration and the owners elected euthanasia. This case report describes the clinical presentation, magnetic resonance imaging, electrodiagnostic and histopathological findings with immunohistochemical analysis in a Norfolk terrier with confirmed dystrophin-deficient muscular dystrophy, which has not been previously described in this breed.

  8. Experimental Validation of a Thermoelastic Model for SMA Hybrid Composites

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.

    2001-01-01

    This study presents results from experimental validation of a recently developed model for predicting the thermomechanical behavior of shape memory alloy hybrid composite (SMAHC) structures, composite structures with an embedded SMA constituent. The model captures the material nonlinearity of the material system with temperature and is capable of modeling constrained, restrained, or free recovery behavior from experimental measurement of fundamental engineering properties. A brief description of the model and analysis procedures is given, followed by an overview of a parallel effort to fabricate and characterize the material system of SMAHC specimens. Static and dynamic experimental configurations for the SMAHC specimens are described and experimental results for thermal post-buckling and random response are presented. Excellent agreement is achieved between the measured and predicted results, fully validating the theoretical model for constrained recovery behavior of SMAHC structures.

  9. Nonlinear Thermoelastic Model for SMAs and SMA Hybrid Composites

    NASA Technical Reports Server (NTRS)

    Turner, Travis L.

    2004-01-01

    A constitutive mathematical model has been developed that predicts the nonlinear thermomechanical behaviors of shape-memory-alloys (SMAs) and of shape-memory-alloy hybrid composite (SMAHC) structures, which are composite-material structures that contain embedded SMA actuators. SMAHC structures have been investigated for their potential utility in a variety of applications in which there are requirements for static or dynamic control of the shapes of structures, control of the thermoelastic responses of structures, or control of noise and vibrations. The present model overcomes deficiencies of prior, overly simplistic or qualitative models that have proven ineffective or intractable for engineering of SMAHC structures. The model is sophisticated enough to capture the essential features of the mechanics of SMAHC structures yet simple enough to accommodate input from fundamental engineering measurements and is in a form that is amenable to implementation in general-purpose structural analysis environments.

  10. Mixing temperature design and properties evaluation for SMA-13 mixture

    NASA Astrophysics Data System (ADS)

    Huang, X. Y.; Li, B. Y.

    2017-01-01

    The mixing temperature of hot asphalt mixture could be reduced by adding WMA additive Sasobit, as well as reducing smoke emissions and energy construction during the mixing construction and paving. The reasonable mixing temperature were investigated in this paper. In addition, high temperature stability, water stability and low-temperature performance of warm asphalt mixture were evaluaterd. The test results indicate that the mixing temperature of SMA-13 with WMA additive Sasobit may reduce 15-20°C at the same energy (compaction times). the dynamic stability were improved after adding WMA additive Sasobit, and the Water stability and low-temperature performance of mixture decreased, while all kinds of asphalt mixture properties can meet the requirements.

  11. Translational Research for Muscular Dystrophy

    DTIC Science & Technology

    2015-07-01

    deposits is due to innate differences in muscle fiber death and clearance within the muscle tissue. It must also be noted that at 1.5 months of age the... Immunology 170: 2742-2749. 15. Maddatu TP, Garvey SM, Shroeder DG, Hampton TG, Cox GA. 2004. Transgenic rescue of neurogenic atrophy in the nmd

  12. Development of damage suppression system using embedded SMA foil in CFRP laminates

    NASA Astrophysics Data System (ADS)

    Ogisu, Toshimichi; Nomura, Masato; Ando, Norio; Takaki, Junji; Kobayashi, Masakazu; Okabe, Tomonaga; Takeda, Nobuo

    2001-07-01

    Some recent studies have suggested possible applications of Shape Memory Alloy (SMA) for a smart health monitoring and suppression of damage growth. The authors have been conducting research and development studies on applications of embedded SMA foil actuators in CFRP laminates as the basic research for next generation aircrafts. First the effective surface treatment for improvement of bonding properties between SMA and CFRP was studied. It was certified that the anodic oxide treatment by 10% NaOH solution was the most effective treatment from the results of peel resistance test and shear strength test. Then, CFRP laminates with embedded SMA foils were successfully fabricated using this effective surface treatment. The damage behavior of quasi-isotropic CFRP laminates with embedded SMA foils was characterized in both quasi-static load-unload and fatigue tests. The relationship between crack density and applied strain was obtained. The recovery stress generated by embedded SMA foils could increase the onset strain of transverse cracking by 0.2%. The onset strain of delmination in CFRP laminates was also increased accordingly. The shear-lag analysis was also conducted to predict the damage evolution in CFRP laminates with embedded SMA foils. The adhesive layers on both sides of SMA foils were treated as shear elements. The theoretical analysis successfully predicted the experimental results.

