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Sample records for facioscapulohumeral dystrophy fshd

  1. Physical Therapy and Facioscapulohumeral Muscular Dystrophy (FSHD)

    MedlinePlus

    Physical Therapy & FSHD Facioscapulohumeral Muscular Dystrophy A Guide for Patients & Physical Therapists Authors: Wendy M. King, P.T., ... expertise and patient preferences. The goals of any physical therapy plan of care are to assist patients to:  ...

  2. Molecular analysis of facioscapulohumeral muscular dystrophy (FSHD)

    SciTech Connect

    Upadhyaya, M.; Maynard, J.; Osborn, M.

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by progressive muscle weakness. The disease locus maps to 4q35 and is associated with a de novo DNA rearrangement, detected by a probe p13E-11 (D4F104S1) which maps proximal to the disease locus. An informative distal flanking marker for this condition is still required. Using p13E-11, we have analyzed 35 FSHD families in which the disease is apparently associated with a new mutation. Twenty three of these cases were found to have a smaller rearranged DNA fragment which was not present in either of the parents. Pulsed-field gel analysis of 5 of these families also revealed evidence of DNA deletion. During the course of this study, we identified one case with a DNA rearrangement which was also present in the unaffected mother, but at very low intensity. This finding has been confirmed by pulsed-field gel analysis, and indicates that the mother is probably a gonosomal mosaic. In order to saturate the FSHD region with new DNA markers, a laser microdissection and microcloning technique was used to construct a genomic library from the distal end of chromosome 4. Of the 72 microclones analyzed, 42 mapped into the relevant 4q35 region. 4 sequences were conserved and may be considered potential candidate genes for FSHD. The microclones mapping to 4q35 are under study to identify additional polymorphic markers for the FSHD region.

  3. Reachable Workspace in Facioscapulohumeral muscular dystrophy (FSHD) by Kinect

    PubMed Central

    Han, Jay J.; Kurillo, Gregorij; Abresch, Richard T.; de Bie, Evan; Nicorici, Alina; Bajcsy, Ruzena

    2014-01-01

    Introduction A depth-ranging sensor (Kinect) based upper extremity motion analysis system was applied to determine the spectrum of reachable workspace encountered in facioscapulohumeral muscular dystrophy (FSHD). Methods Reachable workspaces were obtained from 22 individuals with FSHD and 24 age- and height-matched healthy controls. To allow comparison, total and quadrant reachable workspace relative surface areas (RSA) were obtained by normalizing the acquired reachable workspace by each individual’s arm length. Results Significantly contracted reachable workspace and reduced RSAs were noted for the FSHD cohort compared to controls (0.473±0.188 vs. 0.747±0.082; P<0.0001). With worsening upper extremity function as categorized by the FSHD evaluation subscale II+III, the upper quadrant RSAs decreased progressively, while the lower quadrant RSAs were relatively preserved. There were no side-to-side differences in reachable workspace based on hand-dominance. Discussion This study demonstrates the feasibility and potential of using an innovative Kinect-based reachable workspace outcome measure in FSHD. PMID:24828906

  4. Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD)

    PubMed Central

    Gilbert, J. R.; Stajich, J. M.; Wall, S.; Carter, S. C.; Qiu, H.; Vance, J. M.; Stewart, C. S.; Speer, M. C.; Pufky, J.; Yamaoka, L. H.; Rozear, M.; Samson, F.; Fardeau, M.; Roses, A. D.; Pericak-Vance, M. A.

    1993-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive primary disease of muscle which is usually inherited as an autosomal dominant disorder. FSHD has been localized to the long arm of chromosome 4, specifically to the 4q3.5-qter region. Initially published linkage studies showed no evidence for heterogeneity in FSHD. In the present study we have examined individuals in seven FSHD families. Two-point lod scores show significant evidence for linkage for D4S163 (lod score 3.04 at recombination fraction .21) and D4S139 (lod score 3.84 at recombination fraction .20). D4S171 also gave a positive score (lod score 2.56 at recombination fraction .24). Significant evidence for heterogeneity was found for each of the three markers. Multipoint linkage analysis in this region resulted in a peak multipoint lod score of 6.47. The multipoint analysis supported the two-point studies with odds of 20:1 showing linkage and heterogeneity over linkage and homogeneity. Five of the seven families gave a posterior probability of >95% of being of the linked type, while two families appeared unlinked to this region of 4q (P < .01%). Individuals in the two unlinked families met the clinical criteria for the diagnosis of FSHD, including facial weakness, clavicular flattening, scapula winging, proximal muscle weakness, and myopathic changes on muscle biopsies without inflammatory or mitochondrial pathology. This study demonstrates genetic heterogeneity in FSHD and has important implications for both genetic counseling and the elucidation of the etiology of FSHD. PMID:8328457

  5. Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD)

    SciTech Connect

    Gilbert, J.R.; Stajich, J.M.; Wall, S.; Carter, S.C.; Qiu, H.; Vance, J.M.; Stewart, C.S.; Speer, M.C.; Pufky, J.; Yamaoka, L.H.; Rozear, M.; Roses, A.D.; Pericak-Vance, M.A. ); Samson, F.; Fardeau, M. )

    1993-08-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive primary disease of muscle which is usually inherited as an autosomal dominant disorder. FSHD has been localized to the long arm of chromosome 4, specifically to the 4q3.5-qter region. Initially published linkage studies showed no evidence for heterogeneity in FSHD. In the present study the authors have examined individuals in seven FSHD families. Two-point lod scores show significant evidence for linkage for D4S163 (lod score 3.04 at recombination fraction .21) and D4S139 (lod score 3.84 at recombination fraction .20). D4S171 also gave a positive score (lod score 2.56 at recombination fraction .24). Significant evidence for heterogeneity was found for each of the three markers. Multipoint linkage analysis in this region resulted in a peak multipoint lod score of 6.47. The multipoint analysis supported the two-point studies with odds of 20:1 showing linkage and heterogeneity over linkage and homogeneity. Five of the seven families gave a posterior probability of >95% of being of the linked type, while two families appeared unlinked to this region of 4q (P<.01%). Individuals in the two unlinked families met the clinical criteria for the diagnosis of FSHD, including facial weakness, clavicular flattening, scapula winging, proximal muscle weakness, and myopathic changes on muscle biopsies without inflammatory or mitochondrial pathology. This study demonstrates genetic heterogeneity in FSHD and has important implications for both genetic counseling and the elucidation of the etiology of FSHD. 19 refs., 3 figs., 2 tabs.

  6. Facioscapulohumeral Dystrophy.

    PubMed

    Wang, Leo H; Tawil, Rabi

    2016-07-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a clinically recognizable and relatively common muscular dystrophy. It is inherited mostly as an autosomal dominant disease or in a minority of cases, in a digenic pattern. The disease manifestation is variable and most likely dependent on genetic and epigenetic factors. We review the history, epidemiology, clinical presentation, and genetics of the disease, present the recently elucidated molecular pathogenesis, discuss the pathology and the possible consequence of the inflammation seen in the muscle biopsies, and consider future treatments. PMID:27215221

  7. A cross sectional study of two independent cohorts identifies serum biomarkers for facioscapulohumeral muscular dystrophy (FSHD).

    PubMed

    Petek, Lisa M; Rickard, Amanda M; Budech, Christopher; Poliachik, Sandra L; Shaw, Dennis; Ferguson, Mark R; Tawil, Rabi; Friedman, Seth D; Miller, Daniel G

    2016-07-01

    Measuring the severity and progression of facioscapulohumeral muscular dystrophy (FSHD) is particularly challenging because muscle weakness progresses over long periods of time and can be sporadic. Biomarkers are essential for measuring disease burden and testing treatment strategies. We utilized the sensitive, specific, high-throughput SomaLogic proteomics platform of 1129 proteins to identify proteins with levels that correlate with FSHD severity in a cross-sectional study of two independent cohorts. We discovered biomarkers that correlate with clinical severity and disease burden measured by magnetic resonance imaging. Sixty-eight proteins in the Rochester cohort (n = 48) and 51 proteins in the Seattle cohort (n = 30) had significantly different levels in FSHD-affected individuals when compared with controls (p-value ≤ .005). A subset of these varied by at least 1.5 fold and four biomarkers were significantly elevated in both cohorts. Levels of creatine kinase MM and MB isoforms, carbonic anhydrase III, and troponin I type 2 reliably predicted the disease state and correlated with disease severity. Other novel biomarkers were also discovered that may reveal mechanisms of disease pathology. Assessing the levels of these biomarkers during clinical trials may add significance to other measures of quantifying disease progression or regression. PMID:27185459

  8. Muscle pain as a prominent feature of facioscapulohumeral muscular dystrophy (FSHD): four illustrative case reports.

    PubMed

    Bushby, K M; Pollitt, C; Johnson, M A; Rogers, M T; Chinnery, P F

    1998-12-01

    Clinical studies of facioscapulohumeral muscular dystrophy (FSHD) rarely report muscle pain as a significant feature of the condition. We report four adult patients with FSHD in whom muscle pain was a presenting complaint and remains their most disabling symptom. These four patients were investigated using a pain questionnaire and diary. Inflammatory and metabolic causes of muscle pain were sought by muscle biopsy and a range of biochemical investigations. All patients reported between three and seven different pains of varying site and nature. None of the group had more than one painfree day per month and all complained of disturbed sleep. While some pains could potentially be attributed to postural problems, others were clearly myalgic in nature, though most often not specifically exercise-related. These myalgic pains could be particularly difficult to control. Results of metabolic investigations and muscle biopsy revealed no clue to the pathogenesis of these pains and there was no evidence for any exceptional inflammatory response. We believe that pain in FSHD is an under-reported but significant symptom and that further work is necessary to determine its prevalence, understand its cause and provide effective treatment. PMID:10093064

  9. YAC contigs for 4q35 in the region of the facioscapulohumeral muscular dystrophy (FSHD) gene

    SciTech Connect

    Weiffenbach, B.; DuBois, J.; Manning, S.; Ma, N.S.; Moir, D. ); Schutte, B.C. ); Altherr, M.R. Los Alamos National Lab., NM ); Jacobsen, S.J. ); Stanton, V.P. Jr. )

    1994-02-01

    The authors report here the construction of a genetic linkage map and an overlapping set of clones containing DNA markers linked to the causative locus for facioscapulohumeral muscular dystrophy (FSHD) on 4q35. Multi-point linkage analysis placed eight loci in the following order with odds greater than 1000:1: cen-D4S171-FXI-D4S426-D4S187-D4S130-D4S163-D4S139-D4F35S1-qter. The most likely position of D4S809 was distal to D4F35S1. Thirty-four yeast artificial chromosomes (YACs) were isolated by PCR-based assays for STSs derived from DNA markers with known genetic and physical order. Walking from the insert ends of 2 YACs identified 7 additional YACs, bridging the gaps between three of the markers. Two new YACs were found by hybridization of a cosmid inter-Alu PCR product to dot blots of inter-Alu PCR products of YAC DNA pools. All YAC clones were positioned using the genetic and physical order of the STSs and inter-Alu PCR fingerprint data. Eleven of the YAC-, and two cosmids were mapped by fluorescence in situ hybridization to confirm the location of the clones and to detect chimerism. The 43 YACs were assembled into two contigs. The larger contig spans approximately 2.4 Mb and contains markers closest to the FSHD gene. 53 refs., 3 figs., 3 tabs.

  10. Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Statland, Jeffrey M.; Tawil, Rabi

    2014-01-01

    Facioscapulohumeral muscular dystrophy (FSHSD) is one of the most common adult muscular dystrophies and is divided into types 1 and 2 based on genetic mutation. Clinically both FSHD types 1 and 2 demonstrate often asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms, followed by the distal and then proximal lower extremities later in the disease course. 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 FSHD types 1 and 2 share a common downstream mechanism making it possible that future disease-directed therapies will be effective for both FSHD types 1 and 2. PMID:25037087

  11. Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD)

    PubMed Central

    Jones, Takako I.; Parilla, Megan; Jones, Peter L.

    2016-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is typically an adult onset dominant myopathy. Epigenetic changes in the chromosome 4q35 region linked to both forms of FSHD lead to a relaxation of repression and increased somatic expression of DUX4-fl (DUX4-full length), the pathogenic alternative splicing isoform of the DUX4 gene. DUX4-fl encodes a transcription factor expressed in healthy testis and pluripotent stem cells; however, in FSHD, increased levels of DUX4-fl in myogenic cells lead to aberrant regulation of target genes. DUX4-fl has proven difficult to study in vivo; thus, little is known about its normal and pathogenic roles. The endogenous expression of DUX4-fl in FSHD-derived human muscle and myogenic cells is extremely low, exogenous expression of DUX4-fl in somatic cells rapidly induces cytotoxicity, and, due in part to the lack of conservation beyond primate lineages, viable animal models based on DUX4-fl have been difficult to generate. By contrast, the FRG1 (FSHD region gene 1), which is linked to FSHD, is evolutionarily conserved from invertebrates to humans, and has been studied in several model organisms. FRG1 expression is critical for the development of musculature and vasculature, and overexpression of FRG1 produces a myopathic phenotype, yet the normal and pathological functions of FRG1 are not well understood. Interestingly, DUX4 and FRG1 were recently linked when the latter was identified as a direct transcriptional target of DUX4-FL. To better understand the pathways affected in FSHD by DUX4-fl and FRG1, we generated transgenic lines of Drosophila expressing either gene under control of the UAS/GAL4 binary system. Utilizing these lines, we generated screenable phenotypes recapitulating certain known consequences of DUX4-fl or FRG1 overexpression. These transgenic Drosophila lines provide resources to dissect the pathways affected by DUX4-fl or FRG1 in a genetically tractable organism and may provide insight into both muscle development

  12. Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD).

    PubMed

    Jones, Takako I; Parilla, Megan; Jones, Peter L

    2016-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is typically an adult onset dominant myopathy. Epigenetic changes in the chromosome 4q35 region linked to both forms of FSHD lead to a relaxation of repression and increased somatic expression of DUX4-fl (DUX4-full length), the pathogenic alternative splicing isoform of the DUX4 gene. DUX4-fl encodes a transcription factor expressed in healthy testis and pluripotent stem cells; however, in FSHD, increased levels of DUX4-fl in myogenic cells lead to aberrant regulation of target genes. DUX4-fl has proven difficult to study in vivo; thus, little is known about its normal and pathogenic roles. The endogenous expression of DUX4-fl in FSHD-derived human muscle and myogenic cells is extremely low, exogenous expression of DUX4-fl in somatic cells rapidly induces cytotoxicity, and, due in part to the lack of conservation beyond primate lineages, viable animal models based on DUX4-fl have been difficult to generate. By contrast, the FRG1 (FSHD region gene 1), which is linked to FSHD, is evolutionarily conserved from invertebrates to humans, and has been studied in several model organisms. FRG1 expression is critical for the development of musculature and vasculature, and overexpression of FRG1 produces a myopathic phenotype, yet the normal and pathological functions of FRG1 are not well understood. Interestingly, DUX4 and FRG1 were recently linked when the latter was identified as a direct transcriptional target of DUX4-FL. To better understand the pathways affected in FSHD by DUX4-fl and FRG1, we generated transgenic lines of Drosophila expressing either gene under control of the UAS/GAL4 binary system. Utilizing these lines, we generated screenable phenotypes recapitulating certain known consequences of DUX4-fl or FRG1 overexpression. These transgenic Drosophila lines provide resources to dissect the pathways affected by DUX4-fl or FRG1 in a genetically tractable organism and may provide insight into both muscle development

  13. Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) expression and possible function in mouse tooth germ development.

    PubMed

    Hasegawa, Kana; Wada, Hiroko; Nagata, Kengo; Fujiwara, Hiroaki; Wada, Naohisa; Someya, Hirotaka; Mikami, Yurie; Sakai, Hidetaka; Kiyoshima, Tamotsu

    2016-08-01

    Abnormal expression of Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is involved in the pathogenesis of FSHD. FRG1 is also important for the normal muscular and vascular development. Our previous study showed that FRG1 is one of the highly expressed genes in the mandible on embryonic day 10.5 (E10.5) than on E12.0. In this study, we investigated the temporospatial expression pattern of FRG1 mRNA and protein during the development of the mouse lower first molar, and also evaluated the subcellular localization of the FRG1 protein in mouse dental epithelial (mDE6) cells. The FRG1 expression was identified in the dental epithelial and mesenchymal cells at the initiation and bud stages. It was detected in the inner enamel epithelium at the cap and early bell stages. At the late bell and root formation stages, these signals were detected in ameloblasts and odontoblasts during the formation of enamel and dentin matrices, respectively. The FRG1 protein was localized in the cytoplasm in the mouse tooth germ in vivo, while FRG1 was detected predominantly in the nucleus and faintly in the cytoplasm in mDE6 cells in vitro. In mDE6 cells treated with bone morphogenetic protein 4 (BMP4), the protein expression of FRG1 increased in cytoplasm, suggesting that FRG1 may translocate to the cytoplasm. These findings suggest that FRG1 is involved in the morphogenesis of the tooth germ, as well as in the formation of enamel and dentin matrices and that FRG1 may play a role in the odontogenesis in the mouse following BMP4 stimulation. PMID:27234941

  14. 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

  15. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.

    PubMed

    Lemmers, Richard J L F; Tawil, Rabi; Petek, Lisa M; Balog, Judit; Block, Gregory J; Santen, Gijs W E; Amell, Amanda M; van der Vliet, Patrick J; Almomani, Rowida; Straasheijm, Kirsten R; Krom, Yvonne D; Klooster, Rinse; Sun, Yu; den Dunnen, Johan T; Helmer, Quinta; Donlin-Smith, Colleen M; Padberg, George W; van Engelen, Baziel G M; de Greef, Jessica C; Aartsma-Rus, Annemieke M; Frants, Rune R; de Visser, Marianne; Desnuelle, Claude; Sacconi, Sabrina; Filippova, Galina N; Bakker, Bert; Bamshad, Michael J; Tapscott, Stephen J; Miller, Daniel G; van der Maarel, Silvère M

    2012-12-01

    Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.

  16. Effect of aerobic exercise training and cognitive behavioural therapy on reduction of chronic fatigue in patients with facioscapulohumeral dystrophy: protocol of the FACTS-2-FSHD trial

    PubMed Central

    2010-01-01

    Background In facioscapulohumeral dystrophy (FSHD) muscle function is impaired and declines over time. Currently there is no effective treatment available to slow down this decline. We have previously reported that loss of muscle strength contributes to chronic fatigue through a decreased level of physical activity, while fatigue and physical inactivity both determine loss of societal participation. To decrease chronic fatigue, two distinctly different therapeutic approaches can be proposed: aerobic exercise training (AET) to improve physical capacity and cognitive behavioural therapy (CBT) to stimulate an active life-style yet avoiding excessive physical strain. The primary aim of the FACTS-2-FSHD (acronym for Fitness And Cognitive behavioural TherapieS/for Fatigue and ACTivitieS in FSHD) trial is to study the effect of AET and CBT on the reduction of chronic fatigue as assessed with the Checklist Individual Strength subscale fatigue (CIS-fatigue) in patients with FSHD. Additionally, possible working mechanisms and the effects on various secondary outcome measures at all levels of the International Classification of Functioning, Disability and Health (ICF) are evaluated. Methods/Design A multi-centre, assessor-blinded, randomized controlled trial is conducted. A sample of 75 FSHD patients with severe chronic fatigue (CIS-fatigue ≥ 35) will be recruited and randomized to one of three groups: (1) AET + usual care, (2) CBT + usual care or (3) usual care alone, which consists of no therapy at all or occasional (conventional) physical therapy. After an intervention period of 16 weeks and a follow-up of 3 months, the third (control) group will as yet be randomized to either AET or CBT (approximately 7 months after inclusion). Outcomes will be assessed at baseline, immediately post intervention and at 3 and 6 months follow up. Discussion The FACTS-2-FSHD study is the first theory-based randomized clinical trial which evaluates the effect and the maintenance of effects

  17. Facioscapulohumeral dystrophy: case report and discussion.

    PubMed

    Castellano, Vincenzo; Feinberg, Joseph; Michaels, Jennifer

    2008-09-01

    Facioscapulohumeral dystrophy (FSHD) is often cited as the third most common form of muscular dystrophy. Therefore, it should be considered in patients with complaints of progressive weakness. We present the case of a man with facial, truncal, and leg weakness that initially sought medical attention for lower back pain. Electrodiagnostic testing revealed findings in the trapezius, serratus anterior, biceps, triceps, pectoralis major, tibialis anterior, and gastrocnemius muscles consistent with a myopathic disorder. Subsequent genetic testing identified a FSHD allele size consistent with a FSHD deletion mutation. Therefore, confirming the diagnosis of FSHD. Unfortunately, no effective treatments currently exist for FSHD. However, supportive measures involving physical therapy and the use of orthotics may aid in improving function and mobility. PMID:18815862

  18. Facioscapulohumeral Dystrophy: Case Report and Discussion

    PubMed Central

    Feinberg, Joseph; Michaels, Jennifer

    2008-01-01

    Facioscapulohumeral dystrophy (FSHD) is often cited as the third most common form of muscular dystrophy. Therefore, it should be considered in patients with complaints of progressive weakness. We present the case of a man with facial, truncal, and leg weakness that initially sought medical attention for lower back pain. Electrodiagnostic testing revealed findings in the trapezius, serratus anterior, biceps, triceps, pectoralis major, tibialis anterior, and gastrocnemius muscles consistent with a myopathic disorder. Subsequent genetic testing identified a FSHD allele size consistent with a FSHD deletion mutation. Therefore, confirming the diagnosis of FSHD. Unfortunately, no effective treatments currently exist for FSHD. However, supportive measures involving physical therapy and the use of orthotics may aid in improving function and mobility. PMID:18815862

  19. Birdshot chorioretinopathy in a male patient with facioscapulohumeral muscular dystrophy.

    PubMed

    Papavasileiou, Evangelia; Lobo, Ann-Marie

    2015-01-01

    We report a case of birdshot chorioretinopathy (BSCR) in a patient with facioscapulohumeral muscular dystrophy (FSHD). A 40-year-old male with history of facioscapulohumeral muscular dystrophy with significant facial diplegia and lagophthalmos presents for an evaluation of bilateral choroiditis with vasculitis and optic disc edema. Clinical examination included fundus and autofluorescence photographs, fluorescein angiography, and optical coherence tomography. To our knowledge, this patient represents the first reported case of birdshot chorioretinopathy with facioscapulohumeral muscular dystrophy. Patients with FSHD can present with ocular findings and should be screened with dilated fundus examinations for retinal vascular changes and posterior uveitis. PMID:25861398

  20. Identical de novo mutation at the D4F104S1 locus in monozygotic male twins affected by facioscapulohumeral muscular dystrophy (FSHD) with different clinical expression.

    PubMed Central

    Tupler, R; Barbierato, L; Memmi, M; Sewry, C A; De Grandis, D; Maraschio, P; Tiepolo, L; Ferlini, A

    1998-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a progressive hereditary neuromuscular disorder, transmitted in an autosomal dominant fashion. Its clinical expression is highly variable, ranging from almost asymptomatic subjects to wheelchair dependent patients. The molecular defect has been linked to chromosome 4q35 markers and has been related to deletions of tandemly repeated sequences located in the subtelomeric region detected by probe p13E-11 (D4F104S1). We describe a pair of monozygotic male twins affected by FSHD, carrying an identical de novo p13E-11 EcoRI fragment of paternal origin and showing great variability in the clinical expression of the disease, one being almost asymptomatic and the other severely affected. Their medical history was the same, with the exception of an anti-rabies vaccination performed at the age of 5 in the more severely affected twin. We hypothesise that the vaccination might have triggered an inflammatory immune reaction contributing to the more severe phenotype. Images PMID:9733041

  1. Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry

    PubMed Central

    Nikolic, Ana; Ricci, Giulia; Sera, Francesco; Bucci, Elisabetta; Govi, Monica; Mele, Fabiano; Rossi, Marta; Ruggiero, Lucia; Vercelli, Liliana; Ravaglia, Sabrina; Brisca, Giacomo; Fiorillo, Chiara; Villa, Luisa; Maggi, Lorenzo; Cao, Michelangelo; D'Amico, Maria Chiara; Siciliano, Gabriele; Antonini, Giovanni; Santoro, Lucio; Mongini, Tiziana; Moggio, Maurizio; Morandi, Lucia; Pegoraro, Elena; Angelini, Corrado; Di Muzio, Antonio; Rodolico, Carmelo; Tomelleri, Giuliano; Grazia D'Angelo, Maria; Bruno, Claudio; Berardinelli, Angela; Tupler, Rossella

    2016-01-01

    Objectives Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1–3 repeats (1–3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1–3 DRA. Setting Italy. Participants 66 index cases and 33 relatives carrying 1–3 DRA. Outcomes The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk. Results No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1–3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment. Conclusions The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high

  2. If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD)

    PubMed Central

    Hilbert, James E.; Kissel, John T.; Luebbe, Elizabeth A.; Martens, William B.; McDermott, Michael P.; Sanders, Donald B.; Tawil, Rabi; Thornton, Charles A.; Moxley, Richard T.

    2011-01-01

    Introduction Registries are becoming increasingly important for rare diseases as experimental therapies develop. This report describes the methodology behind the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD) Patients and Family Members to facilitate the development of other rare disease registries. We also highlight data about the pathophysiology and select burdens of DM and FSHD reported at baseline and longitudinally. Methods The Registry consists of de-identified, patient reported information collected at baseline and annually and information from review of medical records. Investigators can use the Registry to analyze de-identified data and to facilitate recruitment into clinical studies. Results To date, the Registry has enrolled 1611 members, facilitated 24 studies, and collected data annually for up to 8 years. Genetic test results were obtained in 56.2% of enrollees. Approximately one-third of members used assistive devices and another one-third reported psychological problems at baseline. Wheelchair use was reported for both short and long distances by 7.0% of DM and 18.1% of FSHD members. Approximately 60% of members reported their employment was affected by their disease. Conclusions Strengths of the Registry include large sample sizes, stringent review of clinical and molecular data, annually updated information, and regular interactions between patients and investigators. Registry data provide new insights into the burdens of DM and FSHD, such as, psychological problems and reduced employment. Opportunities abound for investigators to utilize Registry resources to assess the impact of these and other burdens on health care costs, progression of symptoms, and quality of life. PMID:22155025

  3. Bimaxillary Osteotomy for Jaw Deformity With Facioscapulohumeral Muscular Dystrophy.

    PubMed

    Kawasaki, Takako; Ohba, Seigo; Fujimura, Yuji; Asahina, Izumi

    2016-05-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a subtype of muscular dystrophies which reduces the muscle strength, especially the regions of scapular, shoulder, and upper arms, progressively. According to progressive muscle weakness in FSHD, postoperative stability of patient with FSHD after orthognathic surgery is not reliably acquired same as healthy subjects. A 32-year-old woman with FSHD underwent orthodontic and orthognathic surgical treatment due to jaw deformity. She has been followed up more than 3 years after surgery and acquired skeletal stability. This patient is the first report that showed long-term skeletal stability after orthognathic surgery in patient with FSHD. This patient report suggests that it is possible to apply orthognathic surgical treatment to patients with FSHD. PMID:27054436

  4. Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation

    PubMed Central

    van der Maarel, Silvère M.; Miller, Daniel G.; Tawil, Rabi; Filippova, Galina N.; Tapscott, Stephen J.

    2013-01-01

    Purpose of review In recent years we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder. Recent findings In the majority of cases FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occurs in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements. Summary Recent studies have provided a plausible disease mechanism for FSHD where FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies. PMID:22892954

  5. Whole-body MRI evaluation of facioscapulohumeral muscular dystrophy

    PubMed Central

    Leung, Doris G.; Carrino, John A.; Wagner, Kathryn R.; Jacobs, Michael A.