  13. Genome Sequence of Methanosarcina soligelidi SMA-21, Isolated from Siberian Permafrost-Affected Soil

    PubMed Central

    Shapiro, Nicole; Woyke, Tanja; Horn, Fabian; Bakermans, Corien; Wagner, Dirk

    2015-01-01

    Here, we announce the genome sequence of Methanosarcina soligelidi SMA-21, an anaerobic methanogenic archaeon that was previously isolated from Siberian permafrost-affected soil. The sequencing of strain SMA-21 yielded a 4.06-Mb genome with 41.5% G+C content, containing a total of 2,647 open reading frames. PMID:25908125

  14. Acute intermittent porphyria presenting as progressive muscular atrophy in a young black man.

    PubMed

    Albertyn, C H; Sonderup, M; Bryer, A; Corrigall, A; Meissner, P; Heckmann, J M

    2014-04-01

    Acute intermittent porphyria, the most common porphyria affecting the nervous system, typically presents with neurovisceral crises followed by a motor neuropathy. We describe a 23-year-old black South African man presenting with a progressive stuttering, lower motor neuron syndrome developing over months. He had not experienced pain or neuropsychiatric symptoms. One year after symptom onset he was bed-bound with a flaccid quadriparesis. There was marked amyotrophy, but without fasciculations. Sensation was intact apart from a hypo-aesthetic patch over the thigh. Electrophysiological investigations showed an active motor axonopathy. Urinary porphyrins, delta-aminolaevulinic acid and porphobilinogen were elevated. Mutation analysis revealed the c445C>T (R149X) mutation in the porphobilinogen deaminase gene. The patient responded dramatically to haem arginate and could walk with assistance 2 weeks later. We identified the first molecularly confirmed acute intermittent porphyria in a black South African. The clinical presentation mimicked a progressive lower motor neuron syndrome.

  15. Genetics Home Reference: spinal muscular atrophy with respiratory distress type 1

    MedlinePlus

    ... a protein involved in copying (replicating) DNA ; producing RNA, a chemical cousin of DNA; and producing proteins. ... aid in DNA replication and the production of RNA and proteins. These problems particularly affect alpha-motor ...

  16. Mechanical properties of 50Molybdenum-50Rhenium alloys and their assembly by spinal muscular atrophy

    NASA Astrophysics Data System (ADS)

    Xu, Jianhui

    This study is concerned with the deformation and fracture behaviors, especially strain-rate effect on plasticity in tensile tests, of two 50Mo-50Re alloys at strain rates ranging from 10-6 s-1 to 1 s-1 at room temperature in air. Metallographic observations of the 50Mo-50Re alloys before and after tensile deformation were conducted to understand the relationships among mechanical properties, microstructure and strain rate in these alloys. Understanding the strain-rate effect on mechanical properties of 50Mo-50Re alloys is important for optimizing forming operations, especially sheet forming, of these alloys, which are often used in cathode and aerospace applications. An anomalous strain-rate effect on ductility was observed in the 50Mo-50Re alloys. Ductility was significantly increased by increasing the strain rate from 10-6 s-1 to 1 s-1 in the fully-recrystallized and recovery heat-treated 50Mo-50Re alloys in tension at room temperature. At a low strain rate, fracture was predominantly brittle, while it was more ductile at higher stain rates. At a low strain rate, secondary cracks initiated at grain boundaries and triple junctions were observed in these alloys, which suggested that significant stress concentration was generated by tensile plastic deformation in the vicinity of grain boundaries, especially triple junctions. Electron backscatter diffraction experiments revealed that there was strain concentration at grain boundaries and their triple junctions during tensile deformation in these alloys. The decrease in ductility at low strain rates in the alloys was related to the possible interaction between dislocations and trace interstitial atoms (e.g., H, O, N and C) picked up during production of these alloys. This dissertation also reports the research efforts made to optimize small-scale resistance spot welding (SSRSW) of refractory alloy 50Mo-50Re thin sheet by adjusting seven important welding parameters, including hold time, electrode material, electrode shape, ramp time, weld current, electrode force, and weld time. The strength of the weld was improved from 100 N to 184.7 N after the optimization. The improved welding quality gave rise to the overall quality improvement of the traveling tubes for microwave telecommunication industry. The diameter of nuggets and formation of pores were also discussed in the study. KEYWORDS: Mechanical properties, Refractory alloy, Mo-Re alloy, Strain rate, Resistance spot welding.

  17. Study on loss mechanism of SMA tracheal stent subjected to cough excitation.

    PubMed

    Zhu, Zhiwen; Li, Xinmiao; Xu, Jia

    2015-01-01

    A kind of Ti-Ni shape memory alloy (SMA) hysteretic nonlinear model is developed, and the loss mechanism of a SMA tracheal stent subjected to cough excitation is studied in this paper. Nonlinear differential items are introduced to express the hysteretic phenomena of Ti-Ni SMA, and the fitting effect of the SMA constitutive model on the experimental data is proved by the partial least-square regression method. The nonlinear dynamic model of a Ti-Ni SMA tracheal stent subjected to cough excitation is developed, and the system's dynamic response is obtained. The numerical results show that the system's vibration is little in weak excitation, becomes large with the increase of the stochastic excitation, and finally becomes little again with the further increase of the stochastic excitation; the stochastic resonance phenomenon occurs in the process, which may cause stent fracture or loss.

  18. SMA-SH: Modified Styrene-Maleic Acid Copolymer for Functionalization of Lipid Nanodiscs.

    PubMed

    Lindhoud, Simon; Carvalho, Vanessa; Pronk, Joachim W; Aubin-Tam, Marie-Eve

    2016-04-11

    Challenges in purification and subsequent functionalization of membrane proteins often complicate their biochemical and biophysical characterization. Purification of membrane proteins generally involves replacing the lipids surrounding the protein with detergent molecules, which can affect protein structure and function. Recently, it was shown that styrene-maleic acid copolymers (SMA) can dissolve integral membrane proteins from biological membranes into nanosized discs. Within these nanoparticles, proteins are embedded in a patch of their native lipid bilayer that is stabilized in solution by the amphipathic polymer that wraps the disc like a bracelet. This approach for detergent-free purification of membrane proteins has the potential to greatly simplify purification but does not facilitate conjugation of functional compounds to the membrane proteins. Often, such functionalization involves laborious preparation of protein variants and optimization of labeling procedures to ensure only minimal perturbation of the protein. Here, we present a strategy that circumvents several of these complications through modifying SMA by grafting the polymer with cysteamine. The reaction results in SMA that has solvent-exposed sulfhydrils (SMA-SH) and allows tuning of the coverage with SH groups. Size exclusion chromatography, dynamic light scattering, and transmission electron microscopy demonstrate that SMA-SH dissolves lipid bilayer membranes into lipid nanodiscs, just like SMA. In addition, we demonstrate that, just like SMA, SMA-SH solubilizes proteoliposomes into protein-loaded nanodiscs. We covalently modify SMA-SH-lipid nanodiscs using thiol-reactive derivatives of Alexa Fluor 488 and biotin. Thus, SMA-SH promises to simultaneously tackle challenges in purification and functionalization of membrane proteins.

  19. Porcine models of muscular dystrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein, dystrophin. This disease is modeled by a variety of animal models including several fish models, mice, rats, and dogs. While these models have contributed substantially t...