    2015-01-01

    Introduction Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary disorder that causes progressive muscle wasting. Increasing knowledge of the pathophysiology of FSHD has stimulated interest in developing biomarkers of disease severity. Methods Two groups of MRI scans were analyzed: whole-body scans from 13 subjects with FSHD, and upper and lower extremity scans from 34 subjects with FSHD who participated in the MYO-029 clinical trial. Muscles were scored for fat infiltration and edema-like changes. Fat infiltration scores were compared to muscle strength and function. Results Our analysis reveals a distinctive pattern of both frequent muscle involvement and frequent sparing in FSHD. Averaged fat infiltration scores for muscle groups in the legs correlated with quantitative muscle strength and 10-meter walk times. Discussion Advances in MRI technology allow for the acquisition of rapid, high-quality whole-body imaging in diffuse muscle disease. This technique offers a promising disease biomarker in FSHD and other muscle diseases. PMID:25641525

  6. Chronic Pain in Persons With Myotonic Dystrophy and Facioscapulohumeral Dystrophy

    PubMed Central

    Jensen, Mark P.; Hoffman, Amy J.; Stoelb, Brenda L.; Abresch, Richard T.; Carter, Gregory T.; McDonald, Craig M.

    2009-01-01

    Objective To determine the nature and scope of pain in working-aged adults with myotonic muscular dystrophy (MMD) and facioscapulohumeral muscular dystrophy (FSHD). Design Retrospective, cross-sectional survey. Setting Community-based survey. Participants Convenience sample of subjects with MMD and FSHD. Interventions Not applicable. Main Outcome Measures Overall intensity and duration of pain, pain inference, pain sites, pain treatments, and relief provided by pain treatments. Results More subjects with FSHD (82%) than with MMD (64%) reported pain. The most frequently reported pain sites for both diagnostic groups were lower back (66% MMD, 74% FSHD) and legs (60% MMD, 72% FSHD). Significant differences in pain intensity were found between the diagnostic groups in the hands, legs, knees, ankles, and feet, with patients with MMD reporting greater pain intensity at these sites than patients with FSHD. Age was related to the onset of pain (participants reporting pain were younger than those not reporting pain in the FSHD sample), but pain severity was not significantly associated with age in those reporting pain. Respondents with both diagnoses that reported mobility limitations and used assistive devices (eg, wheelchair, cane) reported more pain severity than those with mobility limitations who did not use assistive devices, who, in turn, reported more pain severity than respondents who reported no mobility limitations at all. The treatments that were reported to provide the greatest pain relief were not necessarily those that were the most frequently tried or still used. Conclusions The findings indicate that pain is a more common problem in persons with FSHD than in persons with MMD, although it is common in both populations. In addition, these pain problems are chronic, underscoring the need to identify and provide effective pain treatments for patients with these neuromuscular diseases. PMID:18226657

  7. Gene discovery for facioscapulohumeral muscular dystrophy by machine learning techniques.

    PubMed

    González-Navarro, Félix F; Belanche-Muñoz, Lluís A; Gámez-Moreno, María G; Flores-Ríos, Brenda L; Ibarra-Esquer, Jorge E; López-Morteo, Gabriel A

    2016-04-28

    Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder that shows a preference for the facial, shoulder and upper arm muscles. FSHD affects about one in 20-400,000 people, and no effective therapeutic strategies are known to halt disease progression or reverse muscle weakness or atrophy. Many genes may be incorrectly regulated in affected muscle tissue, but the mechanisms responsible for the progressive muscle weakness remain largely unknown. Although machine learning (ML) has made significant inroads in biomedical disciplines such as cancer research, no reports have yet addressed FSHD analysis using ML techniques. This study explores a specific FSHD data set from a ML perspective. We report results showing a very promising small group of genes that clearly separates FSHD samples from healthy samples. In addition to numerical prediction figures, we show data visualizations and biological evidence illustrating the potential usefulness of these results. PMID:26960968

  8. Patient Identified Disease Burden in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Johnson, Nicholas E; Quinn, Christine; Eastwood, Eileen; Tawil, Rabi; Heatwole, Chad R

    2013-01-01

    Introduction The multitude of symptoms associated with facioscapulohumeral muscular dystrophy (FSHD) disease burden are of varying importance. The extent of these symptoms and their cumulative effect on the FSHD population is unknown. Methods We conducted interviews with adult FSHD patients to identify which symptoms have the greatest effect on their lives. Each interview was recorded, transcribed, coded, and analyzed using a qualitative framework technique, triangulation, and 3-investigator consensus approach. Results 1375 quotes were obtained through 20 patient interviews. 251 symptoms of importance were identified representing 14 themes of FSHD disease burden. Symptoms associated with mobility impairment, activity limitation, and social role limitation were most frequently mentioned by participants. Conclusions There are multiple themes and symptoms, some previously under-recognized, that play a key role in FSHD disease burden. PMID:23225386

  9. Pulsed-field gel electrophoresis of the D4F104S1 locus reveals the size and the parental origin of the facioscapulohumeral muscular dystrophy (FSHD)-associated deletions

    SciTech Connect

    Wijmenga, C.; Deutekom, J.C.T. van; Padberg, G.W.; Van Ommen, G.J.B.; Hofker, M.H.; Frants, R.R. ); Hewitt, J.E. )

    1994-01-01

    Recently, probe p13E-11 (D4F104S1) was shown to identify de novo DNA rearrangements, which are associated with the development of facioscapulohumeral muscular dystrophy (FSHD). These rearrangements are likely to become instrumental in cloning the FSHD gene itself. Analysis by pulsed-field gel electrophoresis demonstrates that p13E-11 recognizes two highly polymorphic loci, with HindIII restriction fragments ranging in size from about 30 to 320 kb. Haplotype analysis unambiguously assigned one of the two loci to chromosome 4q35. The detection of identical NotI or NruI fragments with both CEB8 (D4F35S1) and p13E-11 demonstrated that the DNA rearrangements are deletions that are restricted to the HindIII fragments detectable by p13E-11. In two cases, the sizes of the deletion could be established and were found to be 25 and 85 kb in length, respectively. So far, the authors have been able to define the parental origin of the mutation in seven different patients and have found that in five cases the maternal allele was involved. 22 refs., 4 figs., 1 tab.

  10. FSHD: copy number variations on the theme of muscular dystrophy

    PubMed Central

    Cabianca, Daphne Selvaggia

    2010-01-01

    In humans, copy number variations (CNVs) are a common source of phenotypic diversity and disease susceptibility. Facioscapulohumeral muscular dystrophy (FSHD) is an important genetic disease caused by CNVs. It is an autosomal-dominant myopathy caused by a reduction in the copy number of the D4Z4 macrosatellite repeat located at chromosome 4q35. Interestingly, the reduction of D4Z4 copy number is not sufficient by itself to cause FSHD. A number of epigenetic events appear to affect the severity of the disease, its rate of progression, and the distribution of muscle weakness. Indeed, recent findings suggest that virtually all levels of epigenetic regulation, from DNA methylation to higher order chromosomal architecture, are altered at the disease locus, causing the de-regulation of 4q35 gene expression and ultimately FSHD. PMID:21149563

  11. Immunohistochemical Characterization of Facioscapulohumeral Muscular Dystrophy Muscle Biopsies

    PubMed Central

    Statland, Jeffrey M; Odrzywolski, Karen J; Shah, Bharati; Henderson, Don; Fricke, Alex F.; van der Maarel, Silvère M; Tapscott, Stephen J; Tawil, Rabi

    2015-01-01

    Background Posited pathological mechanisms in Facioscapulohumeral Muscular Dystrophy (FSHD) include activation in somatic tissue of normally silenced genes, increased susceptibility to oxidative stress, and induction of apoptosis. Objective To determine the histopathological changes in FSHD muscle biopsies and compare to possible pathological mechanisms of disease. Methods We performed a cross-sectional study on quadriceps muscle biopsies from 32 genetically confirmed FSHD participants, compared to healthy volunteers and myotonic dystrophy type 1 as disease controls. Biopsies were divided into groups to evaluate apoptosis rates, capillary density, myonuclear and satellite cell counts. Results Apoptosis rates were increased in FSHD (n=10, 0.74%) compared to myotonic dystrophy type 1 (n=10, 0.14%, P=0.003) and healthy volunteers (n=14, 0.13%, P=0.002). Apoptosis was higher in FSHD patients with the smallest residual D4Z4 fragments. Capillary density was decreased in FSHD1 (n=10, 316 capillaries/mm2) compared to healthy volunteers (n=15, 448 capillaries/mm2, P=0.001). No differences were seen in myonuclear or satellite cell counts. Conclusions Preliminary evidence for increased apoptosis rates and reduced capillary density may reflect histopathological correlates of disease activity in FSHD. The molecular-pathological correlates to these changes warrants further investigation. PMID:26345300

  12. Decreased Nocturnal Movements in Patients with Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Marca, Giacomo Della; Frusciante, Roberto; Dittoni, Serena; Vollono, Catello; Losurdo, Anna; Testani, Elisa; Scarano, Emanuele; Colicchio, Salvatore; Iannaccone, Elisabetta; Tonali, Pietro A.; Ricci, Enzo

    2010-01-01

    Study Objectives: Reduced mobility during sleep characterizes a variety of movement disorders and neuromuscular diseases. Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular dystrophy in the general population, and people with FSHD have poor sleep quality. The aims of the present study were to evaluate nocturnal motor activity in patients with FSHD by means of videopolysomnography and to verify whether activity was associated with modifications in sleep structure. Methods: We enrolled 32 adult patients affected by genetically confirmed FSHD (18 women and 14 men, mean age 45.1 ± 13.4 years) and 32 matched control subjects, (18 women and 14 men, mean age 45.5 ± 11.4 years). Major body movements (MBM) were scored in videopolygraphic recordings in accordance with established criteria. An MBM index was calculated (number of MBM per hour of sleep). Results: The FSHD group showed a decrease in the MBM index (FSHD: 1.2 ± 1.1; control subjects: 2.3 ± 1.2, analysis of variance F = 13.672; p = 0.008). The sleep pattern of patients with FSHD, as compared with that of controls, was characterized by longer sleep latencies, shorter sleep durations, an increased percentage of wake during sleep, and a decreased percentage of rapid eye movement sleep. In the patient group, the MBM index was inversely correlated with severity of disease (Spearman test: r30 = −0.387; p < 0.05). Conclusions: The present findings suggest that patients with FSHD have a reduced number of nocturnal movements, which is related to disease severity. Reduced movement in bed may contribute to the sleep modifications observed in these patients. Citation: Marca GD; Frusciante R; Dittoni S; Vollono C; Losurdo A; Testani E; Scarano E; Colicchio S; Iannaccone E; Tonali PA; Ricci E. Decreased nocturnal movements in patients with facioscapulohumeral muscular dystrophy. J Clin Sleep Med 2010;6(3):276-280. PMID:20572422

  13. Facioscapulohumeral muscular dystrophy and respiratory failure; what about the diaphragm?

    PubMed Central

    Hazenberg, A.; van Alfen, N.; Voet, N.B.M.; Kerstjens, H.A.M.; Wijkstra, P.J.

    2014-01-01

    Introduction We present a case of facioscapulohumeral muscular dystrophy (FSHD) with a diaphragm paralysis as the primary cause of ventilatory failure. FSHD is an autosomal dominant inherited disorder with a restricted pattern of weakness. Although respiratory weakness is a relatively unknown in FSHD, it is not uncommon. Methods We report on the clinical findings of a 68-year old male who presented with severe dyspnea while supine. Results Supplementing our clinical findings with laboratory, electrophysiological and radiological performances led to the diagnosis of diaphragm paralysis. Arterial blood gas in sitting position without supplemental oxygen showed a mild hypercapnia. His sleep improved after starting non-invasive ventilation and his daytime sleepiness disappeared. Discussion We conclude that in patients with FSHD who have symptoms of nocturnal hypoventilation, an adequate assessment of the diaphragm is recommended. This is of great importance as we know that nocturnal hypoventilation can be treated effectively by non-invasive ventilation. PMID:26029575

  14. A radiation hybrid map of 15 loci on the distal long arm of chromosome 4, the region containing the gene responsible for facioscapulohumeral muscular dystrophy (FSHD)

    SciTech Connect

    Winokur, S.T.; Wasmuth, J.H. ); Schutte, B. ); Weiffenbach, B. ); Washington, S.S.; Chakravarti, A. ); McElligot, D. ); Altherr, M.R. Los Alamos National Lab., NM )

    1993-10-01

    A physical map of 4q35 was constructed through radiation hybrid analysis of 134 clones generated from the cell line HHW416, a chromosome 4-only human-hamster somatic cell hybrid. This subtelomeric region contains the as-yet-unidentified gene responsible for facioscapulohumeral muscular dystrophy. The most likely order of 15 loci within 4q35 was determined. The loci ordered on this radiation hybrid map include both genes and polymorphic loci, as well as monomorphic loci which cannot be placed on a genetic linkage map. The physical distance spanning these loci was estimated to be approximately 4.5 Mb, by using a kilobase/centiray conversion factor derived from 4p16.3 marker analysis through the same set of radiation hybrids. The comparison of this physical map to established genetic maps suggests that this region is smaller than initially estimated and that recombination rates are increased near the telomere. 37 refs., 2 figs., 2 tabs.

  15. Population-based incidence and prevalence of facioscapulohumeral dystrophy

    PubMed Central

    Arnts, Hisse; van der Maarel, Silvère M.; Padberg, George W.; Verschuuren, Jan J.G.M.; Bakker, Egbert; Weinreich, Stephanie S.; Verbeek, André L.M.; van Engelen, Baziel G.M.

    2014-01-01

    Objective: To determine the incidence and prevalence of facioscapulohumeral muscular dystrophy (FSHD) in the Netherlands. Methods: Using 3-source capture-recapture methodology, we estimated the total yearly number of newly found symptomatic individuals with FSHD, including those not registered in any of the 3 sources. To this end, symptomatic individuals with FSHD were available from 3 large population-based registries in the Netherlands if diagnosed within a 10-year period (January 1, 2001 to December 31, 2010). Multiplication of the incidence and disease duration delivered the prevalence estimate. Results: On average, 52 people are newly diagnosed with FSHD every year. This results in an incidence rate of 0.3/100,000 person-years in the Netherlands. The prevalence rate was 12/100,000, equivalent to 2,000 affected individuals. Conclusions: We present population-based incidence and prevalence estimates regarding symptomatic individuals with FSHD, including an estimation of the number of symptomatic individuals not present in any of the 3 used registries. This study shows that the total number of symptomatic persons with FSHD in the population may well be underestimated and a considerable number of affected individuals remain undiagnosed. This suggests that FSHD is one of the most prevalent neuromuscular disorders. PMID:25122204

  16. Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears

    PubMed Central

    G, Ricci; M, Zatz; R, Tupler

    2014-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) has been classified as an autosomal dominant myopathy, linked to rearrangements in an array of 3.3 kb tandemly repeated DNA elements (D4Z4) located at the 4q subtelomere (4q35). For the last 20 years, the diagnosis of FSHD has been confirmed in clinical practice by the detection of one D4Z4 allele with a reduced number (≤8) of repeats at 4q35. Although wide inter- and intra-familial clinical variability was found in subjects carrying D4Z4 alleles of reduced size, this DNA testing has been considered highly sensitive and specific. However, several exceptions to this general rule have been reported. Specifically, FSHD families with asymptomatic relatives carrying D4Z4 reduced alleles, FSHD genealogies with subjects affected with other neuromuscular disorders and FSHD affected patients carrying D4Z4 alleles of normal size have been described. In order to explain these findings, it has been proposed that the reduction of D4Z4 repeats at 4q35 could be pathogenic only in certain chromosomal backgrounds, defined as “permissive” specific haplotypes. However, our most recent studies show that the current DNA signature of FSHD is a common polymorphism and that in FSHD families the risk of developing FSHD for carriers of D4Z4 reduced alleles (DRA) depends on additional factors besides the 4q35 locus. These findings highlight the necessity to re-evaluate the significance and the predictive value of DRA, not only for research but also in clinical practice. Further clinical and genetic analysis of FSHD families will be extremely important for studies aiming at dissecting the complexity of FSHD.

  17. Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers

    PubMed Central

    Rahimov, Fedik; King, Oliver D.; Leung, Doris G.; Bibat, Genila M.; Emerson, Charles P.; Kunkel, Louis M.; Wagner, Kathryn R.

    2012-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder caused by contractions of repetitive elements within the macrosatellite D4Z4 on chromosome 4q35. The pathophysiology of FSHD is unknown and, as a result, there is currently no effective treatment available for this disease. To better understand the pathophysiology of FSHD and develop mRNA-based biomarkers of affected muscles, we compared global analysis of gene expression in two distinct muscles obtained from a large number of FSHD subjects and their unaffected first-degree relatives. Gene expression in two muscle types was analyzed using GeneChip Gene 1.0 ST arrays: biceps, which typically shows an early and severe disease involvement; and deltoid, which is relatively uninvolved. For both muscle types, the expression differences were mild: using relaxed cutoffs for differential expression (fold change ≥1.2; nominal P value <0.01), we identified 191 and 110 genes differentially expressed between affected and control samples of biceps and deltoid muscle tissues, respectively, with 29 genes in common. Controlling for a false-discovery rate of <0.25 reduced the number of differentially expressed genes in biceps to 188 and in deltoid to 7. Expression levels of 15 genes altered in this study were used as a “molecular signature” in a validation study of an additional 26 subjects and predicted them as FSHD or control with 90% accuracy based on biceps and 80% accuracy based on deltoids. PMID:22988124

  18. What's in a name? The clinical features of facioscapulohumeral muscular dystrophy.

    PubMed

    Mul, Karlien; Lassche, Saskia; Voermans, Nicol C; Padberg, George W; Horlings, Corinne Gc; van Engelen, Baziel Gm

    2016-06-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an inherited and progressive muscle disorder. Although its name suggests otherwise, it comprises weakness of the facial, shoulder and upper arm muscles, and also of the trunk and leg muscles. Its severity and disease course vary greatly and mild or early FSHD can be difficult to recognise. Knowledge of its subtle signs and symptoms can lead directly to the correct diagnosis without diagnostic delay and without needing multiple diagnostic procedures. We give an overview of the signs and symptoms of FSHD in severe as well as in mild cases, to facilitate correct and instant recognition of this relatively common muscle disorder. PMID:26862222

  19. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy

    PubMed Central

    Tawil, Rabi; Kissel, John T.; Heatwole, Chad; Pandya, Shree; Gronseth, Gary; Benatar, Michael

    2015-01-01

    Objective: To develop recommendations for the evaluation, diagnosis, prognostication, and treatment of facioscapulohumeral muscular dystrophy (FSHD) from a systematic review and analysis of the evidence. Methods: Relevant articles were analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and treatment studies. Recommendations were linked to the strength of the evidence and other factors. Results and recommendations: Available genetic testing for FSHD type 1 is highly sensitive and specific. Although respiratory insufficiency occurs rarely in FSHD, patients with severe FSHD should have routine pulmonary function testing. Routine cardiac screening is not necessary in patients with FSHD without cardiac symptoms. Symptomatic retinal vascular disease is very rare in FSHD. Exudative retinopathy, however, is potentially preventable, and patients with large deletions should be screened through dilated indirect ophthalmoscopy. The prevalence of clinically relevant hearing loss is not clear. In clinical practice, patients with childhood-onset FSHD may have significant hearing loss. Because undetected hearing loss may impair language development, screening through audiometry is recommended for such patients. Musculoskeletal pain is common in FSHD and treating physicians should routinely inquire about pain. There is at present no effective pharmacologic intervention in FSHD. Available studies suggest that scapular fixation is safe and effective. Surgical scapular fixation might be cautiously offered to selected patients. Aerobic exercise in FSHD appears to be safe and potentially beneficial. On the basis of the evidence, patients with FSHD might be encouraged to engage in low-intensity aerobic exercises. PMID:26215877

  20. Computer-based assessment for facioscapulohumeral dystrophy diagnosis.

    PubMed

    Chambers, O; Milenković, J; Pražnikar, A; Tasič, J F

    2015-06-01

    The paper presents a computer-based assessment for facioscapulohumeral dystrophy (FSHD) diagnosis through characterisation of the fat and oedema percentages in the muscle region. A novel multi-slice method for the muscle-region segmentation in the T1-weighted magnetic resonance images is proposed using principles of the live-wire technique to find the path representing the muscle-region border. For this purpose, an exponential cost function is used that incorporates the edge information obtained after applying the edge-enhancement algorithm formerly designed for the fingerprint enhancement. The difference between the automatic segmentation and manual segmentation performed by a medical specialists is characterised using the Zijdenbos similarity index, indicating a high accuracy of the proposed method. Finally, the fat and oedema are quantified from the muscle region in the T1-weighted and T2-STIR magnetic resonance images, respectively, using the fuzzy c-mean clustering approach for 10 FSHD patients. PMID:25910520

  1. FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1).

    PubMed

    Feeney, Sandra J; McGrath, Meagan J; Sriratana, Absorn; Gehrig, Stefan M; Lynch, Gordon S; D'Arcy, Colleen E; Price, John T; McLean, Catriona A; Tupler, Rossella; Mitchell, Christina A

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1. PMID:25695429

  2. FHL1 Reduces Dystrophy in Transgenic Mice Overexpressing FSHD Muscular Dystrophy Region Gene 1 (FRG1)

    PubMed Central

    Feeney, Sandra J.; McGrath, Meagan J.; Sriratana, Absorn; Gehrig, Stefan M.; Lynch, Gordon S.; D’Arcy, Colleen E.; Price, John T.; McLean, Catriona A.; Tupler, Rossella; Mitchell, Christina A.

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1. PMID:25695429

  3. Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics

    PubMed Central

    Chen, Jennifer CJ; King, Oliver D; Zhang, Yuanfan; Clayton, Nicholas P; Spencer, Carrie; Wentworth, Bruce M; Emerson, Charles P; Wagner, Kathryn R

    2016-01-01

    Derepression of DUX4 in skeletal muscle has emerged as a likely cause of pathology in facioscapulohumeral muscular dystrophy (FSHD). Here we report on the use of antisense phosphorodiamidate morpholino oligonucleotides to suppress DUX4 expression and function in FSHD myotubes and xenografts. The most effective was phosphorodiamidate morpholino oligonucleotide FM10, which targets the polyadenylation signal of DUX4. FM10 had no significant cell toxicity, and RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Electroporation of FM10 into FSHD patient muscle xenografts in mice also down-regulated DUX4 and DUX4 targets. These findings demonstrate the potential of antisense phosphorodiamidate morpholino oligonucleotides as an FSHD therapeutic option. PMID:27378237

  4. Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics.

    PubMed

    Chen, Jennifer Cj; King, Oliver D; Zhang, Yuanfan; Clayton, Nicholas P; Spencer, Carrie; Wentworth, Bruce M; Emerson, Charles P; Wagner, Kathryn R

    2016-08-01

    Derepression of DUX4 in skeletal muscle has emerged as a likely cause of pathology in facioscapulohumeral muscular dystrophy (FSHD). Here we report on the use of antisense phosphorodiamidate morpholino oligonucleotides to suppress DUX4 expression and function in FSHD myotubes and xenografts. The most effective was phosphorodiamidate morpholino oligonucleotide FM10, which targets the polyadenylation signal of DUX4. FM10 had no significant cell toxicity, and RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Electroporation of FM10 into FSHD patient muscle xenografts in mice also down-regulated DUX4 and DUX4 targets. These findings demonstrate the potential of antisense phosphorodiamidate morpholino oligonucleotides as an FSHD therapeutic option. PMID:27378237

  5. Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

    PubMed Central

    Himeda, Charis L.; Jones, Takako I.

    2015-01-01

    Abstract Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression. Recent Advances: In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD. Critical Issues: Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets? Future Directions: Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies. Antioxid. Redox Signal. 22, 1463–1482. PMID:25336259

  6. Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2

    PubMed Central

    Mitsuhashi, Satomi; Boyden, Steven E; Estrella, Elicia A; Jones, Takako I; Rahimov, Fedik; Yu, Timothy W; Darras, Basil T; Amato, Anthony A; Folkerth, Rebecca D; Jones, Peter L; Kunkel, Louis M; Kang, Peter B

    2013-01-01

    FSHD2 is a rare form of facioscapulohumeral muscular dystrophy (FSHD) characterized by the absence of a contraction in the D4Z4 macrosatellite repeat region on chromosome 4q35 that is the hallmark of FSHD1. However, hypomethylation of this region is common to both subtypes. Recently, mutations in SMCHD1 combined with a permissive 4q35 allele were reported to cause FSHD2. We identified a novel p.Lys275del SMCHD1 mutation in a family affected with FSHD2 using whole-exome sequencing and linkage analysis. This mutation alters a highly conserved amino acid in the ATPase domain of SMCHD1. Subject III-11 is a male who developed asymmetrical muscle weakness characteristic of FSHD at 13 years. Physical examination revealed marked bilateral atrophy at biceps brachii, bilateral scapular winging, some asymmetrical weakness at tibialis anterior and peroneal muscles, and mild lower facial weakness. Biopsy of biceps brachii in subject II-5, the father of III-11, demonstrated lobulated fibers and dystrophic changes. Endomysial and perivascular inflammation was found, which has been reported in FSHD1 but not FSHD2. Given the previous report of SMCHD1 mutations in FSHD2 and the clinical presentations consistent with the FSHD phenotype, we conclude that the SMCHD1 mutation is the likely cause of the disease in this family. PMID:24128691

  7. Reevaluating Measures of Disease Progression in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Statland, Jeffrey M.; McDermott, Michael P.; Heatwole, Chad; Martens, William B.; Pandya, Shree; van der Kooi, E.L.; Kissel, John T.; Wagner, Kathryn R.; Tawil, Rabi

    2013-01-01

    Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials. PMID:23406877

  8. Determining the role of sarcomeric proteins in facioscapulohumeral muscular dystrophy: a study protocol

    PubMed Central

    2013-01-01

    Background Although muscle weakness is a hallmark of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms that lead to weakness in FSHD remain largely unknown. Recent studies suggest aberrant expression of genes involved in skeletal muscle development and sarcomere contractility, and activation of pathways involved in sarcomeric protein degradation. This study will investigate the contribution of sarcomeric protein dysfunction to the pathogenesis of muscle weakness in FSHD. Methods/Design Evaluation of sarcomeric function using skinned single muscle fiber contractile studies and protein analysis in muscle biopsies (quadriceps femoris and tibialis anterior) from patients with FSHD and age- and gender-matched healthy controls. Patients with other forms of muscular dystrophy and inflammatory myopathy will be included as disease controls to assess whether results are due to changes specific for FSHD, or a consequence of muscle disease in general. A total of 56 participants will be included. Extensive clinical parameters will be measured using MRI, quantitative muscle studies and physical activity assessments. Discussion This study is the first to extensively investigate muscle fiber physiology in FSHD following an earlier pilot study suggesting sarcomeric dysfunction in FSHD. The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention. PMID:24119284

  9. Facioscapulohumeral muscular dystrophy presenting with isolated axial myopathy and bent spine syndrome.

    PubMed

    Kottlors, Michael; Kress, Wolfram; Meng, Gerhard; Glocker, Franz X

    2010-08-01

    Several subtypes of facioscapulohumeral muscular dystrophy (FSHD) with atypical clinical presentation have been described. We report a new, distinct phenotype with progressive bent spine syndrome solely affecting the paraspinal muscles. Magnetic resonance imaging study of the lumbar spine revealed marked atrophy of the paraspinal muscles. The diagnosis was confirmed by DNA testing, which revealed shortened restriction fragments of the D4Z4 repeat on haplotype A in connection with a positive family history. PMID:20658601

  10. Facioscapulohumeral dystrophy myoblasts efficiently repair moderate levels of oxidative DNA damage.

    PubMed

    Bou Saada, Yara; Dib, Carla; Dmitriev, Petr; Hamade, Aline; Carnac, Gilles; Laoudj-Chenivesse, Dalila; Lipinski, Marc; Vassetzky, Yegor S

    2016-04-01

    Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy linked to a deletion of a subset of D4Z4 macrosatellite repeats accompanied by a chromatin relaxation of the D4Z4 array on chromosome 4q. In vitro, FSHD primary myoblasts show altered expression of oxidative-related genes and are more susceptible to oxidative stress. Double homeobox 4 (DUX4) gene, encoded within each D4Z4 unit, is normally transcriptionally silenced but is found aberrantly expressed in skeletal muscles of FSHD patients. Its expression leads to a deregulation of DUX4 target genes including those implicated in redox balance. Here, we assessed DNA repair efficiency of oxidative DNA damage in FSHD myoblasts and DUX4-transfected myoblasts. We have shown that the DNA repair activity is altered neither in FSHD myoblasts nor in immortalized human myoblasts transiently expressing DUX4. DNA damage caused by moderate doses of an oxidant is efficiently repaired while FSHD myoblasts exposed for 24 h to high levels of oxidative stress accumulated more DNA damage than normal myoblasts, suggesting that FSHD myoblasts remain more vulnerable to oxidative stress at high doses of oxidants. PMID:26860865

  11. Oxidative stress and dystrophy Facioscapulohumeral: Effects of vitamin C, vitamin E, zinc gluconate and selenomethionine supplementation.

    PubMed

    Emilie, Passerieux; Maurice, Hayot; Gilles, Carnac; Joel, Pincemail; Jacques, Mercier; Dalila, Chenivesse

    2014-10-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease characterized by progressive weakness and atrophy of specific skeletal muscles. Despite major progress in the understanding of the genetic basis of FSHD, the exact mechanisms that lead to FSHD defects are not completely understood and no curative treatment is available. However, there is growing evidence that oxidative stress may contribute to FSHD pathology. We recently reported that reduced physical performance in patients with FSHD is associated with important redox unbalance and oxidative stress in blood. Hence, we hypothesized that insufficient intake of antioxidant vitamins and minerals may reduce the body capacity to regulate free radical insults, leading to a condition known as oxidative stress that could affect muscle function performance in patients with FSHD. We thus conducted a pilot randomized double-blind placebo-controlled study to test whether oral administration of vitamins and minerals could improve the physical performance of patients with FSHD. The results of this randomized double-blind placebo-controlled trial show that supplementation with vitamin C, vitamin E (as alpha tocopherol), zinc gluconate and selenomethionine in patients with FSHD significantly improves the maximal voluntary contraction and endurance of both quadriceps by enhancing the antioxidants defences and reducing oxidative stress. PMID:26461290

  12. β-Catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy.

    PubMed

    Banerji, Christopher R S; Knopp, Paul; Moyle, Louise A; Severini, Simone; Orrell, Richard W; Teschendorff, Andrew E; Zammit, Peter S

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring (InSpiRe), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe, we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified β-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-α and TNF-α clearly perturbed. To detect transcriptional changes directly elicited by DUX4, gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/β-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development.

  13. β-catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy

    PubMed Central

    Banerji, Christopher R. S.; Knopp, Paul; Moyle, Louise A.; Severini, Simone; Orrell, Richard W.; Teschendorff, Andrew E.; Zammit, Peter S.

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring (InSpiRe), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe, we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified β-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-α and TNF-α clearly perturbed. To detect transcriptional changes directly elicited by DUX4, gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/β-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development. PMID:25551153

  14. Genetics Home Reference: facioscapulohumeral muscular dystrophy

    MedlinePlus

    ... Padberg GW, Lunt PW, van der Maarel SM. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: ... Reviewed : August 2014 Published : August 30, 2016 The resources on this site should not be used as a ... of Health & Human Services National Institutes of Health National Library of ...

  15. Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome.

    PubMed

    Lemmers, Richard J L F; van den Boogaard, Marlinde L; van der Vliet, Patrick J; Donlin-Smith, Colleen M; Nations, Sharon P; Ruivenkamp, Claudia A L; Heard, Patricia; Bakker, Bert; Tapscott, Stephen; Cody, Jannine D; Tawil, Rabi; van der Maarel, Silvère M

    2015-07-01

    Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD. PMID:25820463

  16. Hemizygosity for SMCHD1 in facioscapulohumeral muscular dystrophy type 2: Consequences for 18p deletion syndrome

    PubMed Central

    Lemmers, Richard J.L.F.; van den Boogaard, Marlinde L.; van der Vliet, Patrick J.; Donlin-Smith, Colleen M.; Nations, Sharon P.; Ruivenkamp, Claudia A.L.; Heard, Patricia; Bakker, Bert; Tapscott, Stephen; Cody, Jannine D.; Tawil, Rabi; van der Maarel, Silvère M.

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4 repeat array. The most common form, FSHD1, is caused by a D4Z4 repeat array contraction to a size of 1-10 units (normal range 10–100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss of function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here we describe two FSHD2 families with a 1.2 Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, like these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD. PMID:25820463

  17. Phenotypic and pathologic evaluation of the myd mouse. A candidate model for facioscapulohumeral dystrophy

    SciTech Connect

    Mathews, K.D.; Rapisarda, D.; Bailey, H.L.

    1995-07-01

    Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease of unknown pathogenesis which is characterized by weakness of the face and shoulder girdle. It is associated with a sensorineural hearing loss which may be subclinical. FSHD has been mapped to the distalmost portion of 4q35, although the gene has not yet been identified. Distal 4q has homology with a region of mouse chromosome 8 to which a mouse mutant, myodystrophy (myd), has been mapped. Muscle from homozygotes for the myd mutation appears dystrophic, showing degenerating and regenerating fibers, inflammatory infiltrates, central nuclei, and variation in fiber size. Brainstem auditory evoked potentials reveal a sensorineural hearing loss in myd homozygotes. Based on the homologous genetic map locations, and the phenotypic syndrome of dystrophic muscle with sensorineural hearing loss, we suggest that myd represents an animal model for the human disease FSHD. 28 refs., 4 figs.

  18. High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms

    PubMed Central

    van Dijk, Gaby Pons; van der Kooi, Elly; Behin, Anthony; Smeets, Joep; Timmermans, Janneke; van der Maarel, Silvère; Padberg, George; Voermans, Nicol; van Engelen, Baziel

    2014-01-01

    Summary The exact prevalence and nature of cardiac involvement in facioscapulohumeral muscular dystrophy (FSHD) is unknown. Nevertheless, the current opinion is that symptomatic cardiac disease is rare. We performed a cardiac screening [electrocardiogram (ECG) and echocardiography in the event of ECG abnormalities] in 75 genetically confirmed, ambulant FSHD patients without cardiac symptoms, with an eight-year follow-up of 57 patients, and compared the findings with results of previously performed cardiac screenings in the normal population. Baseline ECG demonstrated incomplete right bundle branch block (RBBB) in 33%, complete RBBB in 4%, and other minor abnormalities in 16%. Echocardiography showed no abnormalities. No significant changes were found after eight years of follow-up. Comparison with ECG abnormalities in the normal population showed a higher prevalence of incomplete RBBB (9.7 times higher) and of complete RBBB (4.8 times higher) in FSHD patients. This study in cardiac asymptomatic FSHD patients shows i) increased prevalence of incomplete RBBB in the absence of cardiomyopathy; ii) no progression of these abnormalities during eight years of follow-up. We conclude that FSHD patients without cardiac complaints do not need specific cardiac screening or surveillance. Furthermore, the increased prevalence of incomplete RBBB in the absence of cardiomyopathy suggests a selective involvement of the His-Purkinje system in FSHD. PMID:25473735

  19. Symptom Burden in Persons with Myotonic and Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Smith, Amanda E.; McMullen, Kara; Jensen, Mark P.; Carter, Gregory T.; Molton, Ivan R.

    2013-01-01

    Objective This study examines the prevalence of pain, fatigue, imbalance, memory impairment and vision loss in persons with myotonic and facioscapulohumeral dystrophy, and their association with functioning. Design A survey (n=170) included measures of severity (0–10 scales) and course of these symptoms, as well as measures of social integration, home competency, mental health and productive activity. Descriptive and regression analyses examined the associations between symptoms and functioning. Results Fatigue (91%), imbalance (82%) and pain (77%) were most commonly reported. The most severe symptom was fatigue (mean severity 5.14 ± 2.81), followed by imbalance (4.95 ± 3.25). Symptoms were most likely to stay the same or worsen since onset. Controlling for potential medical and demographic confounds, symptoms were associated with 17% of the mental health variance, 10% of home competency, 10% of social integration, 16% of productive activity for DM1 and 12% of productive activity for FSHD. Conclusions Pain, fatigue and imbalance are common in persons with muscular dystrophy. Interventions may be useful to mitigate their impact on functioning. Further research should examine these relationships to guide clinical practices. PMID:24247759

  20. High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families.

    PubMed Central

    Zatz, M; Marie, S K; Passos-Bueno, M R; Vainzof, M; Campiotto, S; Cerqueira, A; Wijmenga, C; Padberg, G; Frants, R

    1995-01-01

    A gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has been localized at 4q35. Subsequently, it was found that probe p13E-11 detects a polymorphic EcoRI fragment, usually > 28 kb, in normal individuals, whereas in sporadic and familial FSHD cases, an EcoRI fragment, usually < 28 kb, was found. Although these findings have been amply confirmed, several aspects are as yet either controversial or unsolved. In the present investigation, 34 Brazilian FSHD families were studied at the clinical and the molecular level for the following purposes: to assess the frequency of new mutations and their effect on estimates of biological fitness, to characterize FSHD-associated EcoRI fragments detected with probe p13E-11 in familial--as compared with isolated--FSHD cases, and to assess whether anticipation occurs in multigenerational families. Results from our study suggest that new mutations are apparently frequent for FSHD and may account for at least one-third of the cases, that somatic mosaicism may not be rare, and that biological fitness appeared to be reduced in FSHD, ranging from 0.6 to 0.82 by different estimates, with no difference in sexes. Interestingly, the size of the new EcoRI fragment is apparently smaller in more severely affected isolated patients. Moreover, the age at onset of clinical signs, as well as the age at ascertainment, in patients from multigenerational families suggests that anticipation occurs for FSHD in the majority of the families. Images Figure 1 Figure 2 Figure 3 PMID:7825608

  1. Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy.

    PubMed

    Bao, Bo; Maruyama, Rika; Yokota, Toshifumi

    2016-08-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an inherited autosomal dominant disorder characterized clinically by progressive muscle degeneration. Currently, no curative treatment for this disorder exists. FSHD patients are managed through physiotherapy to improve function and quality of life. Over the last two decades, FSHD has been better understood as a disease genetically characterized by a pathogenic contraction of a subset of macrosatellite repeats on chromosome 4. Specifically, several studies support an FSHD pathogenesis model involving the aberrant expression of the double homeobox protein 4 (DUX4) gene. Hence, potential therapies revolving around inhibition of DUX4 have been explored. One of the potential treatment options is the use of effective antisense oligonucleotides (AOs) to knockdown expression of the myopathic DUX4 gene and its downstream molecules including paired-like homeodomain transcription factor 1 (PITX1). Success in the suppression of PITX1 expression has already been demonstrated systemically in vivo in recent studies. In this article, we will review the pathogenesis of FSHD and the latest research involving the use of antisense knockdown therapy. PMID:27672539

  2. Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy

    PubMed Central

    Bao, Bo; Maruyama, Rika; Yokota, Toshifumi

    2016-01-01

    Summary Facioscapulohumeral muscular dystrophy (FSHD) is an inherited autosomal dominant disorder characterized clinically by progressive muscle degeneration. Currently, no curative treatment for this disorder exists. FSHD patients are managed through physiotherapy to improve function and quality of life. Over the last two decades, FSHD has been better understood as a disease genetically characterized by a pathogenic contraction of a subset of macrosatellite repeats on chromosome 4. Specifically, several studies support an FSHD pathogenesis model involving the aberrant expression of the double homeobox protein 4 (DUX4) gene. Hence, potential therapies revolving around inhibition of DUX4 have been explored. One of the potential treatment options is the use of effective antisense oligonucleotides (AOs) to knockdown expression of the myopathic DUX4 gene and its downstream molecules including paired-like homeodomain transcription factor 1 (PITX1). Success in the suppression of PITX1 expression has already been demonstrated systemically in vivo in recent studies. In this article, we will review the pathogenesis of FSHD and the latest research involving the use of antisense knockdown therapy. PMID:27672539

  3. Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy

    PubMed Central

    Bao, Bo; Maruyama, Rika; Yokota, Toshifumi

    2016-01-01

    Summary Facioscapulohumeral muscular dystrophy (FSHD) is an inherited autosomal dominant disorder characterized clinically by progressive muscle degeneration. Currently, no curative treatment for this disorder exists. FSHD patients are managed through physiotherapy to improve function and quality of life. Over the last two decades, FSHD has been better understood as a disease genetically characterized by a pathogenic contraction of a subset of macrosatellite repeats on chromosome 4. Specifically, several studies support an FSHD pathogenesis model involving the aberrant expression of the double homeobox protein 4 (DUX4) gene. Hence, potential therapies revolving around inhibition of DUX4 have been explored. One of the potential treatment options is the use of effective antisense oligonucleotides (AOs) to knockdown expression of the myopathic DUX4 gene and its downstream molecules including paired-like homeodomain transcription factor 1 (PITX1). Success in the suppression of PITX1 expression has already been demonstrated systemically in vivo in recent studies. In this article, we will review the pathogenesis of FSHD and the latest research involving the use of antisense knockdown therapy.

  4. Impact of Biopsychosocial Factors on Chronic Pain in Persons With Myotonic and Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Miró, Jordi; Raichle, Katherine A.; Carter, Gregory T.; O’Brien, Sarah A.; Abresch, Richard T.; McDonald, Craig M.; Jensen, Mark P.

    2010-01-01

    To assess the role of biopsychosocial factors in patients with type 1 myotonic and facioscapulohumeral muscular dystrophy (MMD1/FSHD) with chronic pain. Associations between psychosocial factors were found to be important in other samples of persons with pain and both psychological functioning and pain interference in a sample of patients suffering from MMD/FSHD. Prospective, multiple group, survey study of 182 patients with confirmed MMD1 and FSHD. Participants completed surveys assessing pain interference and psychological functioning, as well as psychosocial, demographic, and injury-related variables. Analyses indicated that greater catastrophizing was associated with increased pain interference and poorer psychological functioning, pain attitudes were significantly related to both pain interference and psychological functioning, and coping responses were significantly related only to pain interference. In addition, greater perceived social support was associated with better psychological functioning. The results support the use of studying pain in persons with MMD/FSHD from a biopsychosocial perspective, and the importance of identifying psychosocial factors that may play a role in the adjustment to and response to pain secondary to MMD/FSHD. PMID:19414560

  5. Extension of the clinical range of facioscapulohumeral dystrophy: report of six cases

    PubMed Central

    van der Kooi, A J; Visser, M; Rosenberg, N; van den Berg-Vos, R; Wokke, J; Bakker, E; de Visser, M

    2000-01-01

    Consensual diagnostic criteria for facioscapulohumeral dystrophy (FSHD) include onset of the disease in facial or shoulder girdle muscles, facial weakness in more than 50% of affected family members, autosomal dominant inheritance in familial cases, and evidence of myopathic disease in at least one affected member without biopsy features specific to alternative diagnoses.
 Six patients did not meet most of these criteria but were diagnosed as FSHD by DNA testing, which showed small EcoRI fragments on chromosome 4q.
 Their clinical signs and symptoms and results of auxiliary investigations are reported. The patients presented with foot extensor, thigh, or calf muscle weakness. None of them had apparent facial weakness, only one complained of weakness in the shoulders, none had a positive family history. Expert physical examination, however, showed a typical facial expression, an abnormal shoulder configuration on lifting the arms, or scapular winging. This raised the suspicion of FSHD, whereupon DNA analysis was done. In conclusion, the clinical expression of FSHD is much broader than indicated by the nomenclature. The possibility to perform DNA tests is likely to greatly expand the clinical range of FSHD.

 PMID:10864616

  6. Impact of biopsychosocial factors on chronic pain in persons with myotonic and facioscapulohumeral muscular dystrophy.

    PubMed

    Miró, Jordi; Raichle, Katherine A; Carter, Gregory T; O'Brien, Sarah A; Abresch, Richard T; McDonald, Craig M; Jensen, Mark P

    2009-01-01

    To assess the role of biopsychosocial factors in patients with type 1 myotonic and facioscapulohumeral muscular dystrophy (MMD1/FSHD) with chronic pain. Associations between psychosocial factors were found to be important in other samples of persons with pain and both psychological functioning and pain interference in a sample of patients suffering from MMD/FSHD. Prospective, multiple group, survey study of 182 patients with confirmed MMD1 and FSHD. Participants completed surveys assessing pain interference and psychological functioning, as well as psychosocial, demographic, and injury-related variables. Analyses indicated that greater catastrophizing was associated with increased pain interference and poorer psychological functioning, pain attitudes were significantly related to both pain interference and psychological functioning, and coping responses were significantly related only to pain interference. In addition, greater perceived social support was associated with better psychological functioning. The results support the use of studying pain in persons with MMD/FSHD from a biopsychosocial perspective, and the importance of identifying psychosocial factors that may play a role in the adjustment to and response to pain secondary to MMD/FSHD. PMID:19414560

  7. Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers

    PubMed Central

    Arashiro, Patricia; Eisenberg, Iris; Kho, Alvin T.; Cerqueira, Antonia M. P.; Canovas, Marta; Silva, Helga C. A.; Pavanello, Rita C. M.; Verjovski-Almeida, Sergio; Kunkel, Louis M.; Zatz, Mayana

    2009-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disorder that has been associated with a contraction of 3.3-kb repeats on chromosome 4q35. FSHD is characterized by a wide clinical inter- and intrafamilial variability, ranging from wheelchair-bound patients to asymptomatic carriers. Our study is unique in comparing the gene expression profiles from related affected, asymptomatic carrier, and control individuals. Our results suggest that the expression of genes on chromosome 4q is altered in affected and asymptomatic individuals. Remarkably, the changes seen in asymptomatic samples are largely in products of genes encoding several chemokines, whereas the changes seen in affected samples are largely in genes governing the synthesis of GPI-linked proteins and histone acetylation. Besides this, the affected patient and related asymptomatic carrier share the 4qA161 haplotype. Thus, these polymorphisms by themselves do not explain the pathogenicity of the contracted allele. Interestingly, our results also suggest that the miRNAs might mediate the regulatory network in FSHD. Together, our results support the previous evidence that FSHD may be caused by transcriptional dysregulation of multiple genes, in cis and in trans, and suggest some factors potentially important for FSHD pathogenesis. The study of the gene expression profiles from asymptomatic carriers and related affected patients is a unique approach to try to enhance our understanding of the missing link between the contraction in D4Z4 repeats and muscle disease, while minimizing the effects of differences resulting from genetic background. PMID:19339494

  8. Deregulation of the Protocadherin Gene FAT1 Alters Muscle Shapes: Implications for the Pathogenesis of Facioscapulohumeral Dystrophy

    PubMed Central

    Caruso, Nathalie; Herberth, Balàzs; Bartoli, Marc; Puppo, Francesca; Dumonceaux, Julie; Zimmermann, Angela; Denadai, Simon; Lebossé, Marie; Roche, Stephane; Geng, Linda; Magdinier, Frederique; Attarian, Shahram; Bernard, Rafaelle; Maina, Flavio; Levy, Nicolas; Helmbacher, Françoise

    2013-01-01

    Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts. Constitutive inactivation of the protocadherin gene Fat1 uncoupled individual myoblast polarity within chains, altering the shape of selective groups of muscles in the shoulder and face. These shape abnormalities were followed by early onset regionalised muscle defects in adult Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre reproduced muscle shape defects in limb but not face muscles, indicating a cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly, the topography of muscle abnormalities caused by Fat1 loss-of-function resembles that of human patients with facioscapulohumeral dystrophy (FSHD). FAT1 lies near the critical locus involved in causing FSHD, and Fat1 mutant mice also show retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal inner ear patterning, predictive of deafness, reminiscent of another burden of FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was observed in foetal FSHD1 cases. CGH array-based studies identified deletion polymorphisms within a putative regulatory enhancer of FAT1, predictive of tissue-specific depletion of FAT1 expression, which preferentially segregate with FSHD. Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with FSHD. PMID:23785297

  9. Effective Classification and Gene Expression Profiling for the Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    González-Navarro, Félix F.; Belanche-Muñoz, Lluís A.; Silva-Colón, Karen A.

    2013-01-01

    The Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant neuromuscular disorder whose incidence is estimated in about one in 400,000 to one in 20,000. No effective therapeutic strategies are known to halt progression or reverse muscle weakness and atrophy. It is known that the FSHD is caused by modifications located within a D4ZA repeat array in the chromosome 4q, while recent advances have linked these modifications to the DUX4 gene. Unfortunately, the complete mechanisms responsible for the molecular pathogenesis and progressive muscle weakness still remain unknown. Although there are many studies addressing cancer databases from a machine learning perspective, there is no such precedent in the analysis of the FSHD. This study aims to fill this gap by analyzing two specific FSHD databases. A feature selection algorithm is used as the main engine to select genes promoting the highest possible classification capacity. The combination of feature selection and classification aims at obtaining simple models (in terms of very low numbers of genes) capable of good generalization, that may be associated with the disease. We show that the reported method is highly efficient in finding genes to discern between healthy cases (not affected by the FSHD) and FSHD cases, allowing the discovery of very parsimonious models that yield negligible repeated cross-validation error. These models in turn give rise to very simple decision procedures in the form of a decision tree. Current biological evidence regarding these genes shows that they are linked to skeletal muscle processes concerning specific human conditions. PMID:24349187

  10. Quality of life and pain in patients with facioscapulohumeral muscular dystrophy.

    PubMed

    Padua, Luca; Aprile, Irene; Frusciante, Roberto; Iannaccone, Elisabetta; Rossi, Monica; Renna, Rosaria; Messina, Sonia; Frasca, Giuseppina; Ricci, Enzo

    2009-08-01

    The aim of this study was to assess quality of life (QoL) and evaluate the occurrence and characteristics of pain in facioscapulohumeral muscular dystrophy (FSHD) patients. No study has yet assessed QoL in a large group of FSHD patients and, overall, few studies have assessed pain in neuromuscular diseases. We performed a prospective study using a multidimensional protocol including: clinical (according to the Clinical Severity Scale Rev1); genetic (p13E-11 EcoRI fragments Rev1); QoL (Short Form-36); pain (Visual Analog Scale and Portenoy-6 questions); and depression (Beck Depression Inventory) assessment. QoL measures of FSHD were compared with those of Italian norms. Moreover, we correlated QoL and pain measurements with clinical findings. Sixty-five patients were enrolled in the study. QoL was statistically significantly reduced with respect to the Italian normative sample, mainly in physical domains. Our study demonstrated that pain is frequent in FSHD patients. More than half of the patients complained of at least moderate pain. Women complained of slightly higher levels of deterioration in the emotional aspects of QoL than men. Clinical pattern (as assessed by Clinical Severity Scale) was closely related to physical QoL domains: the higher the clinical involvement, the more severe the QoL deterioration. This study provided information that may be crucial in clinical practice: pain may be a relevant aspect in FSHD patients, and prevention strategies or relevant therapies should be considered as appropriate. Moreover, we must pay more attention to gender differences: women can suffer far greater deterioration in the emotional aspects of QoL. Further multidimensional observations are needed. Muscle Nerve 40: 200-205, 2009. PMID:19609906

  11. Design, set-up and utility of the UK facioscapulohumeral muscular dystrophy patient registry.

    PubMed

    Evangelista, Teresinha; Wood, Libby; Fernandez-Torron, Roberto; Williams, Maggie; Smith, Debbie; Lunt, Peter; Hudson, Judith; Norwood, Fiona; Orrell, Richard; Willis, Tracey; Hilton-Jones, David; Rafferty, Karen; Guglieri, Michela; Lochmüller, Hanns

    2016-07-01

    Facioscapulohumeral dystrophy (FSHD) is a rare inherited neuromuscular disease estimated to affect 1/15,000 people. Through basic research, remarkable progress has been made towards the development of targeted therapies. Patient identification, through registries or other means is essential for trial-readiness. The UK FSHD Patient Registry is a patient initiated registry that collects standardised and internationally agreed dataset of self-reported clinical details combined with professionally verified genetic information. It includes four additional questionnaires to capture patient reported outcomes related to pain, quality of life and scapular fixation. Between 2013 and 2015, 518 patients registered 243 males, 241 females with a mean age of 47.8 years. Most of the patients have FSHD type 1 (91.7 %), and weakness of the facial (59.2 %) was the most prevalent symptom at onset, followed by shoulder-girdle muscles (53.3 %) and distal (22.45 %) or proximal lower limb weakness (14.8 %). 85.57 % patients were ambulant or ambulant with assistance at the time of registration, 7.9 % report respiratory insufficiency. The registry has demonstrated utility with the recruitment of patients for a natural history study of infantile onset FSHD, and the longitudinal analysis of patient-related outcomes will provide much-needed baseline information to power future trials. The internationally agreed core dataset enables national registries to participate in a "Global FSHD registry". We suggest that the registry's ability to interoperate with other large datasets will be instrumental for sharing and exploiting data globally. PMID:27159994

  12. Evolutionary analysis of the 3.3 kb tandem repeat sequence associated with facioscapulohumeral muscular dystrophy

    SciTech Connect

    Hewitt, J.E.; Clark, L.N.; Wienberg, J.

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant progressive disorder affecting primarily the facial and shoulder girdle muscles. The FSHD gene has been localized to distal 4q35. Genetic and physical mapping has identified a polymorphic 3.3 kb tandem repeat (D4Z4) which is closely lined to the disease. In the majority of sporadic cases there are de novo DNA rearrangements resulting in loss of an integral number of D4Z4 repeats. Sequencing of D4Z4 showed it to contain two homeoboxes and a previously identified human repeat sequences (L Sau). At present, it is not known how these rearrangements affect the pathogenesis of FSHD; however, D4Z4 clearly has an important function. It is part of a complex, dispersed human tandem repeat family which is evolutionarily conserved with a marked difference in copy number in humans and great apes compared to other species. Given the unique structure and organization of the D4Z4 repeat and its role in the FSHD disease mechanism, we have further investigated the evolutionary conservation of D4Z4. Comparison of Southern blot data from Old and New World monkeys, great apes, and humans shows that this increase in the number of D4Z4-like loci occurred after the divergence of great apes and Old World monkeys. The localization of these loci in great apes has been investigated using fluorescent in situ hybridization. These studies provide evidence that the D4Z4 repeat has evolved very recently in the great ape lineage. An understanding of how this repeat family has arisen and identification of the ancestral locus in Old World monkeys should provide clues as to the role of this sequence in FSHD.