  20. Wasting mechanisms in muscular dystrophy.

    PubMed

    Shin, Jonghyun; Tajrishi, Marjan M; Ogura, Yuji; Kumar, Ashok

    2013-10-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

  1. Testicular atrophy as a risk inguinal hernioplasty.

    PubMed

    Wantz, G E

    1982-04-01

    In my experience, the complication of testicular atrophy after primary hernioplasty occurred only in patients in whom a complete indirect inguinal hernia sac was dissected from the spermatic cord. Avoiding this dissection by leaving the distal part of the sac in place reduces the incidence of the complication. All patients with scrotal inguinal hernias and all patients with recurrent inguinal hernias should have the complications of ischemic orchitis and testicular atrophy explained to them in depth because of the litigious nature of some of the men in whom this condition occurs. Patients who had undergone two or more operations for inguinal hernia should give prior written permission for orchiectomy even though this procedure is rarely necessary. In these patients, the performance of preperitoneal inguinal hernioplasty will permit the surgeon to avoid dissecting previously mobilized spermatic cords and should reduce the incidence of testicular atrophy in men fearful of this complication.

  2. [Iridoschisis, a special form of iris atrophy].

    PubMed

    Agard, E; Malcles, A; El Chehab, H; Ract-Madoux, G; Swalduz, B; Aptel, F; Denis, P; Dot, C

    2013-04-01

    Iridoschisis is a rare degenerative disease characterized by the separation of the anterior iris stroma from the posterior layer. The anterior layer splits into strands, and the free ends float freely in the anterior chamber. We report the case of a 57-year-old man, in whom we incidentally discovered isolated unilateral iris atrophy. The patient had no history of the common causes of atrophy (herpes, pigment dispersion, ocular trauma, etc.). During follow-up, the atrophy gradually worsened, with an increase in the number and bilaterality of the lesions. Ultrasound biomicroscopy (UBM) and optical coherence tomography (OCT) of anterior chamber showed thinning of the anterior iris and cleavage of the iris into two layers, an imaging result which, to our knowledge, has not yet been reported in the literature. Familiarity with iridoschisis is important, due to its frequent association with glaucoma, so that appropriate screening can be carried out at the time of diagnosis and on follow-up.

  3. Histological analysis of esophageal muscular layers from 27 autopsy cases with mixed connective tissue disease (MCTD).

    PubMed

    Uzuki, Miwa; Kamataki, Akihisa; Watanabe, Mika; Sasaki, Nobuhito; Miura, Yasuhiro; Sawai, Takashi

    2011-06-15

    Esophageal symptoms in mixed connective tissue disease (MCTD) have been investigated radiologically. We investigated the esophageal lesions in MCTD histopathologically, and analyzed relationships between these lesions and autoantibodies extracted from the serum of MCTD patients. Esophageal tissues from 27 MCTD patients submitted to autopsy were examined. We compared histopathological features of the esophagus in different wall layers from the mucosa, submucosa, and muscular layer to the adventitia, and in the upper, middle, and lower portions of esophagus. The most striking change observed was severe atrophy and occasional loss of smooth muscle cells in the muscular layer, followed by fibrosis. These muscular changes were particularly prominent in the inner layer of the lower esophagus. Immunohistochemically, degenerated muscular tissues of the esophagus were positive for anti-IgG and anti-C3 antibodies, but not for anti-IgM antibodies. IgG fractions extracted from three MCTD patients were immunohistochemically used to examine whether some antibodies in MCTD patients showed reactivity for esophageal components. The IgG fractions isolated from MCTD patients reacted with smooth muscle from non-connective tissue disease cases, suggesting that some serum antibodies may trigger esophageal changes. These findings suggest that esophageal lesions associated with clinical dysphagia in MCTD may be related to autoantibodies.

  4. Pregnancy and delivery in Leyden-Möbius muscular dystrophy. Case Report.

    PubMed

    Vavrinkova, Blanka; Binder, Tomas

    2015-01-01

    Leyden-Möbius muscular dystrophy is an autosomal recessive hereditary disease of unknown aetiology; it is a congenital disorder of protein metabolism primarily affecting proximal muscle groups leading to progressive muscular dystrophy. It later spreads to the muscles of the pelvic floor and lower extremities. The estimated incidence is 1:200,000. This paper describe a case of pregnancy and delivery in woman with progressive Leyden-Moebius muscular dystrophy. Cesarean section was performed due to progression of the underlying disease. First postoperative day DIC occure and surgical revision of abdominal cavity was performed. Although the uterine suture was strong, diffuse bleeding was present. Blood was not coagulating. Supravaginal amputation of the uterus was performed including left-sided adnexectomy due to bleeding from the left ovarium. Due to the severity of the condition and assumed necessity of long-term controlled ventilation, the patient was transferred to the intensive medicine department. She was dismissed home after 91 days of hospitalisation. Gravidity in advanced muscular dystrophy is rare and associated with a high risk. Due to muscle weakness, diaphragm weakness, atrophy of individual muscle groups, spine deformities and often dislocation of thoracic organs, these patients cannot avoid the caesarean section to end their pregnancy, followed by prolonged intubation and controlled ventilation. During pregnancy, the growing uterus elevates the diaphragm and impairs breathing. Therefore, pregnancies in such patients will probably always have to be ended prematurely.

  5. Progressive cerebral atrophy in neuromyelitis optica.

    PubMed

    Warabi, Yoko; Takahashi, Toshiyuki; Isozaki, Eiji

    2015-12-01

    We report two cases of neuromyelitis optica patients with progressive cerebral atrophy. The patients exhibited characteristic clinical features, including elderly onset, secondary progressive tetraparesis and cognitive impairment, abnormally elevated CSF protein and myelin basic protein levels, and extremely highly elevated serum anti-AQP-4 antibody titer. Because neuromyelitis optica pathology cannot switch from an inflammatory phase to the degenerative phase until the terminal phase, neuromyelitis optica rarely appears as a secondary progressive clinical course caused by axonal degeneration. However, severe intrathecal inflammation and massive destruction of neuroglia could cause a secondary progressive clinical course associated with cerebral atrophy in neuromyelitis optica patients.

  6. Posterior cortical atrophy: a brief review.

    PubMed

    Kirshner, Howard S; Lavin, Patrick J M

    2006-11-01

    Posterior cortical atrophy is a striking clinical syndrome in which a dementing illness begins with visual symptoms. Initially, the problem may seem to be loss of elementary vision, but over time the patient develops features of visual agnosia, topographical difficulty, optic ataxia, simultanagnosia, ocular apraxia (Balint's syndrome), alexia, acalculia, right-left confusion, and agraphia (Gerstmann's syndrome), and later a more generalized dementia. Occasional patients have visual hallucinations and signs of Parkinson's disease or Lewy body dementia. A number of different neuropathologic disorders are associated with posterior cortical atrophy.

  7. [Geographic atrophy imaging using fundus autofluorescence method].

    PubMed

    Dolar-Szczasny, Joanna; Święch-Zubilewicz, Anna; Mackiewicz, Jerzy

    2015-01-01

    Geographic atrophy is a manifestation of the advanced age-related macular degeneration and form of irreversible atrophy of retinal pigment epithelium and photoreceptor layer. Early detection of changes and the ability to evaluate disease progression accurately constitute a key problem in diagnosis and treatment planning. Fundus autofluorescence is a relatively new imaging method considered nowadays to be the best in diagnosis and observing the natural or treatment-altered course of disease. High resolution images showing the 3D distribution of retinal pigment epithelium autofluorescence as lipofuscin index can be obtained owing to the launch of the confocal scanning laser ophthalmoscope.

  8. A unique case of limb-girdle muscular dystrophy type 2A carrying novel compound heterozygous mutations in the human CAPN3 gene.

    PubMed

    Matsubara, E; Tsuchiya, A; Minami, N; Nishino, I; Pappolla, M A; Shoji, M; Abe, K

    2007-07-01

    A unique sib pair afflicted by limb girdle muscular dystrophy type 2A (LGMD2A) is described showing a slowly progressive autosomal recessive type of muscular dystrophy with onset in the third and fourth decades. The patients had early asymmetric muscle involvement characterized by prominent biceps brachii atrophy with sparing of the knee extensors. Additional findings included elevation of serum creatine kinase level, myopathic EMG changes and dystrophic type of pathology on muscle biopsy. Asymmetrical wasting of muscles in the extremities exhibited uniform and highly selective CT imaging patterns. RNA and DNA analyses confirmed novel compound heterozygous mutations (R147X/L212F) in the human CAPN3 gene.

  9. Complementary studies of de Vries type SmA ∗ phase

    NASA Astrophysics Data System (ADS)

    Mikułko, A.; Marzec, M.; Wróbel, S.; Przedmojski, J.; Douali, R.; Legrand, Ch.; Dąbrowski, R.; Haase, W.