  13. Loss of epigenetic silencing of the DUX4 transcription factor gene in facioscapulohumeral muscular dystrophy.

    PubMed

    Hewitt, Jane E

    2015-10-15

    Current genetic and molecular evidence best supports an epigenetic mechanism for facioscapulohumeral muscular dystrophy (FSHD), whereby de-repression of the D4Z4 macrosatellite array leads to aberrant expression of the DUX4 transcription factor in skeletal muscle. This de-repression is triggered by either array contraction or (more rarely) by mutation of the SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) gene. Activation of DUX4 targets, including germline genes and several mammalian retrotransposons, then drives pathogenesis. A direct role for DUX4 mRNA in suppression of nonsense-mediated decay pathways has recently been demonstrated and may also contribute to muscle pathology. Loss of D4Z4 repression in FSHD is observed as hypomethylation of the array accompanied by loss of repressive chromatin marks. The molecular mechanisms of D4Z4 repression are poorly understood, but recent data have identified an Argonaute (AGO)-dependent siRNA pathway. Targeting this pathway by exogenous siRNAs could be a therapeutic strategy for FSHD. PMID:26113644

  14. Socioeconomic burden of amyotrophic lateral sclerosis, myasthenia gravis and facioscapulohumeral muscular dystrophy.

    PubMed

    Schepelmann, Karsten; Winter, Yaroslav; Spottke, Annika E; Claus, Detlef; Grothe, Christoph; Schröder, Rolf; Heuss, Dieter; Vielhaber, Stefan; Mylius, Veit; Kiefer, Reinhard; Schrank, Bertold; Oertel, Wolfgang H; Dodel, Richard

    2010-01-01

    Neuromuscular disorders (NMD) are chronic devastating diseases. The aim of this multicenter cross-sectional study was to evaluate the socioeconomic impact of three NMDs in Germany. Patients (n = 107) with amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) or facioscapulohumeral muscular dystrophy (FSHD) were recruited consecutively in seven centers in Germany. The health-economic data were collected using a "bottom-up" approach consisting of comprehensive questionnaires and patient diaries. Costs were evaluated from the societal perspective in 2009 Euros (EUR). Total annual costs from the societal perspective were EUR 36,380 (95% CI 27,090-47,970) per patient in ALS, EUR 26,240 (95% CI 17,770-37,940) in FSHD and EUR 14,950 (95% CI 10,470-21,730) in MG. The main components of costs were the expenditures of health insurance and the loss of productivity of patients and their caregivers. The following independent cost-driving factors were identified: disease severity, assistance in activities of daily living (ADL), dementia and younger age in ALS, disease severity in FSHD and assistance in ADL, disease severity and assistance in ADL in MG. The socioeconomic burden of NMDs in Germany is considerable. Further studies evaluating both the health-economic and clinical effects of NMD treatment as well as disease management programs and benchmarking activities are necessary. PMID:19629566

  15. De novo facioscapulohumeral muscular dystrophy defined by DNA probe p13E-11 (D4F104S1).

    PubMed Central

    Jardine, P E; Koch, M C; Lunt, P W; Maynard, J; Bathke, K D; Harper, P S; Upadhyaya, M

    1994-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant condition with variable age of onset and severity. Identification of a de novo DNA fragment by probe p13E-11 (D4F104S1) established the diagnosis of new mutation FSHD in 27 of 31 sporadic cases. The clinical data for these certain new mutation cases were as follows: 13 boys, 14 girls; mean age of onset 6.8 years; significant leg weakness in 19/27 (70%) (8/27 (30%) used wheelchairs at a mean age of 17.7 years); high tone sensorineural deafness in 10/27; visual acuity and direct ophthalmoscopy were normal. Congenital facial diplegia and sensorineural deafness in three children suggest that infantile FSHD is not a genetically separate disorder from FSHD. Ascertainment bias may explain the difference in severity between this group and typical familial cases. Molecular analysis for FSHD should be considered in children with either congenital or early onset facial weakness or diplegia. Images PMID:7979495

  16. [Anesthetic Management of a Patient with Facioscapulohumeral Muscular Dystrophy: Importance of Monitoring Neuromuscular Function at Multiple Sites].

    PubMed

    Matsui, Shuhei; Tanaka, Satoshi; Kiyosawa, Kenkichi; Tanaka, Toshiyuki; Kawamata, Mikito

    2015-12-01

    A 39-year-old female with facioscapulohumeral muscular dystrophy (FSHD) was scheduled for thoracoscopic resection of an anterior mediastinal tumor. She had slowly progressive weakness and atrophy in the fascial and shoulder girdle muscles. General anesthesia was induced and maintained with propofol, remifentanil, and fentanyl combined with thoracic paravertebral block. Rocuronium-induced neuromuscular blockade was evaluated with acceleromyography at the corrugator supercilii, masseter, and adductor pollicis muscles. There was no reaction at the atrophic corrugator supercilii muscle in response to train-of-four (TOF) stimulation even before rocuronium administration. In contrast twitch responses at the masseter and adductor pollicis muscles to TOF stimulation could be evoked and the duration of action of rocuronium was found to be similar to that of the normal population. The perioperative course was uneventful. Neuromuscular monitoring sites should be carefully selected in FSHD patients because of possible inability to monitor neuromuscular function at the atrophic muscles. PMID:26790332

  17. Gait propulsion in patients with facioscapulohumeral muscular dystrophy and ankle plantarflexor weakness.

    PubMed

    Rijken, N H M; van Engelen, B G M; de Rooy, J W J; Weerdesteyn, V; Geurts, A C H

    2015-02-01

    Facioscapulohumeral muscular dystrophy is a slowly progressive hereditary disorder resulting in fatty infiltration of eventually most skeletal muscles. Weakness of trunk and leg muscles causes problems with postural balance and gait, and is associated with an increased fall risk. Although drop foot and related tripping are common problems in FSHD, gait impairments are poorly documented. The effect of ankle plantarflexor involvement on gait propulsion has never been addressed. In addition to ankle plantarflexion, gait propulsion is generated through hip flexion and hip extension. Compensatory shifts between these propulsion sources occur when specific muscles are affected. Such a shift may be expected in patients with FSHD since the calves may show early fatty infiltration, whereas iliopsoas and gluteus maximus muscles are often spared for a longer time. In the current study, magnetic resonance imaging was used to assess the percentage of unaffected calf, iliopsoas and gluteus maximus muscles. Joint powers were analyzed in 10 patients with FSHD at comfortable and maximum walking speed to determine the contribution of ankle plantarflexor, hip flexor and hip extensor power to propulsion. Associations between muscle morphology, power generation and gait speed were assessed. Based on multivariate regression analysis, ankle plantarflexor power was the only factor that uniquely contributed to the explained variance of comfortable (R(2)=80%) and maximum (R(2)=86%) walking speed. Although the iliopsoas muscles were largely unaffected, they appeared to be sub-maximally recruited. This submaximal recruitment may be related to poor trunk stability, resulting in a disproportionate effect of calf muscle affliction on gait speed in patients with FSHD. PMID:25687333

  18. Gait propulsion in patients with facioscapulohumeral muscular dystrophy and ankle plantarflexor weakness.

    PubMed

    Rijken, N H M; van Engelen, B G M; de Rooy, J W J; Weerdesteyn, V; Geurts, A C H

    2015-02-01

    Facioscapulohumeral muscular dystrophy is a slowly progressive hereditary disorder resulting in fatty infiltration of eventually most skeletal muscles. Weakness of trunk and leg muscles causes problems with postural balance and gait, and is associated with an increased fall risk. Although drop foot and related tripping are common problems in FSHD, gait impairments are poorly documented. The effect of ankle plantarflexor involvement on gait propulsion has never been addressed. In addition to ankle plantarflexion, gait propulsion is generated through hip flexion and hip extension. Compensatory shifts between these propulsion sources occur when specific muscles are affected. Such a shift may be expected in patients with FSHD since the calves may show early fatty infiltration, whereas iliopsoas and gluteus maximus muscles are often spared for a longer time. In the current study, magnetic resonance imaging was used to assess the percentage of unaffected calf, iliopsoas and gluteus maximus muscles. Joint powers were analyzed in 10 patients with FSHD at comfortable and maximum walking speed to determine the contribution of ankle plantarflexor, hip flexor and hip extensor power to propulsion. Associations between muscle morphology, power generation and gait speed were assessed. Based on multivariate regression analysis, ankle plantarflexor power was the only factor that uniquely contributed to the explained variance of comfortable (R(2)=80%) and maximum (R(2)=86%) walking speed. Although the iliopsoas muscles were largely unaffected, they appeared to be sub-maximally recruited. This submaximal recruitment may be related to poor trunk stability, resulting in a disproportionate effect of calf muscle affliction on gait speed in patients with FSHD.

  19. Muscle Quantitative MR Imaging and Clustering Analysis in Patients with Facioscapulohumeral Muscular Dystrophy Type 1

    PubMed Central

    Lareau-Trudel, Emilie; Le Troter, Arnaud; Ghattas, Badih; Pouget, Jean; Attarian, Shahram; Bendahan, David; Salort-Campana, Emmanuelle

    2015-01-01

    Background Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is the third most common inherited muscular dystrophy. Considering the highly variable clinical expression and the slow disease progression, sensitive outcome measures would be of interest. Methods and Findings Using muscle MRI, we assessed muscular fatty infiltration in the lower limbs of 35 FSHD1 patients and 22 healthy volunteers by two methods: a quantitative imaging (qMRI) combined with a dedicated automated segmentation method performed on both thighs and a standard T1-weighted four-point visual scale (visual score) on thighs and legs. Each patient had a clinical evaluation including manual muscular testing, Clinical Severity Score (CSS) scale and MFM scale. The intramuscular fat fraction measured using qMRI in the thighs was significantly higher in patients (21.9 ± 20.4%) than in volunteers (3.6 ± 2.8%) (p<0.001). In patients, the intramuscular fat fraction was significantly correlated with the muscular fatty infiltration in the thighs evaluated by the mean visual score (p<0.001). However, we observed a ceiling effect of the visual score for patients with a severe fatty infiltration clearly indicating the larger accuracy of the qMRI approach. Mean intramuscular fat fraction was significantly correlated with CSS scale (p≤0.01) and was inversely correlated with MMT score, MFM subscore D1 (p≤0.01) further illustrating the sensitivity of the qMRI approach. Overall, a clustering analysis disclosed three different imaging patterns of muscle involvement for the thighs and the legs which could be related to different stages of the disease and put forth muscles which could be of interest for a subtle investigation of the disease progression and/or the efficiency of any therapeutic strategy. Conclusion The qMRI provides a sensitive measurement of fat fraction which should also be of high interest to assess disease progression and any therapeutic strategy in FSHD1 patients. PMID:26181385

  20. ZNF555 protein binds to transcriptional activator site of 4qA allele and ANT1: potential implication in Facioscapulohumeral dystrophy.

    PubMed

    Kim, Elena; Rich, Jeremy; Karoutas, Adam; Tarlykov, Pavel; Cochet, Emilie; Malysheva, Daria; Mamchaoui, Kamel; Ogryzko, Vasily; Pirozhkova, Iryna

    2015-09-30

    Facioscapulohumeral dystrophy (FSHD) is an epi/genetic satellite disease associated with at least two satellite sequences in 4q35: (i) D4Z4 macrosatellite and (ii) β-satellite repeats (BSR), a prevalent part of the 4qA allele. Most of the recent FSHD studies have been focused on a DUX4 transcript inside D4Z4 and its tandem contraction in FSHD patients. However, the D4Z4-contraction alone is not pathological, which would also require the 4qA allele. Since little is known about BSR, we investigated the 4qA BSR functional role in the transcriptional control of the FSHD region 4q35. We have shown that an individual BSR possesses enhancer activity leading to activation of the Adenine Nucleotide Translocator 1 gene (ANT1), a major FSHD candidate gene. We have identified ZNF555, a previously uncharacterized protein, as a putative transcriptional factor highly expressed in human primary myoblasts that interacts with the BSR enhancer site and impacts the ANT1 promoter activity in FSHD myoblasts. The discovery of the functional role of the 4qA allele and ZNF555 in the transcriptional control of ANT1 advances our understanding of FSHD pathogenesis and provides potential therapeutic targets. PMID:26184877

  1. ZNF555 protein binds to transcriptional activator site of 4qA allele and ANT1: potential implication in Facioscapulohumeral dystrophy

    PubMed Central

    Kim, Elena; Rich, Jeremy; Karoutas, Adam; Tarlykov, Pavel; Cochet, Emilie; Malysheva, Daria; Mamchaoui, Kamel; Ogryzko, Vasily; Pirozhkova, Iryna

    2015-01-01

    Facioscapulohumeral dystrophy (FSHD) is an epi/genetic satellite disease associated with at least two satellite sequences in 4q35: (i) D4Z4 macrosatellite and (ii) β-satellite repeats (BSR), a prevalent part of the 4qA allele. Most of the recent FSHD studies have been focused on a DUX4 transcript inside D4Z4 and its tandem contraction in FSHD patients. However, the D4Z4-contraction alone is not pathological, which would also require the 4qA allele. Since little is known about BSR, we investigated the 4qA BSR functional role in the transcriptional control of the FSHD region 4q35. We have shown that an individual BSR possesses enhancer activity leading to activation of the Adenine Nucleotide Translocator 1 gene (ANT1), a major FSHD candidate gene. We have identified ZNF555, a previously uncharacterized protein, as a putative transcriptional factor highly expressed in human primary myoblasts that interacts with the BSR enhancer site and impacts the ANT1 promoter activity in FSHD myoblasts. The discovery of the functional role of the 4qA allele and ZNF555 in the transcriptional control of ANT1 advances our understanding of FSHD pathogenesis and provides potential therapeutic targets. PMID:26184877

  2. Changes in pain-related beliefs, coping, and catastrophizing predict changes in pain intensity, pain interference, and psychological functioning in individuals with Myotonic Muscular Dystrophy and Facioscapulohumeral Dystrophy

    PubMed Central

    Nieto, Rubén; Raichle, Katherine A.; Jensen, Mark P.; Miró, Jordi

    2011-01-01

    Objectives The primary aim of this study was to test hypothesized associations between changes in psychological variables (i.e., pain beliefs, catastrophizing and coping strategies) and changes in pain intensity and related adjustment (i.e., pain interference and psychological functioning) in individuals with Myotonic Muscular Dystrophy (MMD) and Facioscapulohumeral Muscular Dystrophy (FSHD). Methods A sample of 107 adults with a diagnosis of MMD or FSHD, reporting pain in the past three months, completed assessments at two time-points, separated by about 24 months. Results Results showed that changes in pain-related psychological variables were significantly associated with changes in psychological functioning, pain intensity and pain interference. Specifically, increases in the belief that emotion influences pain, and catastrophizing were associated with decreases in psychological functioning. Increases in the coping strategies of asking for assistance and resting, and the increases of catastrophizing were associated with increases in pain intensity. Finally, increases in pain intensity and asking for assistance were associated with increases in pain interference. Discussion The results support the utility of the biopsychosocial model of pain for understanding pain and its impact in individuals with MMD or FSHD. These findings may inform the design and implementation of psychosocial pain treatments for people with muscular dystrophy and chronic pain. PMID:21642844

  3. Defective Regulation of MicroRNA Target Genes in Myoblasts from Facioscapulohumeral Dystrophy Patients*

    PubMed Central

    Dmitriev, Petr; Stankevicins, Luiza; Ansseau, Eugenie; Petrov, Andrei; Barat, Ana; Dessen, Philippe; Robert, Thomas; Turki, Ahmed; Lazar, Vladimir; Labourer, Emmanuel; Belayew, Alexandra; Carnac, Gilles; Laoudj-Chenivesse, Dalila; Lipinski, Marc; Vassetzky, Yegor S.

    2013-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant hereditary neuromuscular disorder linked to the deletion of an integral number of 3.3-kb-long macrosatellite repeats (D4Z4) within the subtelomeric region of chromosome 4q. Most genes identified in this region are overexpressed in FSHD myoblasts, including the double homeobox genes DUX4 and DUX4c. We have carried out a simultaneous miRNome/transcriptome analysis of FSHD and control primary myoblasts. Of 365 microRNAs (miRNAs) analyzed in this study, 29 were found to be differentially expressed between FSHD and normal myoblasts. Twenty-one microRNAs (miR-1, miR-7, miR-15a, miR-22, miR-30e, miR-32, miR-107, miR-133a, miR-133b, miR-139, miR-152, miR-206, miR-223, miR-302b, miR-331, miR-362, miR-365, miR-382, miR-496, miR-532, miR-654, and miR-660) were up-regulated, and eight were down-regulated (miR-15b, miR-20b, miR-21, miR-25, miR-100, miR-155, miR-345, and miR-594). Twelve of the miRNAs up-regulated in FHSD were also up-regulated in the cells ectopically expressing DUX4c, suggesting that this gene could regulate miRNA gene transcription. The myogenic miRNAs miR-1, miR-133a, miR-133b, and miR-206 were highly expressed in FSHD myoblasts, which nonetheless did not prematurely enter myogenic differentiation. This could be accounted for by the fact that in FSHD myoblasts, functionally important target genes, including cell cycle, DNA damage, and ubiquitination-related genes, escape myogenic microRNA-induced repression. PMID:24145033

  4. Low D4Z4 copy number and gender difference in Korean patients with facioscapulohumeral muscular dystrophy type 1.

    PubMed

    Park, Hyung Jun; Hong, Ji-Man; Lee, Jung Hwan; Lee, Hyung Seok; Shin, Ha Young; Kim, Seung Min; Ki, Chang-Seok; Lee, Ji Hyun; Choi, Young-Chul

    2015-11-01

    The objective of this study was to investigate the clinical and genetic features of Korean patients with facioscapulohumeral muscular dystrophy type 1 (FSHD), and assessed the impact of molecular defects on phenotypic expression. We enrolled 104 FSHD patients from 87 unrelated Korean families with D4Z4 repeat array of less than 11 copies on 4q35. Sixty-one men and forty-three women were enrolled. Median D4Z4 copy number was 4 units and 99 (95%) Korean patients with FSHD carried 1-6 units. The median age at symptom onset was 13 [interquartile range: 8-17] years old. In 100 symptomatic patients, muscle weakness began in facial muscles in 58 patients, shoulder-girdle muscles in 37, and pelvic-girdle muscles in 5. Disease severity was significantly correlated with D4Z4 copy number. In addition, women were more severely affected than men even though there were no differences in age at examination or in D4Z4 copy number between the two genders. This gender difference among Korean patients was the opposite of analysis on individuals of European ancestry. In conclusion, the present study demonstrated the new diagnostic threshold for FSHD in Koreans based on the D4Z4 repeat array size distribution from 1 to 6 units and expanded the clinical spectrum. PMID:26319123

  5. Genetic mapping of human heart-skeletal muscle adenine nucleotide translocator and its relationship to the facioscapulohumeral muscular dystrophy locus

    SciTech Connect

    Haraguchi, Y.; Chung, A.B.; Torroni, A.; Stepien, G.; Shoffner, J.M.; Costigan, D.A.; Polak, M.; Wasmuth, J.J.; Altherr, M.R.; Winokur, S.T.

    1993-05-01

    The mitochondrial heart-skeletal muscle adenine nucleotide translocator (ANT1) was regionally mapped to 4q35-qter using somatic cell hybrids containing deleted chromosome 4. The regional location was further refined through family studies using ANT1 intron and promoter nucleotide polymorphisms recognized by the restriction endonucleases MboII, NdeI, and HaeIII. Two alleles were found, each at a frequency of 0.5. The ANT1 locus was found to be closely linked to D4S139, D4S171, and the dominant skeletal muscle disease locus facioscapulohumeral muscular dystrophy (FSHD). A crossover that separated D4S171 and ANT1 from D4S139 was found. Since previous studies have established the chromosome 4 map order as centromere-D4S171-D4S139-FSHD, it was concluded that ANT1 is located on the side of D4S139, that is opposite from FSHD. This conclusion was confirmed by sequencing the exons and analyzing the transcripts of ANT1 from several FSHD patients and finding no evidence of aberration. 35 refs., 5 figs., 1 tab.

  6. Low D4Z4 copy number and gender difference in Korean patients with facioscapulohumeral muscular dystrophy type 1.

    PubMed

    Park, Hyung Jun; Hong, Ji-Man; Lee, Jung Hwan; Lee, Hyung Seok; Shin, Ha Young; Kim, Seung Min; Ki, Chang-Seok; Lee, Ji Hyun; Choi, Young-Chul

    2015-11-01

    The objective of this study was to investigate the clinical and genetic features of Korean patients with facioscapulohumeral muscular dystrophy type 1 (FSHD), and assessed the impact of molecular defects on phenotypic expression. We enrolled 104 FSHD patients from 87 unrelated Korean families with D4Z4 repeat array of less than 11 copies on 4q35. Sixty-one men and forty-three women were enrolled. Median D4Z4 copy number was 4 units and 99 (95%) Korean patients with FSHD carried 1-6 units. The median age at symptom onset was 13 [interquartile range: 8-17] years old. In 100 symptomatic patients, muscle weakness began in facial muscles in 58 patients, shoulder-girdle muscles in 37, and pelvic-girdle muscles in 5. Disease severity was significantly correlated with D4Z4 copy number. In addition, women were more severely affected than men even though there were no differences in age at examination or in D4Z4 copy number between the two genders. This gender difference among Korean patients was the opposite of analysis on individuals of European ancestry. In conclusion, the present study demonstrated the new diagnostic threshold for FSHD in Koreans based on the D4Z4 repeat array size distribution from 1 to 6 units and expanded the clinical spectrum.

  7. Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy.

    PubMed

    Broucqsault, Natacha; Morere, Julia; Gaillard, Marie-Cécile; Dumonceaux, Julie; Torrents, Julia; Salort-Campana, Emmanuelle; Maues De Paula, André; Bartoli, Marc; Fernandez, Carla; Chesnais, Anne Laure; Ferreboeuf, Maxime; Sarda, Laure; Dufour, Henry; Desnuelle, Claude; Attarian, Shahram; Levy, Nicolas; Nguyen, Karine; Magdinier, Frédérique; Roche, Stéphane

    2013-10-15

    Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, no one knows what triggers muscle defect and when alteration arises. To gain further insights into the molecular mechanisms of the disease, we evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses carrying a short pathogenic D4Z4 array (n = 6) compared with fetuses with a non-pathogenic D4Z4 array (n = 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, we observed a global dysregulation of genes involved in myogenesis including MYOD1 in samples with <11 D4Z4. The DUX4-fl pathogenic transcript was detected in FSHD biopsies but also in controls. Importantly, in FSHD fetuses, we mainly detected the non-spliced DUX4-fl isoform. In addition, several other genes clustered at the 4q35 locus are upregulated in FSHD fetuses. Our study is the first to examine fetuses carrying an FSHD-linked genotype and reveals an extensive dysregulation of several muscle-specific and 4q35 genes at early development stage at a distance from any muscle defect. Overall, our work suggests that even if FSHD is an adult-onset muscular dystrophy, the disease might also involve early molecular defects arising during myogenesis or early differentiation. PMID:23777630

  8. Infantile facioscapulohumeral muscular dystrophy revisited: Expansion of clinical phenotypes in patients with a very short EcoRI fragment.

    PubMed

    Chen, Tai-Heng; Lai, Yu-Hung; Lee, Pei-Lun; Hsu, Jong-Hau; Goto, Kanako; Hayashi, Yukiko K; Nishino, Ichizo; Lin, Chin-Wen; Shih, Hsiang-Hung; Huang, Chao-Ching; Liang, Wen-Chen; Wang, Wen-Fu; Jong, Yuh-Jyh

    2013-04-01

    Contrary to the classical form, infantile facioscapulohumeral muscular dystrophy (FSHD) usually denotes a severe phenotype and is frequently associated with extramuscular involvements. To elucidate the genotype-phenotype correlation in this severe subgroup, we identified a cohort of nine patients with infantile FSHD who also carried a very short (10-13kb) EcoRI fragment. Their current age ranged from 8 to 33 years and age of onset ranged from 0.4 to 5 years. One patient even manifested his first FSHD-related symptoms at as early as 5 months of age, including inability to smile, poor response to call, and infantile spasms. To date, four patients were wheelchair-bound and six patients had asymmetric weakness. Sensorineural hearing loss and abnormal fundoscopic findings were observed in eight and all of patients respectively. Three with the smallest EcoRI fragments (10-11kb, with normal length being 50-300kb) had mental retardation. Two of these had epilepsy. Cardiac arrhythmias were found in five patients. Restrictive ventilatory defects were observed in seven patients, with one progressing to chronic respiratory failure. Two had swallowing difficulties; one of these required gastrostomy. We identified several rarely reported phenotypes in infantile FSHD, including cardiac arrhythmia, respiratory insufficiency, and swallowing difficulties. There seems to be a correlation between the severity of phenotype and the very short EcoRI fragment in the chromosome 4q35 region. We conclude that the high frequency of multi-organ involvements in this severe FSHD variant suggests the need for an early and multidisciplinary intervention. PMID:23434070

  9. Evolutionary Conservation of a Coding Function for D4Z4, the Tandem DNA Repeat Mutated in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Clapp, Jannine ; Mitchell, Laura M. ; Bolland, Daniel J. ; Fantes, Judy ; Corcoran, Anne E. ; Scotting, Paul J. ; Armour, John A. L. ; Hewitt, Jane E. 

    2007-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is caused by deletions within the polymorphic DNA tandem array D4Z4. Each D4Z4 repeat unit has an open reading frame (ORF), termed “DUX4,” containing two homeobox sequences. Because there has been no evidence of a transcript from the array, these deletions are thought to cause FSHD by a position effect on other genes. Here, we identify D4Z4 homologues in the genomes of rodents, Afrotheria (superorder of elephants and related species), and other species and show that the DUX4 ORF is conserved. Phylogenetic analysis suggests that primate and Afrotherian D4Z4 arrays are orthologous and originated from a retrotransposed copy of an intron-containing DUX gene, DUXC. Reverse-transcriptase polymerase chain reaction and RNA fluorescence and tissue in situ hybridization data indicate transcription of the mouse array. Together with the conservation of the DUX4 ORF for >100 million years, this strongly supports a coding function for D4Z4 and necessitates re-examination of current models of the FSHD disease mechanism. PMID:17668377

  10. Distinct Disease Phases in Muscles of Facioscapulohumeral Dystrophy Patients Identified by MR Detected Fat Infiltration

    PubMed Central

    Janssen, Barbara H.; Voet, Nicoline B. M.; Nabuurs, Christine I.; Kan, Hermien E.; de Rooy, Jacky W. J.; Geurts, Alexander C.; Padberg, George W.; van Engelen, Baziel G. M.; Heerschap, Arend

    2014-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an untreatable disease, characterized by asymmetric progressive weakness of skeletal muscle with fatty infiltration. Although the main genetic defect has been uncovered, the downstream mechanisms causing FSHD are not understood. The objective of this study was to determine natural disease state and progression in muscles of FSHD patients and to establish diagnostic biomarkers by quantitative MRI of fat infiltration and phosphorylated metabolites. MRI was performed at 3T with dedicated coils on legs of 41 patients (28 men/13 women, age 34–76 years), of which eleven were re-examined after four months of usual care. Muscular fat fraction was determined with multi spin-echo and T1 weighted MRI, edema by TIRM and phosphorylated metabolites by 3D 31P MR spectroscopic imaging. Fat fractions were compared to clinical severity, muscle force, age, edema and phosphocreatine (PCr)/ATP. Longitudinal intramuscular fat fraction variation was analyzed by linear regression. Increased intramuscular fat correlated with age (p<0.05), FSHD severity score (p<0.0001), inversely with muscle strength (p<0.0001), and also occurred sub-clinically. Muscles were nearly dichotomously divided in those with high and with low fat fraction, with only 13% having an intermediate fat fraction. The intramuscular fat fraction along the muscle’s length, increased from proximal to distal. This fat gradient was the steepest for intermediate fat infiltrated muscles (0.07±0.01/cm, p<0.001). Leg muscles in this intermediate phase showed a decreased PCr/ATP (p<0.05) and the fastest increase in fatty infiltration over time (0.18±0.15/year, p<0.001), which correlated with initial edema (p<0.01), if present. Thus, in the MR assessment of fat infiltration as biomarker for diseased muscles, the intramuscular fat distribution needs to be taken into account. Our results indicate that healthy individual leg muscles become diseased by entering a progressive phase

  11. Distinct disease phases in muscles of facioscapulohumeral dystrophy patients identified by MR detected fat infiltration.

    PubMed

    Janssen, Barbara H; Voet, Nicoline B M; Nabuurs, Christine I; Kan, Hermien E; de Rooy, Jacky W J; Geurts, Alexander C; Padberg, George W; van Engelen, Baziel G M; Heerschap, Arend

    2014-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an untreatable disease, characterized by asymmetric progressive weakness of skeletal muscle with fatty infiltration. Although the main genetic defect has been uncovered, the downstream mechanisms causing FSHD are not understood. The objective of this study was to determine natural disease state and progression in muscles of FSHD patients and to establish diagnostic biomarkers by quantitative MRI of fat infiltration and phosphorylated metabolites. MRI was performed at 3T with dedicated coils on legs of 41 patients (28 men/13 women, age 34-76 years), of which eleven were re-examined after four months of usual care. Muscular fat fraction was determined with multi spin-echo and T1 weighted MRI, edema by TIRM and phosphorylated metabolites by 3D (31)P MR spectroscopic imaging. Fat fractions were compared to clinical severity, muscle force, age, edema and phosphocreatine (PCr)/ATP. Longitudinal intramuscular fat fraction variation was analyzed by linear regression. Increased intramuscular fat correlated with age (p<0.05), FSHD severity score (p<0.0001), inversely with muscle strength (p<0.0001), and also occurred sub-clinically. Muscles were nearly dichotomously divided in those with high and with low fat fraction, with only 13% having an intermediate fat fraction. The intramuscular fat fraction along the muscle's length, increased from proximal to distal. This fat gradient was the steepest for intermediate fat infiltrated muscles (0.07±0.01/cm, p<0.001). Leg muscles in this intermediate phase showed a decreased PCr/ATP (p<0.05) and the fastest increase in fatty infiltration over time (0.18±0.15/year, p<0.001), which correlated with initial edema (p<0.01), if present. Thus, in the MR assessment of fat infiltration as biomarker for diseased muscles, the intramuscular fat distribution needs to be taken into account. Our results indicate that healthy individual leg muscles become diseased by entering a progressive phase

  12. Genetic and Epigenetic Contributors to FSHD

    PubMed Central

    Daxinger, Lucia; Tapscott, Stephen J.; van der Maarel, Silvère M.

    2015-01-01

    Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscle disorder characterized by distinct chromatin changes including DNA hypomethylation of the D4Z4 macrosatellite repeat array on a disease-permissive 4qA allele and aberrant expression of the D4Z4-embedded DUX4 retrogene in skeletal muscle. Insufficient epigenetic repression of the D4Z4 repeat is the result of at least two different genetic mechanisms leading to two forms of disease, FSHD1 and FSHD2. In the case of FSHD1, a contraction of the D4Z4 repeat array is disease causing whereas FSHD2 is most often caused by mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene. Recent studies indicate that a combination of genetic and epigenetic factors that act on the D4Z4 repeat array determine the probability of DUX4 expression in skeletal muscle and disease penetrance and progression. PMID:26356006

  13. Genetic and epigenetic contributors to FSHD.

    PubMed

    Daxinger, Lucia; Tapscott, Stephen J; van der Maarel, Silvère M

    2015-08-01

    Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscle disorder characterized by distinct chromatin changes including DNA hypomethylation of the D4Z4 macrosatellite repeat array on a disease-permissive 4qA allele and aberrant expression of the D4Z4-embedded DUX4 retrogene in skeletal muscle. Insufficient epigenetic repression of the D4Z4 repeat is the result of at least two different genetic mechanisms leading to two forms of disease, FSHD1 and FSHD2. In the case of FSHD1, a contraction of the D4Z4 repeat array is disease causing whereas FSHD2 is most often caused by mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene. Recent studies indicate that a combination of genetic and epigenetic factors that act on the D4Z4 repeat array determine the probability of DUX4 expression in skeletal muscle and disease penetrance and progression. PMID:26356006

  14. Health-related quality of life in ALS, myasthenia gravis and facioscapulohumeral muscular dystrophy.

    PubMed

    Winter, Yaroslav; Schepelmann, Karsten; Spottke, Annika E; Claus, Detlef; Grothe, Christoph; Schröder, Rolf; Heuss, Dieter; Vielhaber, Stefan; Tackenberg, Björn; Mylius, Veit; Reese, Jens-Peter; Kiefer, Reinhard; Schrank, Bertold; Oertel, Wolfgang H; Dodel, Richard

    2010-09-01

    Neuromuscular disorders are rare diseases with a chronic and debilitating course. Unfortunately, data on the health-related quality of life (HRQoL) in neuromuscular diseases are limited. The objective of this multicentre cross-sectional study was to compare the HRQoL in patients with amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD) and myasthenia gravis (MG) and to identify the determinants of the HRQoL in these diseases. We recruited 91 consecutive outpatients with ALS (n = 37), FSHD (n = 17) or MG (n = 37) in seven specialized German health centres. The HRQoL was determined using the 36-Item Short Form Health Survey (SF-36) and the EuroQol (EQ-5D). Independent predictors of the HRQoL were identified using multiple regression analysis. The HRQoL in all domains of the SF-36, except for bodily pain, was significantly reduced. The domains related to physical health (physical functioning, physical role) were most affected. The EQ-5D-index score was most reduced in ALS (0.54) and least reduced in MG (0.89). Independent predictors of a reduced HRQoL were disease severity and depression in ALS, and disease severity, depression, older age and increased body-mass index in MG. The patterns of HRQoL-impairment in neuromuscular disorders share some common features, such as a more pronounced reduction in the HRQoL related to physical health, but there are a number of disease-specific features that should be considered in outcomes of clinical trials and treatment guidelines. In addition to the treatment of motor symptoms, greater attention should be paid to the treatment of depression, which was found to be among the independent predictors of the HRQoL in ALS and MG. PMID:20383521

  15. A tetranucleotide repeat (D4S1652) is linked to facioscapulohumeral dystrophy and shows no linkage disequilibrium with the disease

    SciTech Connect

    Mathews, K.D.; Bailey, H.L.; Mills, K.A.

    1994-09-01

    Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant dystrophy which is associated with a deletion in a subtelomeric repeat element on 4q35. The gene has not yet been identified. The probe detecting this deletion (D4F104S1) is not chromosome 4-specific, and at least one large family has been identified which is not linked to chromosome 4. Thus, persymptomatic/prenatal diagnosis can only be provided to families that are proven to be chromosome 4-linked or where a new mutation is demonstrated. The markers available to demonstrate linkage to chromosome 4, D4S139, D4S163, and D4F35S1, are VNTRs. We have used D4S1652, a tetranucleotide repeat recently identified by the Cooperative Human Linkage Center, in our FSHD families. We found it is completely linked to the 4q35 VNTRs and to the disease phenotype. Physical mapping, using radiation hybrids and somatic cell hybrids, places D4S1652 between D4S139, an interval of approximately 1 Mb. We have used D4S1652 to look for linkage disequilibrium in our FSHD patient population. This result is of interest because of our hypothesis that the deletion in the subtelomeric repeat element alters transcription of a more proximal gene through a position effect. Previously available markers have been unsatisfactory for this experiment because of difficulty comparing numerous VNTR alleles across families. We observed 4, easily distinguished, D4S1652 alleles in our families. We studied 14 chromosomes associated with disease phenotype and 55 chromosomes from nontransmitting parents. We found no evidence for linkage disequilibrium ({chi}{sup 2}=1.313, nonsignificant). This result will need confirmation with a larger patient population, but is consistent with the clinical observation that there is a high rate of a new mutation in this disorder.

  16. Towards the finer mapping of facioscapulohumeral muscular dystrophy at 4q35: Construction of a laser microdissection library

    SciTech Connect

    Upadhyaya, M.; Osborn, M.; Maynard, J.

    1995-06-19

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder which has been mapped to the 4q35 region. In order to saturate this distal 4q region with DNA markers, a laser-based chromosomal microdissection and microcloning procedure was used to construct a genomic library from the distal 20% of chromosome 4, derived from a single human metaphase spread. Of the 100 microclones analyzed from this library, 94 clones contained inserts sized from 80-800 bp, with an average size of 340 bp. Less than 20% of these clones hybridized to human repeat sequences. Seventy-two single-copy clones were further characterized by Southern blot hybridization against a DNA panel of somatic cell hybrids, containing various regions of chromosome 4. Forty-two clones mapped to chromosome 4, of which 8 clones mapped into the relevant 4q35 region. Twenty of these chromosome 4-specific clones were screened against {open_quotes}zoo-blots{close_quotes}; 11 clones, of which 3 mapped to 4q35, identified conserved sequences. This is the first report to describe the isolation of potential expressed sequences derived from the FSHD region. These chromosome region-specific microclones will be useful in the construction of the physical map of the region, the positional cloning of potential disease-associated genes, and the identification of additional polymorphic markers from within the distal 4q region. 47 refs., 6 figs., 1 tab.

  17. SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy.

    PubMed

    Robin, Jérôme D; Ludlow, Andrew T; Batten, Kimberly; Gaillard, Marie-Cécile; Stadler, Guido; Magdinier, Frédérique; Wright, Woodring E; Shay, Jerry W

    2015-12-01

    DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10-20 kb (enhancers/repressors) to many megabases during intra- and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of genes located up to 10 Mb from the telomeres (Telomere Position Effect-Over Long Distances [TPE-OLD]). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2, suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD.

  18. SORBS2 transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

    PubMed Central

    Robin, Jérôme D.; Ludlow, Andrew T.; Batten, Kimberly; Gaillard, Marie-Cécile; Stadler, Guido; Magdinier, Frédérique; Wright, Woodring E.; Shay, Jerry W.

    2015-01-01

    DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10–20 kb (enhancers/repressors) to many megabases during intra- and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of genes located up to 10 Mb from the telomeres (Telomere Position Effect–Over Long Distances [TPE-OLD]). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2, suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD. PMID:26359233

  19. SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy.

    PubMed

    Robin, Jérôme D; Ludlow, Andrew T; Batten, Kimberly; Gaillard, Marie-Cécile; Stadler, Guido; Magdinier, Frédérique; Wright, Woodring E; Shay, Jerry W

    2015-12-01

    DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10-20 kb (enhancers/repressors) to many megabases during intra- and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of genes located up to 10 Mb from the telomeres (Telomere Position Effect-Over Long Distances [TPE-OLD]). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2, suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD. PMID:26359233

  20. Emerging preclinical animal models for FSHD.

    PubMed

    Lek, Angela; Rahimov, Fedik; Jones, Peter L; Kunkel, Louis M

    2015-05-01

    Facioscapulohumeral dystrophy (FSHD) is a unique and complex genetic disease that is not entirely solved. Recent advances in the field have led to a consensus genetic premise for the disorder, enabling researchers to now pursue the design of preclinical models. In this review we explore all available FSHD models (DUX4-dependent and -independent) for their utility in therapeutic discovery and potential to yield novel disease insights. Owing to the complex nature of FSHD, there is currently no single model that accurately recapitulates the genetic and pathophysiological spectrum of the disorder. Existing models emphasize only specific aspects of the disease, highlighting the need for more collaborative research and novel paradigms to advance the translational research space of FSHD. PMID:25801126

  1. Safety and efficacy of a 6-month home-based exercise program in patients with facioscapulohumeral muscular dystrophy

    PubMed Central

    Bankolé, Landry-Cyrille; Millet, Guillaume Y.; Temesi, John; Bachasson, Damien; Ravelojaona, Marion; Wuyam, Bernard; Verges, Samuel; Ponsot, Elodie; Antoine, Jean-Christophe; Kadi, Fawzi; Féasson, Léonard

    2016-01-01

    Abstract Background: Previous randomized controlled trials investigating exercise training programs in facioscapulohumeral muscular dystrophy (FSHD) patients are scarce and of short duration only. This study assessed the safety and efficacy of a 6-month home-based exercise training program on fitness, muscle, and motor function in FSHD patients. Methods: Sixteen FSHD patients were randomly assigned to training (TG) and control (CG) groups (both n = 8) in a home-based exercise intervention. Training consisted of cycling 3 times weekly for 35 minutes (combination of strength, high-intensity interval, and low-intensity aerobic) at home for 24 weeks. Patients in CG also performed an identical training program (CTG) after 24 weeks. The primary outcome was change in peak oxygen uptake (VO2 peak) measured every 6 weeks. The principal secondary outcomes were maximal quadriceps strength (MVC) and local quadriceps endurance every 12 weeks. Other outcome measures included maximal aerobic power (MAP) and experienced fatigue every 6 weeks, 6-minute walking distance every 12 weeks, and muscle characteristics from vastus lateralis biopsies taken pre- and postintervention. Results: The compliance rate was 91% in TG. Significant improvements with training were observed in the VO2 peak (+19%, P = 0.002) and MAP by week 6 and further to week 24. Muscle endurance, MVC, and 6-minute walking distance increased and experienced fatigue decreased. Muscle fiber cross-sectional area and citrate synthase activity increased by 34% (P = 0.008) and 46% (P = 0.003), respectively. Dystrophic pathophysiologic patterns were not exacerbated. Similar improvements were experienced by TG and CTG. Conclusions: A combined strength and interval cycling exercise-training program compatible with patients’ daily professional and social activities leads to significant functional benefits without compromising muscle tissue. PMID:27495097

  2. Muscular dystrophy in a patient with multiple sclerosis. Another "double-trouble"?

    PubMed

    Parissis, Dimitrios; Ioannidis, Panagiotis; Bakirtzis, Christos; Grigoriadis, Nikolaos; Karacostas, Dimitrios

    2015-07-01

    Facioscapulohumeral muscular dystrophy (FSHD) is considered a relatively common muscular dystrophy affecting approximately 1:15,000 individuals in the general population. Single case reports have described the rare co-occurrence of FSHD with other hereditary neuromuscular disorders, leading to atypical phenotypes. We report herein the case of a 26-year-old woman with genetically proven FSHD, who additionally developed otherwise typical multiple sclerosis (MS). Although there is no direct relationship between FSHD and MS, they might, nevertheless, share some common pathophysiological mechanisms, as recent research suggests. In particular, we comment on the potential, but not yet proven, role of immunological factors in the pathogenesis of FSHD. PMID:26195054

  3. Muscular dystrophy in a patient with multiple sclerosis. Another "double-trouble"?

    PubMed

    Parissis, Dimitrios; Ioannidis, Panagiotis; Bakirtzis, Christos; Grigoriadis, Nikolaos; Karacostas, Dimitrios

    2015-07-01

    Facioscapulohumeral muscular dystrophy (FSHD) is considered a relatively common muscular dystrophy affecting approximately 1:15,000 individuals in the general population. Single case reports have described the rare co-occurrence of FSHD with other hereditary neuromuscular disorders, leading to atypical phenotypes. We report herein the case of a 26-year-old woman with genetically proven FSHD, who additionally developed otherwise typical multiple sclerosis (MS). Although there is no direct relationship between FSHD and MS, they might, nevertheless, share some common pathophysiological mechanisms, as recent research suggests. In particular, we comment on the potential, but not yet proven, role of immunological factors in the pathogenesis of FSHD.

  4. Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity

    PubMed Central

    Sacconi, Sabrina; Camaño, Pilar; de Greef, Jessica C.; Lemmers, Richard J. L. F.; Salviati, Leonardo; Boileau, Pascal; de Munain Arregui, Adolfo Lopez; van der Maarel, Silvère M.; Desnuelle, Claude

    2013-01-01

    Objective To identify the genetic and epigenetic defects in patients presenting with a facioscapulohumeral (FSHD) clinical phenotype without D4Z4 contractions on chromosome 4q35 tested by linear gel electrophoresis (LGE) and Southern blot analysis. Design and patients We studied 16 patients displaying an FSHD-like phenotype, with normal cardiovascular and respiratory function, a myopathic pattern on EMG, and a muscle biopsy being normal or displaying only mild and a specific dystrophic changes. We sequenced the genes calpain 3 (CAPN3), valosin containing protein (VCP) and four and a half LIM domains protein 1 (FHL1) and we analyzed the D4Z4 repeat arrays by extensive genotyping and DNA methylation analysis. Results We identified one patient carrying a complex rearrangement in the FSHD locus that masked the D4Z4 contraction associated with FSHD1 in standard genetic testing, one patient with somatic mosaicism for the D4Z4 4q35 contraction, six patients that were diagnosed with FSHD2, four patients with CAPN3 mutations, two patients with a VCP mutation, No mutations were detected in FHL1, and in two patients we could not identify the genetic defect. Conclusions In patients presenting an FSHD-like clinical phenotype with a negative molecular testing for FSHD consider: 1) detailed genetic testing including D4Z4 contraction of permissive hybrid D4Z4 repeat arrays, p13E-11 probe deletions, D4Z4 hypomethylation in absence of repeat contraction as observed in FSHD2, 2) mutations in CAPN3 even in the absence of protein deficiency on western blot analysis 3) VCP mutations even in the absence cognitive impairment, Paget disease and typical inclusion in muscle biopsy. PMID:21984748

  5. The Krüppel-like Factor 15 as a Molecular Link between Myogenic Factors and a Chromosome 4q Transcriptional Enhancer Implicated in Facioscapulohumeral Dystrophy*

    PubMed Central

    Dmitriev, Petr; Petrov, Andrei; Ansseau, Eugenie; Stankevicins, Luiza; Charron, Sébastien; Kim, Elena; Bos, Tomas Jan; Robert, Thomas; Turki, Ahmed; Coppée, Frédérique; Belayew, Alexandra; Lazar, Vladimir; Carnac, Gilles; Laoudj, Dalila; Lipinski, Marc; Vassetzky, Yegor S.

    2011-01-01

    Facioscapulohumeral muscular dystrophy (FSHD), a dominant hereditary disease with a prevalence of 7 per 100,000 individuals, is associated with a partial deletion in the subtelomeric D4Z4 repeat array on chromosome 4q. The D4Z4 repeat contains a strong transcriptional enhancer that activates promoters of several FSHD-related genes. We report here that the enhancer within the D4Z4 repeat binds the Krüppel-like factor KLF15. KLF15 was found to be up-regulated during myogenic differentiation induced by serum starvation or by overexpression of the myogenic differentiation factor MYOD. When overexpressed, KLF15 activated the D4Z4 enhancer and led to overexpression of DUX4c (Double homeobox 4, centromeric) and FRG2 (FSHD region gene 2) genes, whereas its silencing caused inactivation of the D4Z4 enhancer. In immortalized human myoblasts, the D4Z4 enhancer was activated by the myogenic factor MYOD, an effect that was abolished upon KLF15 silencing or when the KLF15-binding sites within the D4Z4 enhancer were mutated, indicating that the myogenesis-related activation of the D4Z4 enhancer was mediated by KLF15. KLF15 and several myogenesis-related factors were found to be expressed at higher levels in myoblasts, myotubes, and muscle biopsies from FSHD patients than in healthy controls. We propose that KLF15 serves as a molecular link between myogenic factors and the activity of the D4Z4 enhancer, and it thus contributes to the overexpression of the DUX4c and FRG2 genes during normal myogenic differentiation and in FSHD. PMID:21937448

  6. Filling in the Gap of Human Chromosome 4: Single Molecule Real Time Sequencing of Macrosatellite Repeats in the Facioscapulohumeral Muscular Dystrophy Locus

    PubMed Central

    Morioka, Masaki Suimye; Kitazume, Miwako; Osaki, Ken; Wood, Jonathan; Tanaka, Yujiro

    2016-01-01

    A majority of facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of macrosatellite repeats called D4Z4 that are located in the subtelomeric region of human chromosome 4q35. Sequencing the FSHD locus has been technically challenging due to its long size and nearly identical nature of repeat elements. Here we report sequencing and partial assembly of a BAC clone carrying an entire FSHD locus by a single molecule real time (SMRT) sequencing technology which could produce long reads up to about 18 kb containing D4Z4 repeats. De novo assembly by Hierarchical Genome Assembly Process 1 (HGAP.1) yielded a contig of 41 kb containing all but a part of the most distal D4Z4 element. The validity of the sequence model was confirmed by an independent approach employing anchored multiple sequence alignment by Kalign using reads containing unique flanking sequences. Our data will provide a basis for further optimization of sequencing and assembly conditions of D4Z4. PMID:27002334

  7. Filling in the Gap of Human Chromosome 4: Single Molecule Real Time Sequencing of Macrosatellite Repeats in the Facioscapulohumeral Muscular Dystrophy Locus.

    PubMed

    Morioka, Masaki Suimye; Kitazume, Miwako; Osaki, Ken; Wood, Jonathan; Tanaka, Yujiro

    2016-01-01

    A majority of facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of macrosatellite repeats called D4Z4 that are located in the subtelomeric region of human chromosome 4q35. Sequencing the FSHD locus has been technically challenging due to its long size and nearly identical nature of repeat elements. Here we report sequencing and partial assembly of a BAC clone carrying an entire FSHD locus by a single molecule real time (SMRT) sequencing technology which could produce long reads up to about 18 kb containing D4Z4 repeats. De novo assembly by Hierarchical Genome Assembly Process 1 (HGAP.1) yielded a contig of 41 kb containing all but a part of the most distal D4Z4 element. The validity of the sequence model was confirmed by an independent approach employing anchored multiple sequence alignment by Kalign using reads containing unique flanking sequences. Our data will provide a basis for further optimization of sequencing and assembly conditions of D4Z4. PMID:27002334

  8. Antisense targeting of 3' end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach.

    PubMed

    Marsollier, Anne-Charlotte; Ciszewski, Lukasz; Mariot, Virginie; Popplewell, Linda; Voit, Thomas; Dickson, George; Dumonceaux, Julie

    2016-04-15

    Defects in mRNA 3'end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Here, we choose facioscapulohumeral dystrophy (FSHD) as a model to determine whether or not targeting key 3' end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the Double homeobox 4 (DUX4) transcription factor leading to altered pathogenic deregulation of multiple genes in muscles. Here, we demonstrate that targeting either the mRNA polyadenylation signal and/or cleavage site is an efficient strategy to down-regulate DUX4 expression and to decrease the abnormally high-pathological expression of genes downstream of DUX4. We conclude that targeting key functional 3' end elements involved in pre-mRNA to mRNA maturation with antisense drugs can lead to efficient gene silencing and is thus a potentially effective therapeutic strategy for at least FSHD. Moreover, polyadenylation is a crucial step in the maturation of almost all eukaryotic mRNAs, and thus all mRNAs are virtually eligible for this antisense-mediated knockdown strategy. PMID:26787513

  9. Early-onset facioscapulohumeral muscular dystrophy type 1 with some atypical features.

    PubMed

    Dorobek, Małgorzata; van der Maarel, Silvère M; Lemmers, Richard J L F; Ryniewicz, Barbara; Kabzińska, Dagmara; Frants, Rune R; Gawel, Malgorzata; Walecki, Jerzy; Hausmanowa-Petrusewicz, Irena

    2015-04-01

    Facioscapulohumeral muscular dystrophy cases with facial weakness before the age of 5 and signs of shoulder weakness by the age of 10 are defined as early onset. Contraction of the D4Z4 repeat on chromosome 4q35 is causally related to facioscapulohumeral muscular dystrophy type 1, and the residual size of the D4Z4 repeat shows a roughly inverse correlation with the severity of the disease. Contraction of the D4Z4 repeat on chromosome 4q35 is believed to induce a local change in chromatin structure and consequent transcriptional deregulation of 4qter genes. We present early-onset cases in the Polish population that amounted to 21% of our total population with facioscapulohumeral muscular dystrophy. More than 27% of them presented with severe phenotypes (wheelchair dependency). The residual D4Z4 repeat sizes ranged from 1 to 4 units. In addition, even within early-onset facioscapulohumeral muscular dystrophy type 1 phenotypes, some cases had uncommon features (head drop, early disabling contractures, progressive ptosis, and respiratory insufficiency and cardiomyopathy).

  10. New Insights into Genotype-phenotype Correlations in Chinese Facioscapulohumeral Muscular Dystrophy: A Retrospective Analysis of 178 Patients

    PubMed Central

    Lin, Feng; Wang, Zhi-Qiang; Lin, Min-Ting; Murong, Shen-Xing; Wang, Ning

    2015-01-01

    Background: Facioscapulohumeral muscular dystrophy (FSHD), a common autosomal dominant muscular disorder, is caused by contraction of the D4Z4 repeats on 4q35. The complicated genotype-phenotype correlation among different ethnic population remains a controversial subject. We aimed to refine this correlation in order to provide new information for genetic counseling. Methods: Here, a cohort of 136 Chinese families including 178 affected individuals and 137 unaffected members were investigated. Genetic analyses were performed using the p13E-11, 4qA and 4qB probes after pulsed field gel electrophoresis separation and southern blotting. A 10-grade FSHD clinical severity scale was adopted for clinical assessment. The genotype-phenotype correlation was established by linear regression analyses. Results: We observed a roughly inversed correlation between the short EcoRI fragment size and age-corrected clinical severity score in 154 symptomatic patients (P < 0.05). Compared to male patients, a significant higher proportion of females in both asymptomatic carriers and severe patients showed larger variation in the size of short EcoRI fragment. A high incidence (19/42, 45.2%) of asymptomatic (or minimally affected) carriers was found in familial members. Conclusions: Although the number of D4Z4 repeats is known as one of the critical influences on genotype-phenotype correlation, a majority of phenotypic spectrum was still incompatible with their heterozygous contraction of the D4Z4 repeat, especial in female cases. Our results suggest that there are multi-factors synergistically modulating the phenotypic expression. PMID:26112708

  11. The FSHD2 Gene SMCHD1 Is a Modifier of Disease Severity in Families Affected by FSHD1

    PubMed Central

    Sacconi, Sabrina; Lemmers, Richard J.L.F.; Balog, Judit; van der Vliet, Patrick J.; Lahaut, Pauline; van Nieuwenhuizen, Merlijn P.; Straasheijm, Kirsten R.; Debipersad, Rashmie D.; Vos-Versteeg, Marianne; Salviati, Leonardo; Casarin, Alberto; Pegoraro, Elena; Tawil, Rabi; Bakker, Egbert; Tapscott, Stephen J.; Desnuelle, Claude; van der Maarel, Silvère M.