    2006-11-01

    Two chiral liquid crystalline compounds have been investigated, namely 4-(1-methylheptyloxycarbonyl) phenyl-4'nonylbiphenyl-4-carboxylate (MHPNBC), 3-(2-fluor-octyloxy)-6-(4octyl-phenyl) pyridine (FOOPP) to study the SmA ∗-SmC ∗ transition. For both substances strong electroclinic effect is observed in the SmA ∗ phase what indicates that it is the so-called de Vries SmA ∗ phase. To study the paralectric-ferroelectric de Vries type transition electrooptic, dielectric as well as SAXS methods have been applied.

  10. Percutaneous Thrombin Injection to Complete SMA Pseudoaneurysm Exclusion After Failing of Endograft Placement

    SciTech Connect

    Szopinski, Piotr Ciostek, Piotr; Pleban, Eliza; Iwanowski, Jaroslaw; Krol, Malgorzata Serafin-; Marianowska, Agnieszka; Noszczyk, Wojciech

    2005-05-15

    Visceral aneurysms are potentially life-threatening vascular lesions. Superior mesenteric artery (SMA) pseudoaneurysms are a rare but well-recognized complication of chronic pancreatitis. Open surgical repair of such an aneurysm, especially in patients after previous surgical treatment, might be dangerous and risky. Stent graft implantation makes SMA pseudoaneurysm exclusion possible and therefore avoids a major abdominal operation. Percutaneous direct thrombin injection is also one of the methods of treating aneurysms in this area. We report a first case of percutaneous ultrasound-guided thrombin injection to complete SMA pseudoaneurysm exclusion after an unsuccessful endograft placement. Six-month follow-up did not demonstrate any signs of aneurysm recurrence.

  11. Grey matter atrophy in patients suffering from multiple sclerosis.

    PubMed

    Kincses, Zsigmond Tamás; Tóth, Eszter; Bankó, Nóra; Veréb, Dániel; Szabó, Nikoletta; Csete, Gergő; Faragó, Péter; Király, András; Bencsik, Krisztina; Vécsei, László

    2014-09-30

    White matter lesions are defining characteristics of multiple sclerosis (MS), whereas grey matter involvement is a less recognised attribute. Recent investigations using dedicated imaging approaches have made it possible to depict cortical lesions. Additionally, grey matter atrophy may be estimated using various methods. Several studies have suggested that grey matter atrophy closely correlates to clinical disability. In this review we have collected information on grey matter atrophy in MS and the effect of disease modifying therapies upon brain atrophy.

  12. Seismic Risk Mitigation of Historical Minarets Using SMA Wire Dampers

    SciTech Connect

    El-Attar, Adel G.; Saleh, Ahmed M.; El-Habbal, Islam R.

    2008-07-08

    This paper presents the results of a research program sponsored by the European Commission through project WIND-CHIME (Wide Range Non-INtrusive Devices toward Conservation of HIstorical Monuments in the MEditerranean Area), in which the possibility of using advanced seismic protection technologies to preserve historical monuments in the Mediterranean area is investigated. In the current research, two outstanding Egyptian Mamluk-Style minarets, are investigated. The first is the southern minaret of Al-Sultaniya (1340 A.D, 739 Hijri Date (H.D.)), the second is the minaret of Qusun minaret (1337 A.D, 736 H.D.), both located within the city of Cairo. Based on previous studies on the minarets by the authors, a seismic retrofit technique is proposed. The technique utilizes shape memory alloy (SMA) wires as dampers for the upper, more flexible, parts of the minarets in addition to vertical pre-stressing of the lower parts found to be prone to tensile cracking under ground excitation. The effectiveness of the proposed technique is numerically evaluated via nonlinear transient dynamic analyses. The results indicate the effectiveness of the technique in mitigating the seismic hazard, demonstrated by the effective reduction in stresses and in dynamic response.

  13. SMA applications in an innovative multishot deployment mechanism

    NASA Technical Reports Server (NTRS)

    Stella, D.; Pedrazzoli, G.; Secci, G.; Portelli, C.