    2013-01-01

    Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4 to a size of 1–10 units. The residual number of D4Z4 units inversely correlates with clinical severity, but significant clinical variability exists. Each unit contains a copy of the DUX4 retrogene. Repeat contractions are associated with changes in D4Z4 chromatin structure that increase the likelihood of DUX4 expression in skeletal muscle, but only when the repeat resides in a genetic background that contains a DUX4 polyadenylation signal. Mutations in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier of D4Z4, also result in the increased likelihood of DUX4 expression in individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may act as a genetic modifier in FSHD1. We describe three unrelated individuals with FSHD1 presenting an unusual high clinical severity based on their upper-sized FSHD1 repeat array of nine units. Each of these individuals also carries a mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4 expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which the FSHD2 gene can act as modifier for disease severity in families affected by FSHD1. PMID:24075187

  12. Facioscapulohumeral muscular dystrophy and Charcot-Marie-Tooth neuropathy 1A - evidence for “double trouble” overlapping syndromes

    PubMed Central

    2013-01-01

    Background We report on a patient with genetically confirmed overlapping diagnoses of CMT1A and FSHD. This case adds to the increasing number of unique patients presenting with atypical phenotypes, particularly in FSHD. Even if a mutation in one disease gene has been found, further genetic testing might be warranted in cases with unusual clinical presentation. Case presentation The reported 53 years old male patient suffered from walking difficulties and foot deformities first noticed at age 20. Later on, he developed scapuloperoneal and truncal muscle weakness, along with atrophy of the intrinsic hand and foot muscles, pes cavus, claw toes and a distal symmetric hypoesthesia. Motor nerve conduction velocities were reduced to 20 m/s in the upper extremities, and not educible in the lower extremities, sensory nerve conduction velocities were not attainable. Electromyography showed both, myopathic and neurogenic changes. A muscle biopsy taken from the tibialis anterior muscle showed a mild myopathy with some neurogenic findings and hypertrophic type 1 fibers. Whole-body muscle MRI revealed severe changes in the lower leg muscles, tibialis anterior and gastrocnemius muscles were highly replaced by fatty tissue. Additionally, fatty degeneration of shoulder girdle and straight back muscles, and atrophy of dorsal upper leg muscles were seen. Taken together, the presenting features suggested both, a neuropathy and a myopathy. Patient’s family history suggested an autosomal dominant inheritance. Molecular testing revealed both, a hereditary motor and sensory neuropathy type 1A (HMSN1A, also called Charcot-Marie-Tooth neuropathy 1A, CMT1A) due to a PMP22 gene duplication and facioscapulohumeral muscular dystrophy (FSHD) due to a partial deletion of the D4Z4 locus (19 kb). Conclusion Molecular testing in hereditary neuromuscular disorders has led to the identification of an increasing number of atypical phenotypes. Nevertheless, finding the right diagnosis is crucial

  13. A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes.

    PubMed

    Ricci, Giulia; Ruggiero, Lucia; Vercelli, Liliana; Sera, Francesco; Nikolic, Ana; Govi, Monica; Mele, Fabiano; Daolio, Jessica; Angelini, Corrado; Antonini, Giovanni; Berardinelli, Angela; Bucci, Elisabetta; Cao, Michelangelo; D'Amico, Maria Chiara; D'Angelo, Grazia; Di Muzio, Antonio; Filosto, Massimiliano; Maggi, Lorenzo; Moggio, Maurizio; Mongini, Tiziana; Morandi, Lucia; Pegoraro, Elena; Rodolico, Carmelo; Santoro, Lucio; Siciliano, Gabriele; Tomelleri, Giuliano; Villa, Luisa; Tupler, Rossella

    2016-06-01

    Based on the 7-year experience of the Italian Clinical Network for FSHD, we revised the FSHD clinical form to describe, in a harmonized manner, the phenotypic spectrum observed in FSHD. The new Comprehensive Clinical Evaluation Form (CCEF) defines various clinical categories by the combination of different features. The inter-rater reproducibility of the CCEF was assessed between two examiners using kappa statistics by evaluating 56 subjects carrying the molecular marker used for FSHD diagnosis. The CCEF classifies: (1) subjects presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) subjects with muscle weakness limited to scapular girdle or facial muscles (category B subcategories B1, B2), (3) asymptomatic/healthy subjects (category C, subcategories C1, C2), (4) subjects with myopathic phenotype presenting clinical features not consistent with FSHD canonical phenotype (D, subcategories D1, D2). The inter-rater reliability study showed an excellent concordance of the final four CCEF categories with a κ equal to 0.90; 95 % CI (0.71; 0.97). Absolute agreement was observed for categories C and D, an excellent agreement for categories A [κ = 0.88; 95 % CI (0.75; 1.00)], and a good agreement for categories B [κ = 0.79; 95 % CI (0.57; 1.00)]. The CCEF supports the harmonized phenotypic classification of patients and families. The categories outlined by the CCEF may assist diagnosis, genetic counseling and natural history studies. Furthermore, the CCEF categories could support selection of patients in randomized clinical trials. This precise categorization might also promote the search of genetic factor(s) contributing to the phenotypic spectrum of disease. PMID:27126453

  14. Experienced fatigue in facioscapulohumeral dystrophy, myotonic dystrophy, and HMSN-I

    PubMed Central

    Kalkman, J; Schillings, M; van der Werf, S P; Padberg, G; Zwarts, M; van Engelen, B G M; Bleijenberg, G

    2005-01-01

    Objective: To assess the prevalence of severe fatigue and its relation to functional impairment in daily life in patients with relatively common types of neuromuscular disorders. Methods: 598 patients with a neuromuscular disease were studied (139 with facioscapulohumeral dystrophy, 322 with adult onset myotonic dystrophy, and 137 with hereditary motor and sensory neuropathy type I). Fatigue severity was assessed with Checklist Individual Strength (CIS-fatigue). Functional impairments in daily life were measured with the short form 36 item health questionnaire (SF-36). Results: The three different neuromuscular patient groups were of similar age and sex. Severe experienced fatigue was reported by 61–74% of the patients. Severely fatigued patients had more problems with physical functioning, social functioning, mental health, bodily pain, and general health perception. There were some differences between the three disorders in the effects of fatigue. Conclusions: Severe fatigue is reported by the majority of patients with relatively common types of neuromuscular disorders. Because experienced fatigue severity is associated with the severity of various functional impairments in daily life, it is a clinically and socially relevant problem in this group of patients. PMID:16170086

  15. Correction of the FSHD myoblast differentiation defect by fusion with healthy myoblasts.

    PubMed

    Dib, Carla; Bou Saada, Yara; Dmitriev, Petr; Richon, Catherine; Dessen, Philippe; Laoudj-Chenivesse, Dalila; Carnac, Gilles; Lipinski, Marc; Vassetzky, Yegor S

    2016-01-01

    Facioscapulohumeral dystrophy (FSHD) is a neuromuscular disease with a prevalence that could reach 1 in 8,000 characterized by progressive asymmetric muscle weakness. Myoblasts isolated from FSHD muscles exhibit morphological differentiation defects and show a distinct transcription profile. These abnormalities may be linked to the muscle weakness in FSHD patients. We have tested whether fusion of FSHD myoblasts with primary myoblasts isolated from healthy individuals could correct the differentiation defects. Our results show that the number of hybrid myotubes with normal phenotype increased with the percentage of normal myoblasts initially cultured. We demonstrated that a minimum of 50% of normal nuclei is required for a phenotypic correction of the FSHD phenotype. Moreover, transcriptomic profiles of phenotypically corrected hybrid myotubes showed that the expression of deregulated genes in FSHD myotubes became almost normal. The number of deregulated pathways also decreased from 39 in FSHD myotubes to one in hybrid myotubes formed with 40% FSHD and 60% normal myoblasts. We thus propose that while phenotypical and functional correction of FSHD is feasible, it requires more than 50% of normal myoblasts, it creates limitations for cell therapy in the FSHD context. PMID:26218298

  16. Facioscapulohumeral muscular dystrophy presenting as shoulder pain in a baseball player.

    PubMed

    Kaar, Scott; Hazard, Dale; Miller, Bruce S

    2005-09-01

    Facioscapulohumeral muscular dystrophy is a commonly occurring myopathy that affects the facial and periscapular musculature. We describe a case in a high school throwing athlete that presented as shoulder pain with throwing a baseball. The patient has begun an intensive physical therapy training program that targets his weak scapular stabilizers as well as altering his throwing mechanics. His symptoms have improved, and he is able to continue competing in throwing sports at a high level.

  17. Isolation and characterization of two overlapping cosmid clones from the 4q35 region, near the facioscapulohumeral muscular dystrophy locus

    SciTech Connect

    Deidda, G.; Grisanti, P.; Vigneti, E.

    1994-09-01

    The gene for facioscapulohumeral muscular dystrophy (FSHD) has been localized by linkage analysis to the 4q35 region. The most telomeric p13E-11 prove has been shown to detect 4q35 DNA rearrangements in both sporadic and familial cases of the disease. With the aim of constructing a detailed physical map of the 4q35 region and searching for the mutant gene, we used p13E-11 probe to isolate cosmid clones from a human genomic library in a pCos-EMBL 2 vector. Two positive clones were isolated, clones 3 and 5, which partially overlap and carry human genomic inserts of 42 and 45 kb, respectively. The cosmids share a common region containing the p13E-11 region and a stretch of KpnI units consisting of 3.2 kb tandemly repeated sequences (about 10). The restriction maps were constructed using the following enzymes: Bam HI, BgIII, Eco RI, EcoRV, KpnI and Sfi I. Clone 3 extends 4 kb upstream of C5 and stops within the Kpn repeats. Clone 5 extends 4 kb downstream from the Kpn repeats and it presents an additional EcoRI site. Clone 5 contains a stretch of Kpn sequences of nearly 32 kb, corresponding to 10 Kpn repeats; clone 3 contains a stretch of 29 kb corresponding to 9 Kpn repeats, as determined by PFGE analysis of partial digestion of the clones. Clone 5 seems to contain the entire Eco RI region prone to rearrangements in FSHD patients. From clone 5 several subclones were obtained, from the Kpn region and from the region spanning from the last Kpn repeat to the cloning site. No single copy sequences were detected. Subclones from the 3{prime} end region contain beta-satellite or Sau3A-like sequences. In situ hybridization with the whole C5 cosmid shows hybridization signals at the tip of chromosome 4 (4q35) and chromosome 10 (10q26), in the pericentromeric region of chromosome 1 (1q12) and in the p12 region of the acrocentric chromosomes (chr. 21, 22, 13, 14, 15).

  18. Computer method for the analysis of evoked motor unit potentials. 2. Duchenne, limb-girdle, facioscapulohumeral and myotonic muscular dystrophies.

    PubMed Central

    Ballantyne, J P; Hansen, S

    1975-01-01

    Single motor unit potentials recorded from surface electrodes over the extensor digitorum brevis muscle and evoked by stimulation of the anterior tibial nerve at the ankle were obtained by a computer subtraction method. Their latencies, durations, amplitudes, and areas were measured in control subjects and patients with Duchenne, limb-girdle, facioscapulohumeral, and myotonic muscular dystrophy. Lateral popliteal motor nerve conduction velocities were also recorded. In the muscular dystrophies there was a significant increase in both the latencies and durations of motor unit potentials, the latter in notable contrast with the findings of conventional needle electromyography. Fastest motor conduction velocities were significantly reduced in the limb-girdle, facioscapulohumeral, and myotonic muscular dystrophy patients, while the shortest distal motor latencies were significantly prolonged in these patients and those with Duchenne muscular dystrophy. The results support the presence of a definitive neurogenic influence in the muscular dystrophies. PMID:1151411

  19. Identification of variants in the 4q35 gene FAT1 in patients with a facioscapulohumeral dystrophy-like phenotype.

    PubMed

    Puppo, Francesca; Dionnet, Eugenie; Gaillard, Marie-Cécile; Gaildrat, Pascaline; Castro, Christel; Vovan, Catherine; Bertaux, Karine; Bernard, Rafaelle; Attarian, Shahram; Goto, Kanako; Nishino, Ichizo; Hayashi, Yukiko; Magdinier, Frédérique; Krahn, Martin; Helmbacher, Françoise; Bartoli, Marc; Lévy, Nicolas

    2015-04-01

    Facioscapulohumeralmuscular dystrophy (FSHD) is linked to copy-number reduction (N < 10) of the 4q D4Z4 subtelomeric array, in association with DUX4-permissive haplotypes. This main form is indicated as FSHD1. FSHD-like phenotypes may also appear in the absence of D4Z4 copy-number reduction. Variants of the SMCHD1 gene have been reported to associate with D4Z4 hypomethylation in DUX4-compatible haplotypes, thus defining FSHD2. Recently, mice carrying a muscle-specific knock-out of the protocadherin gene Fat1 or its constitutive hypomorphic allele were shown to develop muscular and nonmuscular defects mimicking human FSHD. Here, we report FAT1 variants in a group of patients presenting with neuromuscular symptoms reminiscent of FSHD. The patients do not carry D4Z4 copy-number reduction, 4q hypomethylation, or SMCHD1 variants. However, abnormal splicing of the FAT1 transcript is predicted for all identified variants. To determine their pathogenicity, we elaborated a minigene approach coupled to an antisense oligonucleotide (AON) assay. In vitro, four out of five selected variants induced partial or complete alteration of splicing by creating new splice sites or modifying splicing regulators. AONs confirmed these effects. Altered transcripts may affect FAT1 protein interactions or stability. Altogether, our data suggest that defective FAT1 is associated with an FSHD-like phenotype. PMID:25615407

  20. Evaluation of position effect variegation of the transcription of genes from the FSHD candidate region

    SciTech Connect

    Winokur, S.T.; Wasmuth, J.J.; Altherr, M.R.

    1994-09-01

    The gene for facioscapulohumeral muscular dystrophy (FSHD) lies in close proximity to the telomere of 4q. Deletion of several copies of a 3.2 kb tandem repeat have been associated with FSHD, although no genes have been identified within this repeat. We have shown that this repeat, as well as other repeats in the FSHD region, resemble constitutive heterochromatin both by sequence analysis and FISH cross-hybridization. We hypothesize that alterations in chromatin structure near the telomere of 4q due to deletion of these heterochromatic elements may lead to a position effect variegation of nearby genes. To test this hypothesis, we have isolated exons and candidate cDNAs from the FSHD region. A 2 kb polyadenylated cDNA was isolated from both fetal and infant brain cDNA libraries. Another cDNA hybridizes to a 7 kb skeletal muscle transcript on a Northern blot. Both of these cDNAs are chromosome 4-specific and map to the FSHD region. We have examined the expression pattern of these genes by RT-PCR, RNase protection and Northern analysis. Total RNA was isolated from normal and FSHD-affected lymphoblasts and from human-hamster somatic cell hybrids in which the normal and affected chromosomes 4 from FSHD patients were segregated. RT-PCR and RNase protection were then employed as quantitive assays to evaluate the potential for position effect variegation on RNA production in FSHD patients.

  1. Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways

    PubMed Central

    Rickard, Amanda M.; Petek, Lisa M.; Miller, Daniel G.

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is caused by chromatin relaxation that results in aberrant expression of the transcription factor Double Homeobox 4 (DUX4). DUX4 protein is present in a small subset of FSHD muscle cells, making its detection and analysis of its effects historically difficult. Using a DUX4-activated reporter, we demonstrate the burst expression pattern of endogenous DUX4, its method of signal amplification in the unique shared cytoplasm of the myotube, and FSHD cell death that depends on its activation. Transcriptome analysis of DUX4-expressing cells revealed that DUX4 activation disrupts RNA metabolism including RNA splicing, surveillance and transport pathways. Cell signaling, polarity and migration pathways were also disrupted. Thus, DUX4 expression is sufficient for myocyte death, and these findings suggest mechanistic links between DUX4 expression and cell migration, supporting recent descriptions of phenotypic similarities between FSHD and an FSHD-like condition caused by FAT1 mutations. PMID:26246499

  2. Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways.

    PubMed

    Rickard, Amanda M; Petek, Lisa M; Miller, Daniel G

    2015-10-15

    Facioscapulohumeral muscular dystrophy (FSHD) is caused by chromatin relaxation that results in aberrant expression of the transcription factor Double Homeobox 4 (DUX4). DUX4 protein is present in a small subset of FSHD muscle cells, making its detection and analysis of its effects historically difficult. Using a DUX4-activated reporter, we demonstrate the burst expression pattern of endogenous DUX4, its method of signal amplification in the unique shared cytoplasm of the myotube, and FSHD cell death that depends on its activation. Transcriptome analysis of DUX4-expressing cells revealed that DUX4 activation disrupts RNA metabolism including RNA splicing, surveillance and transport pathways. Cell signaling, polarity and migration pathways were also disrupted. Thus, DUX4 expression is sufficient for myocyte death, and these findings suggest mechanistic links between DUX4 expression and cell migration, supporting recent descriptions of phenotypic similarities between FSHD and an FSHD-like condition caused by FAT1 mutations. PMID:26246499

  3. Wnt/β-catenin signaling suppresses DUX4 expression and prevents apoptosis of FSHD muscle cells

    PubMed Central

    Block, Gregory J.; Narayanan, Divya; Amell, Amanda M.; Petek, Lisa M.; Davidson, Kathryn C.; Bird, Thomas D.; Tawil, Rabi; Moon, Randall T.; Miller, Daniel G.

    2013-01-01

    Facioscapulohumeral muscular dystrophy is a dominantly inherited myopathy associated with chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4. DUX4 is encoded within each unit of the D4Z4 array where it is normally transcriptionally silenced and packaged as constitutive heterochromatin. Truncation of the array to less than 11 D4Z4 units (FSHD1) or mutations in SMCHD1 (FSHD2) results in chromatin relaxation and a small percentage of cultured myoblasts from these individuals exhibit infrequent bursts of DUX4 expression. There are no cellular or animal models to determine the trigger of the DUX4 producing transcriptional bursts and there has been a failure to date to detect the protein in significant numbers of cells from FSHD-affected individuals. Here, we demonstrate for the first time that myotubes generated from FSHD patients express sufficient amounts of DUX4 to undergo DUX4-dependent apoptosis. We show that activation of the Wnt/β-catenin signaling pathway suppresses DUX4 transcription in FSHD1 and FSHD2 myotubes and can rescue DUX4-mediated myotube apoptosis. In addition, reduction of mRNA transcripts from Wnt pathway genes β-catenin, Wnt3A and Wnt9B results in DUX4 activation. We propose that Wnt/β-catenin signaling is important for transcriptional repression of DUX4 and identify a novel group of therapeutic targets for the treatment of FSHD. PMID:23821646

  4. Skeletal muscle imaging in facioscapulohumeral muscular dystrophy, pattern and asymmetry of individual muscle involvement.

    PubMed

    Rijken, N H M; van der Kooi, E L; Hendriks, J C M; van Asseldonk, R J G P; Padberg, G W; Geurts, A C H; van Engelen, B G M

    2014-12-01

    To better understand postural and movement disabilities, the pattern of total body muscle fat infiltration was analyzed in a large group of patients with facioscapulohumeral muscular dystrophy. Additionally, we studied whether residual D4Z4 repeat array length adjusted for age and gender could predict the degree of muscle involvement. Total body computed tomography scans of 70 patients were used to assess the degree of fat infiltration of 42 muscles from neck to ankle level on a semi-quantitative scale. Groups of muscles that highly correlated regarding fat infiltration were identified using factor analysis. Linear regression analysis was performed using muscle fat infiltration as the dependent variable and D4Z4 repeat length and age as independent variables. A pattern of muscle fat infiltration in facioscapulohumeral muscular dystrophy could be constructed. Trunk muscles were most frequently affected. Of these, back extensors were more frequently affected than previously reported. Asymmetry in muscle involvement was seen in 45% of the muscles that were infiltrated with fat. The right-sided upper extremity showed significantly higher scores for fat infiltration compared to the left side, which could not be explained by handedness. It was possible to explain 29% of the fat infiltration based on D4Z4 repeat length, corrected for age and gender. Based on our results we conclude that frequent involvement of fat infiltration in back extensors, in addition to the abdominal muscles, emphasizes the extent of trunk involvement, which may have a profound impact on postural control even in otherwise mildly affected patients.

  5. Effects of vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation on muscle function and oxidative stress biomarkers in patients with facioscapulohumeral dystrophy: a double-blind randomized controlled clinical trial.

    PubMed

    Passerieux, Emilie; Hayot, Maurice; Jaussent, Audrey; Carnac, Gilles; Gouzi, Fares; Pillard, Fabien; Picot, Marie-Christine; Böcker, Koen; Hugon, Gerald; Pincemail, Joel; Defraigne, Jean O; Verrips, Theo; Mercier, Jacques; Laoudj-Chenivesse, Dalila

    2015-04-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease characterized by progressive weakness and atrophy of specific skeletal muscles. As growing evidence suggests that oxidative stress may contribute to FSHD pathology, antioxidants that might modulate or delay oxidative insults could help in maintaining FSHD muscle function. Our primary objective was to test whether oral administration of vitamin C, vitamin E, zinc gluconate, and selenomethionine could improve the physical performance of patients with FSHD. Adult patients with FSHD (n=53) were enrolled at Montpellier University Hospital (France) in a randomized, double-blind, placebo-controlled pilot clinical trial. Patients were randomly assigned to receive 500 mg vitamin C, 400mg vitamin E, 25mg zinc gluconate and 200 μg selenomethionine (n=26), or matching placebo (n=27) once a day for 17 weeks. Primary outcomes were changes in the two-minute walking test (2-MWT), maximal voluntary contraction, and endurance limit time of the dominant and nondominant quadriceps (MVCQD, MVCQND, TlimQD, and TlimQND, respectively) after 17 weeks of treatment. Secondary outcomes were changes in the antioxidant status and oxidative stress markers. Although 2-MWT, MVCQ, and TlimQ were all significantly improved in the supplemented group at the end of the treatment compared to baseline, only MVCQ and TlimQ variations were significantly different between groups (MVCQD: P=0.011; MVCQND: P=0.004; TlimQD: P=0.028; TlimQND: P=0.011). Similarly, the vitamin C (P<0.001), vitamin E as α-tocopherol (P<0.001), vitamin C/vitamin E ratio (P=0.017), vitamin E γ/α ratio (P=0.022) and lipid peroxides (P<0.001) variations were significantly different between groups. In conclusion, vitamin E, vitamin C, zinc, and selenium supplementation has no significant effect on the 2-MWT, but improves MVCQ and TlimQ of both quadriceps by enhancing the antioxidant defenses and reducing oxidative stress. This trial was registered at

  6. Effects of vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation on muscle function and oxidative stress biomarkers in patients with facioscapulohumeral dystrophy: a double-blind randomized controlled clinical trial.

    PubMed

    Passerieux, Emilie; Hayot, Maurice; Jaussent, Audrey; Carnac, Gilles; Gouzi, Fares; Pillard, Fabien; Picot, Marie-Christine; Böcker, Koen; Hugon, Gerald; Pincemail, Joel; Defraigne, Jean O; Verrips, Theo; Mercier, Jacques; Laoudj-Chenivesse, Dalila

    2015-04-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease characterized by progressive weakness and atrophy of specific skeletal muscles. As growing evidence suggests that oxidative stress may contribute to FSHD pathology, antioxidants that might modulate or delay oxidative insults could help in maintaining FSHD muscle function. Our primary objective was to test whether oral administration of vitamin C, vitamin E, zinc gluconate, and selenomethionine could improve the physical performance of patients with FSHD. Adult patients with FSHD (n=53) were enrolled at Montpellier University Hospital (France) in a randomized, double-blind, placebo-controlled pilot clinical trial. Patients were randomly assigned to receive 500 mg vitamin C, 400mg vitamin E, 25mg zinc gluconate and 200 μg selenomethionine (n=26), or matching placebo (n=27) once a day for 17 weeks. Primary outcomes were changes in the two-minute walking test (2-MWT), maximal voluntary contraction, and endurance limit time of the dominant and nondominant quadriceps (MVCQD, MVCQND, TlimQD, and TlimQND, respectively) after 17 weeks of treatment. Secondary outcomes were changes in the antioxidant status and oxidative stress markers. Although 2-MWT, MVCQ, and TlimQ were all significantly improved in the supplemented group at the end of the treatment compared to baseline, only MVCQ and TlimQ variations were significantly different between groups (MVCQD: P=0.011; MVCQND: P=0.004; TlimQD: P=0.028; TlimQND: P=0.011). Similarly, the vitamin C (P<0.001), vitamin E as α-tocopherol (P<0.001), vitamin C/vitamin E ratio (P=0.017), vitamin E γ/α ratio (P=0.022) and lipid peroxides (P<0.001) variations were significantly different between groups. In conclusion, vitamin E, vitamin C, zinc, and selenium supplementation has no significant effect on the 2-MWT, but improves MVCQ and TlimQ of both quadriceps by enhancing the antioxidant defenses and reducing oxidative stress. This trial was registered at

  7. A focal domain of extreme demethylation within D4Z4 in FSHD2

    PubMed Central

    Hartweck, Lynn M.; Anderson, Lindsey J.; Lemmers, Richard J.; Dandapat, Abhijit; Toso, Erik A.; Dalton, Joline C.; Tawil, Rabi; Day, John W.; van der Maarel, Silvère M.

    2013-01-01

    Objective: Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease with an unclear genetic mechanism. Most patients have a contraction of the D4Z4 macrosatellite repeat array at 4qter, which is thought to cause partial demethylation (FSHD1) of the contracted allele. Demethylation has been surveyed at 3 restriction enzyme sites in the first repeat and only a single site across the entire array, and current models postulate that a generalized D4Z4 chromatin alteration causes FSHD. The background of normal alleles has confounded the study of epigenetic alterations; however, rare patients (FSHD2) have a form of the disease in which demethylation is global, i.e., on all D4Z4 elements throughout the genome. Our objective was to take advantage of the global nature of FSHD2 to identify where disease-relevant methylation changes occur within D4Z4. Methods: Using bisulfite sequencing of DNA from blood and myoblast cells, methylation levels at 74 CpG sites across 3 disparate regions within D4Z4 were measured in FSHD2 patients and controls. Results: We found that rates of demethylation caused by FSHD2 are not consistent across D4Z4. We identified a focal region of extreme demethylation within a 5′ domain, which we named DR1. Other D4Z4 regions, including the DUX4 ORF, were hypomethylated but to a much lesser extent. Conclusions: These data challenge the simple view that FSHD is caused by a broad “opening” of D4Z4 and lead us to postulate that the region of focal demethylation is the site of action of the key D4Z4 chromatin regulatory factors that go awry in FSHD. PMID:23284062

  8. Homolog of the polymorphic 4q35 FSHD locus (p13E-11; D4F104S1) maps to 10qter; exclusion as a second FSHD locus in a large Danish family

    SciTech Connect

    Frants, R.R.; Bakker, E.; Vossen, R.H.A.M.

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) has been mapped to 4q35 and shown to be associated with deletions that are detectable using probe p13E-11 (D4104S1). These deletions reside within highly polymorphic restriction fragments (20-300 kb) which can normally only be resolved completely using pulsed-field gel electrophoresis (PFGE). Family studies showed that p13E-11 detects two non-allelic loci, only one of which originates from 4q35 origin. In 20 CEPH families, 8 individuals were identified showing a `small` EcoRI fragment detectable by conventional Southern blotting. Linkage analysis allowed assignment of these fragments to 10qter (D10S212 and D10S180) in all families tested. Since FSHD shows genetic heterogeneity, this second p13E-11 locus on 10qter became an interesting candidate as a second FSHD family did not provide evidence for linkage on chromosome 10qter.

  9. Post-and prenatal testing for FSHD: Diagnostic approach for sporadic and familial cases

    SciTech Connect

    Bakker, E.; Wielen, M.J.R. van der; Losekoot, M.

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder. A major locus for FSHD was localized at the distal part of chromosome 4q. More recently, a disease associated DNA rearrangement was detected with the polymorphic probe p13E-11 (D4F104S1). In most FSHD patients, a shortened (< 28 kb instead of 50-300 kb) allele was detected. In sporadic patients a de novo deletion was found to be associated with the occurrence of FSHD. Diagnostically there were a number of problems to overcome. (1) About 5% of families show no linkage to chromosome 4q35. (2) Some 10% normal individuals show a shortened p13E11 allele, which is located at chromosome 10q. Our diagnostic strategy is as follows: If in sporadic patients a shortened p13E-11 allele is detected and neither parent shows this allele, then a de novo deletion has occurred and FSHD is proven. If no shortened allele is detected FSHD is less likely. In case one of the parents shows a shortened allele then clinical investigations and linkage studies are performed for both chromosome 4 and 10 markers. In familial cases both p13E-11 and polymorphic markers are tested. A shortened p13E-11 allele and/or chromosome 4 haplotype segregating with FSHD can be used for presymptomatic and prenatal diagnosis. Up to now, 45 sporadic cases and 21 families were referred for diagnosis. In 22 sporadic cases a shortened allele was detected, 13 were proven de novo. The first prenatal test was recently performed. The index patient was a de novo case with a shortened allele; the fetus had inherited this allele.

  10. [Dyspnea caused by bullae in a muscular dystrophy patient on chronic intermittent ventilatory support].

    PubMed

    van Santen, G; Meuzelaar, J J; Tulleken, J E; Zijlstra, J G; Meinesz, A F; van der Werf, T S

    1999-12-11

    A 65-year-old patient, ex-smoker, with facioscapulohumeral muscular dystrophy (FSHD) had been on home non invasive ventilatory support for three years when he experienced gradual increase of dyspnoea. The chest radiograph showed large bullae occupying most of the right hemithorax, with compression of lung tissue, mediastinal shift, and compression of the left lower lobe. Bullectomy resulted in rapid clinical and radiographic improvement. This is the first report of beneficial effects of emergency bullectomy in FSHD. Bullectomy has proved most successful in patients with localized bullae and compression of surrounding lung tissue. Patients with respiratory infections and bronchiectasis benefit less. PMID:10627757

  11. Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2.

    PubMed

    van den Boogaard, Marlinde L; Lemmers, Richard J F L; Camaño, Pilar; van der Vliet, Patrick J; Voermans, Nicol; van Engelen, Baziel G M; Lopez de Munain, Adolfo; Tapscott, Stephen J; van der Stoep, Nienke; Tawil, Rabi; van der Maarel, Silvère M

    2016-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 function-affecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance. PMID:25782668

  12. Novel mitochondrial tRNA Leu(CUN) transition and D4Z4 partial deletion in a patient with a facioscapulohumeral phenotype.

    PubMed

    Filosto, Massimiliano; Tonin, Paola; Scarpelli, Mauro; Savio, Chiara; Greco, Francesca; Mancuso, Michelangelo; Vattemi, Gaetano; Govoni, Vittorio; Rizzuto, Nicolò; Tupler, Rossella; Tomelleri, Giuliano

    2008-03-01

    Point mutations in mtDNA-encoded tRNA genes frequently cause isolated myopathies but rarely cause the facioscapulohumeral phenotype. We report on a patient affected with chronic progressive weakness of facioscapulohumeral/peroneal muscles whose muscle biopsy showed a mitochondrial myopathy. mtDNA direct sequencing and RFLP analysis revealed a heteroplasmic transition T12313C which disrupts a conserved site in the T Psi C stem of the tRNA(Leu(CUN)) gene and fulfills the accepted criteria of pathogenicity. A partial deletion of the nuclear DNA D4Z4 region with residual repeat sizes of 25 kb was also found in the patient and in her mother. This is the first reported case of mitochondrial myopathy/facioscapulohumeral muscular dystrophy (FSHD) "double trouble". PMID:18343111

  13. Different types of fatigue in patients with facioscapulohumeral dystrophy, myotonic dystrophy and HMSN-I. Experienced fatigue and physiological fatigue.

    PubMed

    Kalkman, Joke S; Zwarts, Machiel J; Schillings, Maartje L; van Engelen, Baziel G M; Bleijenberg, Gijs

    2008-09-01

    Although fatigue is a common symptom in neuromuscular disorders, little is known about different types of fatigue. Sixty-five FSHD, 79 adult-onset MD and 73 HMSN type I patients were studied. Experienced fatigue was assessed with the CIS-fatigue subscale. Physiological fatigue was measured during a 2-min sustained maximal voluntary contraction of the biceps brachii muscle using the twitch interpolation technique to assess central activation failure (CAF) and peripheral fatigue. Experienced fatigue, CAF and peripheral fatigue appeared to be predominantly separate types of fatigue. PMID:18690504

  14. miR-411 is up-regulated in FSHD myoblasts and suppresses myogenic factors

    PubMed Central

    2013-01-01

    Background Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disorder, which is linked to the contraction of the D4Z4 array at chromosome 4q35. Recent studies suggest that this shortening of the D4Z4 array leads to aberrant expression of double homeobox protein 4 (DUX4) and causes FSHD. In addition, misregulation of microRNAs (miRNAs) has been reported in muscular dystrophies including FSHD. In this study, we identified a miRNA that is differentially expressed in FSHD myoblasts and investigated its function. Methods To identify misregulated miRNAs and their potential targets in FSHD myoblasts, we performed expression profiling of both miRNA and mRNA using TaqMan Human MicroRNA Arrays and Affymetrix Human Genome U133A plus 2.0 microarrays, respectively. In addition, we over-expressed miR-411 in C2C12 cells to determine the effect of miR-411 on myogenic markers. Results Using miRNA and mRNA expression profiling, we identified 8 miRNAs and 1,502 transcripts that were differentially expressed in FSHD myoblasts during cell proliferation. One of the 8 differentially expressed miRNAs, miR-411, was validated by quantitative RT-PCR in both primary (2.1 fold, p<0.01) and immortalized (2.7 fold, p<0.01) myoblasts. In situ hybridization showed cytoplasmic localization of miR-411 in FSHD myoblasts. By analyzing both miRNA and mRNA data using Partek Genomics Suite, we identified 4 mRNAs potentially regulated by miR-411 including YY1 associated factor 2 (YAF2). The down-regulation of YAF2 in immortalized myoblasts was validated by immunoblotting (−3.7 fold, p<0.01). C2C12 cells were transfected with miR-411 to determine whether miR-411 affects YAF2 expression in myoblasts. The results showed that over-expression of miR-411 reduced YAF2 mRNA expression. In addition, expression of myogenic markers including Myod, myogenin, and myosin heavy chain 1 (Myh1) were suppressed by miR-411. Conclusions The study demonstrated that miR-411 was differentially

  15. PARP1 Differentially Interacts with Promoter region of DUX4 Gene in FSHD Myoblasts

    PubMed Central

    Sharma, Vishakha; Pandey, Sachchida Nand; Khawaja, Hunain; Brown, Kristy J; Hathout, Yetrib; Chen, Yi-Wen

    2016-01-01

    Objective The goal of the study is to identity proteins, which interact with the promoter region of double homeobox protein 4 (DUX4) gene known to be causative for the autosomal dominant disorder Facioscapulohumeral Muscular Dystrophy (FSHD). Methods We performed a DNA pull down assay coupled with mass spectrometry analysis to identify proteins that interact with a DUX4 promoter probe in Rhabdomyosarcomca (RD) cells. We selected the top ranked protein poly (ADP-ribose) polymerase 1 (PARP1) from our mass spectrometry data for further ChIP-qPCR validation using patients' myoblasts. We then treated FSHD myoblasts with PARP1 inhibitors to investigate the role of PARP1 in the FSHD myoblasts. Results In our mass spectrometry analysis, PARP1 was found to be the top ranked protein interacting preferentially with the DUX4 promoter probe in RD cells. We further validated this interaction by immunoblotting in RD cells (2-fold enrichment compared to proteins pulled down by a control probe, p<0.05) and ChIP-qPCR in patients' myoblasts (65-fold enrichment, p<0.01). Interestingly, the interaction was only observed in FSHD myoblasts but not in the control myoblasts. Upon further treatment of FSHD myoblasts with PARP1 inhibitors, we showed that treatment with a PARP1 inhibitor, 3-aminobenzamide (0.5 mM), for 24 h had a suppression of DUX4 (2.6 fold, p<0.05) and ZSCAN4, a gene previously shown to be upregulated by DUX4, (1.6 fold, p<0.01) in FSHD myoblasts. Treatment with fisetin (0.5 mM), a polyphenol compound with PARP1 inhibitory property, for 24 h also suppressed the expression of DUX4 (44.8 fold, p<0.01) and ZSCAN4 (2.2 fold, p<0.05) in the FSHD myoblasts. We further showed that DNA methyltransferase 1 (DNMT1), a gene regulated by PARP1 was also enriched at the DUX4 promoter in RD cells through immunoblotting (2-fold, p<0.01) and immortalized FSHD myoblasts (42-fold, p<0.01) but not control myoblasts through ChIP qPCR. Conclusion Our results showed that PARP1 and DNMT1

  16. Dynamic stability during level walking and obstacle crossing in persons with facioscapulohumeral muscular dystrophy.

    PubMed

    Rijken, N H M; van Engelen, B G M; Geurts, A C H; Weerdesteyn, V

    2015-09-01

    Patients with FSHD suffer from progressive skeletal muscle weakness, which is associated with an elevated fall risk. To obtain insight into fall mechanisms in this patient group, we aimed to assess dynamic stability during level walking and obstacle crossing in patients at different disease stages. Ten patients with at least some lower extremity weakness were included, of whom six were classified as moderately affected and four as mildly affected. Ten healthy controls were also included. Level walking at comfortable speed was assessed, as well as crossing a 10 cm high wooden obstacle. We assessed forward and lateral dynamic stability, as well as spatiotemporal and kinematics variables. During level walking, the moderately affected group demonstrated a lower walking speed, which was accompanied by longer step times and smaller step lengths, yet dynamic stability was unaffected. When crossing the obstacle, however, the moderately affected patients demonstrated reduced forward stability margins during the trailing step, which was accompanied by an increased toe clearance and greater trunk and hip flexion. This suggests that during level walking, the patients effectively utilized compensatory strategies for maintaining dynamic stability, but that the moderately affected group lacked the capacity to fully compensate for the greater stability demands imposed by obstacle crossing, rendering them unable to maintain optimal stability levels. The present results highlight the difficulties that FSHD patients experience in performing this common activity of daily living and may help explain their propensity to fall in the forward direction.

  17. Dynamic stability during level walking and obstacle crossing in persons with facioscapulohumeral muscular dystrophy.

    PubMed

    Rijken, N H M; van Engelen, B G M; Geurts, A C H; Weerdesteyn, V

    2015-09-01

    Patients with FSHD suffer from progressive skeletal muscle weakness, which is associated with an elevated fall risk. To obtain insight into fall mechanisms in this patient group, we aimed to assess dynamic stability during level walking and obstacle crossing in patients at different disease stages. Ten patients with at least some lower extremity weakness were included, of whom six were classified as moderately affected and four as mildly affected. Ten healthy controls were also included. Level walking at comfortable speed was assessed, as well as crossing a 10 cm high wooden obstacle. We assessed forward and lateral dynamic stability, as well as spatiotemporal and kinematics variables. During level walking, the moderately affected group demonstrated a lower walking speed, which was accompanied by longer step times and smaller step lengths, yet dynamic stability was unaffected. When crossing the obstacle, however, the moderately affected patients demonstrated reduced forward stability margins during the trailing step, which was accompanied by an increased toe clearance and greater trunk and hip flexion. This suggests that during level walking, the patients effectively utilized compensatory strategies for maintaining dynamic stability, but that the moderately affected group lacked the capacity to fully compensate for the greater stability demands imposed by obstacle crossing, rendering them unable to maintain optimal stability levels. The present results highlight the difficulties that FSHD patients experience in performing this common activity of daily living and may help explain their propensity to fall in the forward direction. PMID:26130572

  18. Culture Conditions Affect Expression of DUX4 in FSHD Myoblasts.

    PubMed

    Pandey, Sachchida Nand; Khawaja, Hunain; Chen, Yi-Wen

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is believed to be caused by aberrant expression of double homeobox 4 (DUX4) due to epigenetic changes of the D4Z4 region at chromosome 4q35. Detecting DUX4 is challenging due to its stochastic expression pattern and low transcription level. In this study, we examined different cDNA synthesis strategies and the sensitivity for DUX4 detection. In addition, we investigated the effects of dexamethasone and knockout serum replacement (KOSR) on DUX4 expression in culture. Our data showed that DUX4 was consistently detected in cDNA samples synthesized using Superscript III. The sensitivity of DUX4 detection was higher in the samples synthesized using oligo(dT) primers compared to random hexamers. Adding dexamethasone to the culture media significantly suppressed DUX4 expression in immortalized (1.3 fold, p < 0.01) and primary (4.7 fold, p < 0.01) FSHD myoblasts, respectively. Culture medium with KOSR increased DUX4 expression and the response is concentration dependent. The findings suggest that detection strategies and culture conditions should be carefully considered when studying DUX4 in cultured cells. PMID:26007167

  19. Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

    PubMed Central

    Sancisi, Valentina; Germinario, Elena; Esposito, Alessandra; Morini, Elisabetta; Peron, Samantha; Moggio, Maurizio; Tomelleri, Giuliano; Danieli-Betto, Daniela

    2013-01-01

    Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice overexpressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here, we show that in FRG1-overexpressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform, resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC-actin ratio and a reduced sensitivity to Ca2+. We demonstrate that the decrease of Ca2+ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression. PMID:24305066

  20. Expression of FSHD-related DUX4-FL alters proteostasis and induces TDP-43 aggregation

    PubMed Central

    Homma, Sachiko; Beermann, Mary Lou; Boyce, Frederick M; Miller, Jeffrey Boone

    2015-01-01

    Objective Pathogenesis in facioscapulohumeral muscular dystrophy (FSHD) appears to be due to aberrant expression, particularly in skeletal muscle nuclei, of the full-length isoform of DUX4 (DUX4-FL). Expression of DUX4-FL is known to alter gene expression and to be cytotoxic, but cell responses to DUX4-FL are not fully understood. Our study was designed to identify cellular mechanisms of pathogenesis caused by DUX4-FL expression. Methods We used human myogenic cell cultures to analyze the effects of DUX4-FL when it was expressed either from its endogenous promoter in FSHD cells or by exogenous expression using BacMam vectors. We focused on determining the effects of DUX4-FL on protein ubiquitination and turnover and on aggregation of TDP-43. Results Human FSHD myotubes with endogenous DUX4-FL expression showed both altered nuclear and cytoplasmic distributions of ubiquitinated proteins and aggregation of TDP-43 in DUX4-FL-expressing nuclei. Similar changes were found upon exogenous expression of DUX4-FL, but were not seen upon expression of the non-toxic short isoform DUX4-S. DUX4-FL expression also inhibited protein turnover in a model system and increased the amounts of insoluble ubiquitinated proteins and insoluble TDP-43. Finally, inhibition of the ubiquitin–proteasome system with MG132 produced TDP-43 aggregation similar to DUX4-FL expression. Interpretations Our results identify DUX4-FL-induced inhibition of protein turnover and aggregation of TDP-43, which are pathological changes also found in diseases such as amyotrophic lateral sclerosis and inclusion body myopathy, as potential pathological mechanisms in FSHD. PMID:25750920

  1. New multiplex PCR-based protocol allowing indirect diagnosis of FSHD on single cells: can PGD be offered despite high risk of recombination?

    PubMed Central

    Barat-Houari, Mouna; Nguyen, Karine; Bernard, Rafaëlle; Fernandez, Céline; Vovan, Catherine; Bareil, Corinne; Van Kien, Philippe Khau; Thorel, Delphine; Tuffery-Giraud, Sylvie; Vasseur, Francis; Attarian, Shahram; Pouget, Jean; Girardet, Anne; Lévy, Nicolas; Claustres, Mireille

    2010-01-01

    Molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) involves the heterozygous contraction of the number of tandemly repeated D4Z4 units at chromosome 4q35.2. FSHD is associated with a range of 1–10 D4Z4 units instead of 11–150 in normal controls. Several factors complicate FSHD molecular diagnosis, especially the cis-segregation of D4Z4 contraction with a 4qA allele, whereas D4Z4 shortening is silent both on alleles 4qB and 10q. Discrimination of pathogenic 4q-D4Z4 alleles from highly homologous 10q-D4Z4 arrays requires the use of the conventional Southern blot, which is not suitable at the single-cell level. Preimplantation genetic diagnosis (PGD) is a frequent request from FSHD families with several affected relatives. We aimed to develop a rapid and sensitive PCR-based multiplex approach on single cells to perform an indirect familial segregation study of pathogenic alleles. Among several available polymorphic markers at 4q35.2, the four most proximal (D4S2390, D4S1652, D4S2930 and D4S1523, <1.23 Mb) showing the highest heterozygote frequencies (67–91%) were selected. Five recombination events in the D4S2390-D4S1523 interval were observed among 144 meioses. In the D4S2390-D4Z4 interval, no recombination event occurred among 28 FSHD meioses. Instead, a particular haplotype segregated with both clinical and molecular status, allowing the characterization of an at-risk allele in each tested FSHD family (maximal LOD score 2.98 for θ=0.0). This indirect protocol can easily complement conventional techniques in prenatal diagnosis. Although our multiplex PCR-based approach technically fulfils guidelines for single-cell analysis, the relatively high recombination risk hampers its application to PGD. PMID:19935833

  2. The FSHD-associated repeat, D4Z4, is a member of a dispersed family of homeobox-containing repeats, subsets of which are clustered on the short arms of the acrocentric chromosomes

    SciTech Connect

    Lyle, R.; Wright, T.J.; Clark, L.N.; Hewitt, J.E.

    1995-08-10

    Facioscapulohumeral muscular dystrophy (FSHD) is in autosomal dominant neuromuscular disorder that maps to human chromosome 4q35. FSHD is tightly linked to a polymorphic 3.3-kb tandem repeat locus, D4Z4. D4Z4 is a complex repeat: it contains a novel homeobox sequence and two other repetitive sequence motifs. In most sporadic FSHD cases, a specific DNA rearrangement, deletion of copies of the repeat at D4Z4, is associated with development of the disease. However, no expressed sequences from D4Z4 have been identified. We have previously shown that there are other loci similar to D4Z4 within the genome. In this paper we describe the isolation of two YAC clones that map to chromosome 14 and that contain multiple copies of a D4Z4-like repeat. Isolation of cDNA clones that map to the acrocentric chromosomes and Southern blot analysis of somatic cell hybrids show that there are similar loci on all of the acrocentric chromosomes. D4Z4 is a member of a complex repeat family, and PCR analysis of somatic cell hybrids shows an organization into distinct subfamilies. The implications of this work in relation to the molecular mechanism of FSHD pathogenesis is discussed. We propose the name 3.3-kb repeat for this family of repetitive sequence elements. 44 refs., 7 figs.

  3. Molecular combing compared to Southern blot for measuring D4Z4 contractions in FSHD.

    PubMed

    Vasale, Jessica; Boyar, Fatih; Jocson, Michael; Sulcova, Vladimira; Chan, Patricia; Liaquat, Khalida; Hoffman, Carol; Meservey, Marc; Chang, Isabell; Tsao, David; Hensley, Kerri; Liu, Yan; Owen, Renius; Braastad, Corey; Sun, Weimin; Walrafen, Pierre; Komatsu, Jun; Wang, Jia-Chi; Bensimon, Aaron; Anguiano, Arturo; Jaremko, Malgorzata; Wang, Zhenyuan; Batish, Sat; Strom, Charles; Higgins, Joseph

    2015-12-01

    We compare molecular combing to Southern blot in the analysis of the facioscapulohumeral muscular dystrophy type 1 locus (FSHD1) on chromosome 4q35-qter (chr 4q) in genomic DNA specimens sent to a clinical laboratory for FSHD testing. A de-identified set of 87 genomic DNA specimens determined by Southern blot as normal (n = 71), abnormal with D4Z4 macrosatellite repeat array contractions (n = 7), indeterminate (n = 6), borderline (n = 2), or mosaic (n = 1) was independently re-analyzed by molecular combing in a blinded fashion. The molecular combing results were identical to the Southern blot results in 75 (86%) of cases. All contractions (n = 7) and mosaics (n = 1) detected by Southern blot were confirmed by molecular combing. Of the 71 samples with normal Southern blot results, 67 (94%) had concordant molecular combing results. The four discrepancies were either mosaic (n = 2), rearranged (n = 1), or borderline by molecular combing (n = 1). All indeterminate Southern blot results (n = 6) were resolved by molecular combing as either normal (n = 4), borderline (n = 1), or rearranged (n = 1). The two borderline Southern blot results showed a D4Z4 contraction on the chr 4qA allele and a normal result by molecular combing. Molecular combing overcomes a number of technical limitations of Southern blot by providing direct visualization of D4Z4 macrosatellite repeat arrays on specific chr 4q and chr 10q alleles and more precise D4Z4 repeat sizing. This study suggests that molecular combing has superior analytical validity compared to Southern blot for determining D4Z4 contraction size, detecting mosaicism, and resolving borderline and indeterminate Southern blot results. Further studies are needed to establish the clinical validity and diagnostic accuracy of these findings in FSHD. PMID:26420234

  4. CRISPR/dCas9-mediated Transcriptional Inhibition Ameliorates the Epigenetic Dysregulation at D4Z4 and Represses DUX4-fl in FSH Muscular Dystrophy.

    PubMed

    Himeda, Charis L; Jones, Takako I; Jones, Peter L

    2016-03-01

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent myopathies, affecting males and females of all ages. Both forms of the disease are linked by epigenetic derepression of the D4Z4 macrosatellite repeat array at chromosome 4q35, leading to aberrant expression of D4Z4-encoded RNAs in skeletal muscle. Production of full-length DUX4 (DUX4-fl) mRNA from the derepressed D4Z4 array results in misexpression of DUX4-FL protein and its transcriptional targets, and apoptosis, ultimately leading to accumulated muscle pathology. Returning the chromatin at the FSHD locus to its nonpathogenic, epigenetically repressed state would simultaneously affect all D4Z4 RNAs, inhibiting downstream pathogenic pathways, and is thus an attractive therapeutic strategy. Advances in CRISPR/Cas9-based genome editing make it possible to target epigenetic modifiers to an endogenous disease locus, although reports to date have focused on more typical genomic regions. Here, we demonstrate that a CRISPR/dCas9 transcriptional inhibitor can be specifically targeted to the highly repetitive FSHD macrosatellite array and alter the chromatin to repress expression of DUX4-fl in primary FSHD myocytes. These results implicate the promoter and exon 1 of DUX4 as potential therapeutic targets and demonstrate the utility of CRISPR technology for correction of the epigenetic dysregulation in FSHD. PMID:26527377

  5. DICER/AGO-dependent epigenetic silencing of D4Z4 repeats enhanced by exogenous siRNA suggests mechanisms and therapies for FSHD

    PubMed Central

    Lim, Jong-Won; Snider, Lauren; Yao, Zizhen; Tawil, Rabi; Van Der Maarel, Silvère M.; Rigo, Frank; Bennett, C. Frank; Filippova, Galina N.; Tapscott, Stephen J.

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the DUX4 transcription factor in skeletal muscle. The DUX4 retrogene is encoded in the D4Z4 macrosatellite repeat array, and smaller array size or a mutation in the SMCHD1 gene results in inefficient epigenetic repression of DUX4 in skeletal muscle, causing FSHD1 and FSHD2, respectively. Previously we showed that the entire D4Z4 repeat is bi-directionally transcribed with the generation of small si- or miRNA-like fragments and suggested that these might suppress DUX4 expression through the endogenous RNAi pathway. Here we show that exogenous siRNA targeting the region upstream of the DUX4 transcription start site suppressed DUX4 mRNA expression and increased both H3K9 methylation and AGO2 recruitment. In contrast, similarly targeted MOE-gapmer antisense oligonucleotides that degrade RNA but do not engage the RNAi pathway did not repress DUX4 expression. In addition, knockdown of DICER or AGO2 using either siRNA or MOE-gapmer chemistries resulted in the induction of DUX4 expression in control muscle cells that normally do not express DUX4, indicating that the endogenous RNAi pathway is necessary to maintain repression of DUX4 in control muscle cells. Together these data demonstrate a role of the endogenous RNAi pathway in repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat, and show that enhancing the activity of this pathway by supplying exogenous siRNA oligonucleotides represents a potential therapeutic approach to silencing DUX4 in FSHD. PMID:26041815

  6. DICER/AGO-dependent epigenetic silencing of D4Z4 repeats enhanced by exogenous siRNA suggests mechanisms and therapies for FSHD.

    PubMed

    Lim, Jong-Won; Snider, Lauren; Yao, Zizhen; Tawil, Rabi; Van Der Maarel, Silvère M; Rigo, Frank; Bennett, C Frank; Filippova, Galina N; Tapscott, Stephen J

    2015-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the DUX4 transcription factor in skeletal muscle. The DUX4 retrogene is encoded in the D4Z4 macrosatellite repeat array, and smaller array size or a mutation in the SMCHD1 gene results in inefficient epigenetic repression of DUX4 in skeletal muscle, causing FSHD1 and FSHD2, respectively. Previously we showed that the entire D4Z4 repeat is bi-directionally transcribed with the generation of small si- or miRNA-like fragments and suggested that these might suppress DUX4 expression through the endogenous RNAi pathway. Here we show that exogenous siRNA targeting the region upstream of the DUX4 transcription start site suppressed DUX4 mRNA expression and increased both H3K9 methylation and AGO2 recruitment. In contrast, similarly targeted MOE-gapmer antisense oligonucleotides that degrade RNA but do not engage the RNAi pathway did not repress DUX4 expression. In addition, knockdown of DICER or AGO2 using either siRNA or MOE-gapmer chemistries resulted in the induction of DUX4 expression in control muscle cells that normally do not express DUX4, indicating that the endogenous RNAi pathway is necessary to maintain repression of DUX4 in control muscle cells. Together these data demonstrate a role of the endogenous RNAi pathway in repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat, and show that enhancing the activity of this pathway by supplying exogenous siRNA oligonucleotides represents a potential therapeutic approach to silencing DUX4 in FSHD. PMID:26041815

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

    The aim of this study was to analyze motor unit reorganization in different types of progressive muscular dystrophies and congenital myopathies. The study population consisted of patients with genetically verified progressive muscular dystrophies: Duchenne (DMD) (n=54), Becker (BMD) (n=30), facio-scapulo-humeral (FSHD) (n=37), and Emery-Dreifuss (E-DD) (n=26). Patients with probable limb-girdle dystrophy (L-GD) (n=58) and congenital myopathies (n=35) were also included in the study. Quantitative EMG recordings were obtained from 469 muscles. Muscle activity at rest and during slight voluntary and maximal muscle contraction was analyzed. The motor unit activity potential (MUAP) duration, amplitude, area, size index (SI), polyphasicity, and the presence of "outliers" were evaluated. Diminished values of MUAP parameters and decreased maximal amplitude of maximal muscle contraction were recorded most frequently in DMD and mainly in the biceps brachii muscles. SI was the most frequently changed EMG parameter. "Outliers" with amplitude below the normal range were recorded more frequently then a decreased mean MUAP amplitude (what could indicate a very high sensitivity of this EMG parameter). Pathological interference pattern was recorded in 34.7% of biceps brachii and in 21.2% of rectus femoris muscles. In FSHD, decreased MUAP duration and SI and pathological interference pattern with low amplitude were recorded most frequently in the tibial anterior and deltoid muscles. The presence of potentials with reduced parameters is a result of decreasing motor unit area (reduced number and size of muscle fibers), while high amplitude potentials recorded in BMD and E-DD could indicate a slow and mild course of disease and muscle regeneration. PMID:26188938

  9. Facioscapulohumeral distrophy and physiotherapy: a literary review

    PubMed Central

    Corrado, Bruno; Ciardi, Gianluca

    2015-01-01

    [Purpose] The purpose of this review was to critically evaluate the literature concerning the physiotherapy of facioscapulohumeral dystrophy, and to determine an effective protocol for physiotherapy treatments, which can be adapted to patient characteristics. [Methods] A bibliographic research was carried out of research papers held in the following databases: PUBMED, PEDRO, MEDLINE, EDS BASE INDEX. The inclusion criteria for acceptance of the studies to the review were randomized controlled trials (RCTs) concerning a sample no smaller than 10 people and a medium- or long-term report of the results achieved. [Results] Just six of the works satisfied the inclusion criteria, and just three of them were useful for the review. However, these studies were difficult to compare. [Conclusion] At present, there are few studies concerning facioscapulohumeral dystrophy in the literature, and the few that are available rule out the utility of the techniques used. Therefore, more RCTs of new treatment strategies are needed. PMID:26311987

  10. Aberrant splicing in transgenes containing introns, exons, and V5 epitopes: lessons from developing an FSHD mouse model expressing a D4Z4 repeat with flanking genomic sequences.