    1991-01-01

    An innovative Deployment and Retraction hinge Mechanism (DARM) in the frame of a technological program is examined. The mechanism includes two restraint/release devices, which enable it to be stable in its stowed or deployed position while sustaining all associated loads, and to carry its payload by remote command. The main characteristics of the DARM are as follows: deployment and retraction movements are spring actuated; the available amount of functional sequences is almost unlimited; and no use of electrical motors is made. These features were accomplished by: the application of a special kinematic scheme to the mechanical connection between the spring motor and the swivel head arm; and the use of shape memory alloys (SMA) actuators for both release and spring recharge functions. DARM is thus a mechanism which can find many applications in the general space scenario of in-orbit maintenance and servicing. In such a frame, the DARM typical concept, which has a design close to very simple one-shot deployment mechanisms, has a good chance to replace existing analog machines. Potential items that could be moved by DARM are: booms for satellite instruments; antenna reflector tips; entire antenna reflectors; and solar panels.

  14. Seismic Risk Mitigation of Historical Minarets Using SMA Wire Dampers

    NASA Astrophysics Data System (ADS)

    El-Attar, Adel G.; Saleh, Ahmed M.; El-Habbal, Islam R.

    2008-07-01

    This paper presents the results of a research program sponsored by the European Commission through project WIND-CHIME (Wide Range Non-INtrusive Devices toward Conservation of HIstorical Monuments in the MEditerranean Area), in which the possibility of using advanced seismic protection technologies to preserve historical monuments in the Mediterranean area is investigated. In the current research, two outstanding Egyptian Mamluk-Style minarets, are investigated. The first is the southern minaret of Al-Sultaniya (1340 A.D, 739 Hijri Date (H.D.)), the second is the minaret of Qusun minaret (1337 A.D, 736 H.D.), both located within the city of Cairo. Based on previous studies on the minarets by the authors, a seismic retrofit technique is proposed. The technique utilizes shape memory alloy (SMA) wires as dampers for the upper, more flexible, parts of the minarets in addition to vertical pre-stressing of the lower parts found to be prone to tensile cracking under ground excitation. The effectiveness of the proposed technique is numerically evaluated via nonlinear transient dynamic analyses. The results indicate the effectiveness of the technique in mitigating the seismic hazard, demonstrated by the effective reduction in stresses and in dynamic response.

  15. Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy

    ClinicalTrials.gov

    2016-08-02

    Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

  16. Genetics Home Reference: multiple system atrophy

    MedlinePlus

    ... inability to hold the body upright and balanced (postural instability). The other type of multiple system atrophy , known as MSA-C, is characterized by cerebellar ataxia , which causes problems with coordination and balance. This form of the condition can also include ...

  17. Anabolic Steroid Reversal of Denervation Atrophy

    DTIC Science & Technology

    2012-03-01

    10-1-0932 TITLE: Anabolic Steroid Reversal of Denervation Atrophy PRINCIPAL INVESTIGATOR: Dr. Jonathan E. Isaacs...certainly “denervation atrophy” plays a significant role. Anabolic steroids , which have been shown to cause hypertrophy of muscle fibers, increase net...of satellite cells to muscle fibers. In conclusion, there did not seem to be a functional benefit for anabolic steroid treatment following

  18. Progressive hemifacial atrophy. A natural history study.

    PubMed Central

    Miller, M T; Spencer, M A

    1995-01-01

    PURPOSE: To describe two very different natural history courses in 2 patients with hemifacial atrophy. Progressive hemifacial atrophy (Parry-Romberg syndrome, Romberg syndrome, PHA) is characterized by slowly progressive atrophy, frequently involving only one side of the face, primarily affecting the subcutaneous tissue and fat. The onset usually occurs during the first 2 decades of life. The cause and pathophysiology are unknown. Ophthalmic involvement is common, with progressive enophthalmos a frequent finding. Pupillary disturbances, heterochromia, uveitis, pigmentary disturbances of the ocular fundus, and restrictive strabismus have also been reported. Neurologic findings may be present, but the natural history and progression of ocular findings are often not described in the literature. METHODS: We studied the records and present findings of 2 patients with progressive hemifacial atrophy who were observed in our institution over a 10-year period. RESULTS: Both patients showed progression of ophthalmic findings, primarily on the affected side. One patient has had chronic uveitis with secondary cataract and glaucoma, in addition to retinal pigmentary changes. She also had a third-nerve paresis of the contralateral eye and mild seizure activity. The other patient had mild uveitis, some progression of