    PubMed

    Ansseau, Eugénie; Domire, Jacqueline S; Wallace, Lindsay M; Eidahl, Jocelyn O; Guckes, Susan M; Giesige, Carlee R; Pyne, Nettie K; Belayew, Alexandra; Harper, Scott Q

    2015-01-01

    The DUX4 gene, encoded within D4Z4 repeats on human chromosome 4q35, has recently emerged as a key factor in the pathogenic mechanisms underlying Facioscapulohumeral muscular dystrophy (FSHD). This recognition prompted development of animal models expressing the DUX4 open reading frame (ORF) alone or embedded within D4Z4 repeats. In the first published model, we used adeno-associated viral vectors (AAV) and strong viral control elements (CMV promoter, SV40 poly A) to demonstrate that the DUX4 cDNA caused dose-dependent toxicity in mouse muscles. As a follow-up, we designed a second generation of DUX4-expressing AAV vectors to more faithfully genocopy the FSHD-permissive D4Z4 repeat region located at 4q35. This new vector (called AAV.D4Z4.V5.pLAM) contained the D4Z4/DUX4 promoter region, a V5 epitope-tagged DUX4 ORF, and the natural 3' untranslated region (pLAM) harboring two small introns, DUX4 exons 2 and 3, and the non-canonical poly A signal required for stabilizing DUX4 mRNA in FSHD. AAV.D4Z4.V5.pLAM failed to recapitulate the robust pathology of our first generation vectors following delivery to mouse muscle. We found that the DUX4.V5 junction sequence created an unexpected splice donor in the pre-mRNA that was preferentially utilized to remove the V5 coding sequence and DUX4 stop codon, yielding non-functional DUX4 protein with 55 additional residues on its carboxyl-terminus. Importantly, we further found that aberrant splicing could occur in any expression construct containing a functional splice acceptor and sequences resembling minimal splice donors. Our findings represent an interesting case study with respect to AAV.D4Z4.V5.pLAM, but more broadly serve as a note of caution for designing constructs containing V5 epitope tags and/or transgenes with downstream introns and exons. PMID:25742305

  11. 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

  12. Rippling muscle disease and facioscapulohumeral dystrophy-like phenotype in a patient carrying a heterozygous CAV3 T78M mutation and a D4Z4 partial deletion: Further evidence for “double trouble” overlapping syndromes

    PubMed Central

    Ricci, Giulia; Scionti, Isabella; Alì, Greta; Volpi, Leda; Zampa, Virna; Fanin, Marina; Angelini, Corrado; Politano, Luisa; Tupler, Rossella; Siciliano, Gabriele

    2012-01-01

    We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the patient’s muscle biopsy demonstrated a reduction of caveolin-3 staining, compatible with the diagnosis of caveolinopathy. Interestingly, consistent with the possible diagnosis of FSHD, the patient carried a 35 kb D4Z4 allele on chromosome 4q35. We discuss the hypothesis that the two genetic mutations may exert a synergistic effect in determining the phenotype observed in this patient. PMID:22245016

  13. Alternative splicing and muscular dystrophy

    PubMed Central

    Pistoni, Mariaelena; Ghigna, Claudia; Gabellini, Davide

    2013-01-01

    Alternative splicing of pre-mRNAs is a major contributor to proteomic diversity and to the control of gene expression in higher eukaryotic cells. For this reasons, alternative splicing is tightly regulated in different tissues and developmental stages and its disruption can lead to a wide range of human disorders. The aim of this review is to focus on the relevance of alternative splicing for muscle function and muscle disease. We begin by giving a brief overview of alternative splicing, muscle-specific gene expression and muscular dystrophy. Next, to illustrate these concepts we focus on two muscular dystrophy, myotonic muscular dystrophy and facioscapulohumeral muscular dystrophy, both associated to disruption of splicing regulation in muscle. PMID:20603608

  14. Scalpel or Straitjacket: CRISPR/Cas9 Approaches for Muscular Dystrophies.

    PubMed

    Himeda, Charis L; Jones, Takako I; Jones, Peter L

    2016-04-01

    Versatility of CRISPR/Cas9-based platforms makes them promising tools for the correction of diverse genetic/epigenetic disorders. Here we contrast the use of these genome editing tools in two myopathies with very different molecular origins: Duchenne muscular dystrophy, a monogenetic disease, and facioscapulohumeral muscular dystrophy, an epigenetic disorder with unique therapeutic challenges. PMID:26917062

  15. Duchenne muscular dystrophy

    MedlinePlus

    Pseudohypertrophic muscular dystrophy; Muscular dystrophy - Duchenne type ... Duchenne muscular dystrophy is a form of muscular dystrophy . It worsens quickly. Other muscular dystrophies (including Becker's muscular dystrophy ) get ...

  16. 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 ...

  17. 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 ...

  18. 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 ...

  19. Gene search in the FSHD region on 4q35

    SciTech Connect

    Deutekom, J.C.T. van; Romberg, S.; Geel, M. van

    1994-09-01

    In the search for the FSHD gene on 4q35, four overlapping cosmids spanning a region of 95 kb including the deletion-prone repeated units were subcloned as well as subjected to cDNA selection and exon trap strategies. A total of 300 selected clones with an average length of 500 bp were mapped back to the cosmids. None of the clones appeared to be single copy. Sequence data of most clones and the related genomic regions were compared. cDNA clones with a high homolgy (>90%) and a low repetitive hybridization pattern were further analyzed by Zoo- and Northern blotting and by sequence analysis programs like GRAIL. Excellent and good exons could be identified and some clones showed evolutionary conservation. With the best cDNA, genomic and exon trap clones, several cDNA libraries were screened. The obtained cDNAs identified different genes, none of which originated from 4q35. 3{prime} RACE experiments were performed using primers derived of predicted exons especially in a 2.2 kb EcoRI fragment about 20 kb centromeric of the repeats. So far, only non-4q35 genes could be identified. Altogether, our results support other recent studies indicating that the FSHD gene is most likely not encoded by the 3.3 kb repeated units. Moreover, the region centromeric of these repeats appeared to contain abundant repetitive sequences and homologies to several other chromosomes, complicating the identification of the FSHD gene.

  20. Meaning of Muscular Dystrophy

    MedlinePlus

    ... Help White House Lunch Recipes 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- ...

  1. Corneal dystrophies

    PubMed Central

    Klintworth, Gordon K

    2009-01-01

    The term corneal dystrophy embraces a heterogenous group of bilateral genetically determined non-inflammatory corneal diseases that are restricted to the cornea. The designation is imprecise but remains in vogue because of its clinical value. Clinically, the corneal dystrophies can be divided into three groups based on the sole or predominant anatomical location of the abnormalities. Some affect primarily the corneal epithelium and its basement membrane or Bowman layer and the superficial corneal stroma (anterior corneal dystrophies), the corneal stroma (stromal corneal dystrophies), or Descemet membrane and the corneal endothelium (posterior corneal dystrophies). Most corneal dystrophies have no systemic manifestations and present with variable shaped corneal opacities in a clear or cloudy cornea and they affect visual acuity to different degrees. Corneal dystrophies may have a simple autosomal dominant, autosomal recessive or X-linked recessive Mendelian mode of inheritance. Different corneal dystrophies are caused by mutations in the CHST6, KRT3, KRT12, PIP5K3, SLC4A11, TACSTD2, TGFBI, and UBIAD1 genes. Knowledge about the responsible genetic mutations responsible for these disorders has led to a better understanding of their basic defect and to molecular tests for their precise diagnosis. Genes for other corneal dystrophies have been mapped to specific chromosomal loci, but have not yet been identified. As clinical manifestations widely vary with the different entities, corneal dystrophies should be suspected when corneal transparency is lost or corneal opacities occur spontaneously, particularly in both corneas, and especially in the presence of a positive family history or in the offspring of consanguineous parents. Main differential diagnoses include various causes of monoclonal gammopathy, lecithin-cholesterol-acyltransferase deficiency, Fabry disease, cystinosis, tyrosine transaminase deficiency, systemic lysosomal storage diseases (mucopolysaccharidoses

  2. Emerging strategies for cell and gene therapy of the muscular dystrophies

    PubMed Central

    Muir, Lindsey A.; Chamberlain, Jeffrey S.

    2016-01-01

    The muscular dystrophies are a heterogeneous group of over 40 disorders that are characterised by muscle weakness and wasting. The most common are Duchenne muscular dystrophy and Becker muscular dystrophy, which result from mutations within the gene encoding dystrophin; myotonic dystrophy type 1, which results from an expanded trinucleotide repeat in the myotonic dystrophy protein kinase gene; and facioscapulohumeral dystrophy, which is associated with contractions in the subtelomeric region of human chromosome 1. Currently the only treatments involve clinical management of symptoms, although several promising experimental strategies are emerging. These include gene therapy using adeno-associated viral, lentiviral and adenoviral vectors and nonviral vectors, such as plasmid DNA. Exon-skipping and cell-based therapies have also shown promise in the effective treatment and regeneration of dystrophic muscle. The availability of numerous animal models for Duchenne muscular dystrophy has enabled extensive testing of a wide range of therapeutic approaches for this type of disorder. Consequently, we focus here on the therapeutic developments for Duchenne muscular dystrophy as a model of the types of approaches being considered for various types of dystrophy. We discuss the advantages and limitations of each therapeutic strategy, as well as prospects and recent successes in the context of future clinical applications. PMID:19555515

  3. 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 ...

  4. A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing.

    PubMed

    Dai, Yi; Wei, Xiaoming; Zhao, Yanhuan; Ren, Haitao; Lan, Zhangzhang; Yang, Yun; Chen, Lin; Cui, Liying

    2015-08-01

    Muscular dystrophies and congenital myopathies are a large group of heterogeneous inherited muscle disorders. The spectrum of muscular dystrophies and congenital myopathies extends to more than 50 diseases today, even excluding the common forms Duchenne Muscular Dystrophy, Myotonic Dystrophy and Facioscapulohumeral Dystrophy. Unfortunately, even by critical clinical evaluation and muscle pathology, diagnosis is still difficult. To potentially remediate this difficulty, we applied a microarray-based targeted next-generation sequencing (NGS) technology to diagnose these patients. There were 55 consecutive unrelated patients who underwent the test, 36 of which (65%) were found to have a causative mutation. Our result shows the accuracy and efficiency of next-generation sequencing in clinical circumstances and reflects the features and relative distribution of inherited myopathies in the Chinese population.

  5. Distal Myopathies: Case Studies.

    PubMed

    Shaibani, Aziz

    2016-08-01

    About 15% of myopathies present with distal weakness. Lack of sensory deficit, and preservation of sensory responses and deep tendon reflexes, favors a myopathic cause for distal weakness. Electromyogram confirms this diagnosis. Profuse spontaneous discharges are common in inflammatory, metabolic, and myofibrillar myopathy (MFM). If the clinical picture indicates a specific disease such as facioscapulohumeral muscular dystrophy (FSHD), genetic testing provides the quickest diagnosis. Otherwise, muscle biopsy can distinguish specific features. The common causes of myopathic distal weakness are FSHD, myotonic dystrophy, and inclusion body myositis. Other causes include MFM, distal muscular dystrophies, metabolic myopathies, and congenital myopathies. PMID:27445241

  6. Myotonic Muscular Dystrophy

    MedlinePlus

    ... a Difference How to Get Involved Donate Myotonic Muscular Dystrophy (MMD) Share print email share facebook twitter google plus linkedin Myotonic Muscular Dystrophy (MMD) What is myotonic muscular dystrophy (MMD)? Myotonic ...

  7. 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. ...

  8. Myotonic Dystrophy

    PubMed Central

    Thornton, Charles A.

    2014-01-01

    Myotonic dystrophy (dystrophia myotonica, DM) is one of the most common lethal monogenic disorders in populations of European descent. Myotonic dystrophy type 1 (DM1) was first described over a century ago. DM1 is caused by expansion of a CTG triplet repeat in the 3' non-coding region of DMPK, the gene encoding the DM protein kinase. More recently a second form of the disease, myotonic dystrophy type 2 (DM2) was recognized, which results from repeat expansion in a different gene. The DM2 expansion involves a CCTG repeat in the first intron of Zinc Finger 9 (ZNF9). Both disorders have autosomal dominant inheritance and multisystem features, including myotonic myopathy, cataract, and cardiac conduction disease. Studies suggest that the shared clinical features of DM1 and DM2 involve a novel genetic mechanism in which repetitive RNA exerts a toxic effect. The RNA toxicity stems from the expanded repeat in the transcripts from the mutant DM alleles. This chapter will review the clinical presentation and pathophysiology of DM, and discuss current management and future potential for developing targeted therapies. PMID:25037086

  9. Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4.

    PubMed

    Balog, Judit; Thijssen, Peter E; Shadle, Sean; Straasheijm, Kirsten R; van der Vliet, Patrick J; Krom, Yvonne D; van den Boogaard, Marlinde L; de Jong, Annika; F Lemmers, Richard J L; Tawil, Rabi; Tapscott, Stephen J; van der Maarel, Silvère M

    2015-01-01

    Facioscapulohumeral muscular dystrophy is caused by incomplete epigenetic repression of the transcription factor DUX4 in skeletal muscle. A copy of DUX4 is located within each unit of the D4Z4 macrosatellite repeat array and its derepression in somatic cells is caused by either repeat array contraction (FSHD1) or by mutations in the chromatin repressor SMCHD1 (FSHD2). While DUX4 expression has thus far only been detected in FSHD muscle and muscle cell cultures, and increases with in vitro myogenic differentiation, the D4Z4 chromatin structure has only been studied in proliferating myoblasts or non-myogenic cells. We here show that SMCHD1 protein levels at D4Z4 decline during muscle cell differentiation and correlate with DUX4 derepression. In FSHD2, but not FSHD1, the loss of SMCHD1 repressor activity is partially compensated by increased Polycomb Repressive Complex 2 (PRC2)-mediated H3K27 trimethylation at D4Z4, a situation that can be mimicked by SMCHD1 knockdown in control myotubes. In contrast, moderate overexpression of SMCHD1 results in DUX4 silencing in FSHD1 and FSHD2 myotubes demonstrating that DUX4 derepression in FSHD is reversible. Together, we show that in FSHD1 and FSHD2 the decline in SMCHD1 protein levels during muscle cell differentiation renders skeletal muscle sensitive to DUX4. PMID:26575099

  10. Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4

    PubMed Central

    Balog, Judit; Thijssen, Peter E.; Shadle, Sean; Straasheijm, Kirsten R.; van der Vliet, Patrick J.; Krom, Yvonne D.; van den Boogaard, Marlinde L.; de Jong, Annika; F Lemmers, Richard J. L.; Tawil, Rabi; Tapscott, Stephen J.; van der Maarel, Silvère M.

    2015-01-01

    Facioscapulohumeral muscular dystrophy is caused by incomplete epigenetic repression of the transcription factor DUX4 in skeletal muscle. A copy of DUX4 is located within each unit of the D4Z4 macrosatellite repeat array and its derepression in somatic cells is caused by either repeat array contraction (FSHD1) or by mutations in the chromatin repressor SMCHD1 (FSHD2). While DUX4 expression has thus far only been detected in FSHD muscle and muscle cell cultures, and increases with in vitro myogenic differentiation, the D4Z4 chromatin structure has only been studied in proliferating myoblasts or non-myogenic cells. We here show that SMCHD1 protein levels at D4Z4 decline during muscle cell differentiation and correlate with DUX4 derepression. In FSHD2, but not FSHD1, the loss of SMCHD1 repressor activity is partially compensated by increased Polycomb Repressive Complex 2 (PRC2)–mediated H3K27 trimethylation at D4Z4, a situation that can be mimicked by SMCHD1 knockdown in control myotubes. In contrast, moderate overexpression of SMCHD1 results in DUX4 silencing in FSHD1 and FSHD2 myotubes demonstrating that DUX4 derepression in FSHD is reversible. Together, we show that in FSHD1 and FSHD2 the decline in SMCHD1 protein levels during muscle cell differentiation renders skeletal muscle sensitive to DUX4. PMID:26575099

  11. The cone dystrophies.

    PubMed

    Simunovic, M P; Moore, A T

    1998-01-01

    The cone dystrophies are a heterogeneous group of inherited disorders that result in dysfunction of the cone photoreceptors and sometimes their post-receptoral pathways. The major clinical features of cone dystrophy are photophobia, reduced visual acuity and abnormal colour vision. Ganzfeld electroretinography shows reduced or absent cone responses. On the basis of their natural history, the cone dystrophies may be broadly divided into two groups: stationary and progressive cone dystrophies. The stationary cone dystrophies have received more attention, and subsequently our knowledge of their molecular genetic, psychophysical and clinical characteristics is better developed. Various methods of classification have been proposed for the progressive cone dystrophies, but none is entirely satisfactory, largely because the underlying disease mechanisms are poorly understood. Multidisciplinary studies involving clinical assessment, molecular genetics, electrophysiology and psychophysics should lead to an improved understanding of the pathogenesis of these disorders.

  12. 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)

  13. Embryological pigment epithelial dystrophies.

    PubMed

    François, J

    1976-01-01

    The embryological pigment epithelial dystrophies may be due, although rather rarely, to chemical factors, such as antibiotics and thalidomide, to ionizing radiation and to infectious factors, syphilis or viral infections, such as mumps, measles, varicella, or cytomegalovirus. The most frequent and the most typical dystrophy is, nevertheless, the rubella epitheliopathy with its widespread scattered black pigment deposits, found predominantly in the posterior pole, and its unaffected visual functions. The macular dystrophy associated with deaf-mutism is also often due to a maternal rubella infection.

  14. What Are the Types of Muscular Dystrophy?

    MedlinePlus

    ... means "present from birth." Congenital MD affects both boys and girls, who often require support to sit or stand ... lordosis (pronounced lawr-DOH-sis ) FSHD affects teen boys and girls typically but may occur as late as age ...

  15. How Is Muscular Dystrophy Diagnosed?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How is muscular dystrophy diagnosed? Skip sharing on social media links Share this: Page Content The first step in diagnosing muscular dystrophy (MD) is a visit with a health care ...

  16. Occult Macular Dystrophy

    PubMed Central

    Sayman Muslubaş, Işıl; Arf, Serra; Hocaoğlu, Mümin; Özdemir, Hakan; Karaçorlu, Murat

    2016-01-01

    Occult macular dystrophy is an inherited macular dystrophy characterized by a progressive decline of bilateral visual acuity with normal fundus appearance, fluorescein angiogram and full-field electroretinogram. This case report presents a 20-year-old female patient with bilateral progressive decline of visual acuity for six years. Her visual acuity was 3-4/10 in both eyes. Anterior segment and fundus examination, fluorescein angiogram and full-field electroretinogram were normal. She could read all Ishihara pseudoisochromatic plates. Fundus autofluorescence imaging was normal. There was a mild central hyporeflectance on fundus infrared reflectance imaging in both eyes. Reduced foveal thickness and alterations of the photoreceptor inner and outer segment junction were observed by optical coherence tomography in both eyes. Central scotoma was also found by microperimetry and reduced central response was revealed by multifocal electroretinogram in both eyes. These findings are consistent with the clinical characteristics of occult macular dystrophy. PMID:27800268

  17. Social adjustment in adult males affected with progressive muscular dystrophy.

    PubMed

    Eggers, S; Zatz, M

    1998-02-01

    Adult male patients affected with Becker (BMD, N = 22), limb girdle (LGMD, N = 22) and facioscapulohumeral (FSHMD, N = 18) muscular dystrophy were interviewed to assess for the first time how the disease's severity and recurrence risk (RR) magnitude alter their social adjustment. BMD (X-linked recessive) is the severest form and confers an intermediate RR because all daughters will be carriers, LGMD (autosomal-recessive) is moderately severe with a low RR in the absence of consanguineous marriage, and FSHMD (autosomal-dominant) is clinically the mildest of these three forms of MD but with the highest RR, of 50%. Results of the semistructured questionnaire [WHO (1988): Psychiatric Disability Assessment Schedule] showed no significant difference between the three clinical groups, but more severely handicapped patients as well as patients belonging to lower socioeconomic levels from all clinical groups showed poorer social adjustment. Taken together, myopathic patients displayed intermediate social dysfunction compared to controls and schizophrenics studied by Jablensky [1988: WHO Psychiatric Disability Assessment Schedule]. Since the items of major dysfunction proportion among myopathic patients concern intimate relationships (70%), interest in working among those unemployed (67%), and social isolation (53%), emotional support and social and legal assistance should concentrate on these aspects. Interestingly, the results of this study also suggest that high RRs do not affect relationships to the opposite sex.

  18. Derivation of FSHD1 affected human embryonic stem cell line Genea049.

    PubMed

    Dumevska, Biljana; Chami, Omar; McKernan, Robert; Goel, Divya; Schmidt, Uli

    2016-03-01

    The Genea049 human embryonic stem cell line was derived from a donated, fully commercially consented ART blastocyst, carrying a deletion in 4q35 with only 5 D4Z4 repeats by PGD linkage analysis, indicative of FSHD1. Following ICM outgrowth on inactivated human feeders, karyotype was confirmed as 46, XX by CGH and STR analysis demonstrated a female Allele pattern. The hESC line had pluripotent cell morphology, 90% of cells expressed Nanog, 96% Oct4, 80% Tra1-60 and 99% SSEA4, gave a Pluritest Pluripotency score of 23.16, Novelty of 1.43 and demonstrated Alkaline Phosphatase activity. The cell line was negative for Mycoplasma and visible contamination. PMID:27346016

  19. Derivation of FSHD1 affected human embryonic stem cell line Genea050.

    PubMed

    Dumevska, Biljana; Chami, Omar; Main, Heather; McKernan, Robert; Goel, Divya; Schmidt, Uli

    2016-03-01

    The Genea050 human embryonic stem cell line was derived from a donated, fully commercially consented ART blastocyst, carrying a deletion in 4q35 with only 5 D4Z4 repeats by PGD linkage analysis, indicative of FSHD1. Following ICM outgrowth on inactivated human feeders, karyotype was confirmed as 46, XY and STR analysis demonstrated a male Allele pattern. The hESC line had pluripotent cell morphology, 92% of cells expressed Nanog, 97% Oct4, 79% Tra1-60 and 99% SSEA4, gave a Pluritest Pluripotency score of 25.45, Novelty of 1.45 demonstrated Alkaline Phosphatase activity and tri-lineage teratoma formation. The cell line was negative for Mycoplasma and visible contamination. PMID:27346025

  20. Derivation of FSHD1 affected human embryonic stem cell line Genea096.

    PubMed

    Dumevska, Biljana; Schaft, Julia; McKernan, Robert; Goel, Divya; Schmidt, Uli

    2016-03-01

    The Genea096 human embryonic stem cell line was derived from a donated, fully commercially consented ART blastocyst, carrying a deletion in 4q35 with only 6 D4Z4 repeats by PGD linkage analysis, indicative of FSHD1. Following ICM outgrowth on inactivated human feeders, karyotype was confirmed as 46, XX by CGH and STR analysis demonstrated a female Allele pattern. The hESC line had pluripotent cell morphology, 64% of cells expressed Nanog, 93% Oct4, 58% Tra1-60 and 93% SSEA4 and a Pluritest Pluripotency score of 39.41, Novelty of 1.25. The cell line was negative for Mycoplasma and visible contamination. PMID:27346027

  1. Genetics Home Reference: tibial muscular dystrophy

    MedlinePlus

    ... Names for This Condition tardive tibial muscular dystrophy TMD Udd distal myopathy Udd-Markesbery muscular dystrophy Udd ... titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord. 2008 Dec;18(12):922-8. ...

  2. Development of a genomic DNA reference material panel for myotonic dystrophy type 1 (DM1) genetic testing.

    PubMed

    Kalman, Lisa; Tarleton, Jack; Hitch, Monica; Hegde, Madhuri; Hjelm, Nick; Berry-Kravis, Elizabeth; Zhou, Lili; Hilbert, James E; Luebbe, Elizabeth A; Moxley, Richard T; Toji, Lorraine

    2013-07-01

    Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3' untranslated region of the DMPK gene that encodes a serine-threonine kinase. Patients with larger repeats tend to have a more severe phenotype. Clinical laboratories require reference and quality control materials for DM1 diagnostic and carrier genetic testing. Well-characterized reference materials are not available. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community, the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, and the Coriell Cell Repositories, has established and characterized cell lines from patients with DM1 to create a reference material panel. The CTG repeats in genomic DNA samples from 10 DM1 cell lines were characterized in three clinical genetic testing laboratories using PCR and Southern blot analysis. DMPK alleles in the samples cover four of five DM1 clinical categories: normal (5 to 34 repeats), mild (50 to 100 repeats), classical (101 to 1000 repeats), and congenital (>1000 repeats). We did not identify or establish Coriell cell lines in the premutation range (35 to 49 repeats). These samples are publicly available for quality control, proficiency testing, test development, and research and should help improve the accuracy of DM1 testing. PMID:23680132

  3. Progressive cone dystrophy.

    PubMed Central

    Ripps, H; Noble, K G; Greenstein, V C; Siegel, I M; Carr, R E

    1987-01-01

    Psychophysical, reflectometric, and electrophysiological studies were performed on four members of a dominant pedigree with progressive cone dystrophy. The two youngest individuals were asymptomatic at the initial examination, and none of the subjects complained of problems associated with night vision. Absent or grossly reduced cone-mediated ERG responses revealed the widespread loss of cone function. Moderate elevations (1 log unit) in absolute threshold together with reductions in rhodopsin levels in the midperipheral retina provided evidence of a mild impairment of the rod system also, although not to the degree seen in a cone-rod dystrophy. The progressive nature of the disease was apparent from the case histories and the changes in visual performance that occurred on re-test after a 5-year interval. Likewise, the results of incremental threshold measurements at several retinal loci suggested that peripheral cones may be affected earlier and more severely than those in the central retina. PMID:3502298

  4. Evaluation of myocardial involvement in muscular dystrophy with Thallium-201 emission computed tomography

    SciTech Connect

    Yamamoto, S.; Kawai, N.; Matsushima, H.; Okada, M.; Yamauchi, K.; Yokota, M.; Hayashi, H.; Sotobata, I.; Sakuma, S.

    1985-05-01

    The clinical usefulness of quantitative analysis of thallium-201 emission computed tomography (ECT) for evaluation of left ventricular myocardial fibrosis was assessed on 45 patients with Duchenne(D), facioscapulohumeral(FSH), limbgirdle(LG) and myotonic(M) dystrophy. Trans-,long- and short-axial images were interpreted quantitatively using circumferential profile analysis, and the fibrotic tissue size (%FIB) was estimated by integration of hypoperfused areas in 6 to 8 consecutive short-axial slices. Lung/mediastinum count ratios (L/M ratio) were also assessed. Distinct ECT defects were found in 42 patients (all cases of D, FSH and LG, and 2 of 5 MTs). ECT defects were observed specifically in the posterolateral wall (71%) and apex (58%) in D, and were scattered in all LV walls in FSHG, LG and MT. ECG and VCG underestimated the extent of myocardial fibrosis in 17 patients (40%). Percent FIBs coincided with fibrotic tissue sizes proven by autopsy. Body-surface ECG should be influenced by cardiac position and rotation in the thorax, which were often observed in these disease entities. These factors were also assessed with ECT. The authors conclude; ECT to be useful for non-invasive evaluation of myocardial fibrosis in patients with various types of muscular dystrophy.

  5. Sarcoglycans in muscular dystrophy.

    PubMed

    Hack, A A; Groh, M E; McNally, E M

    Muscular dystrophy is a heterogeneous genetic disease that affects skeletal and cardiac muscle. The genetic defects associated with muscular dystrophy include mutations in dystrophin and its associated glycoproteins, the sarcoglycans. Furthermore, defects in dystrophin have been shown to cause a disruption of the normal expression and localization of the sarcoglycan complex. Thus, abnormalities of sarcoglycan are a common molecular feature in a number of dystrophies. By combining biochemistry, molecular cell biology, and human and mouse genetics, a growing understanding of the sarcoglycan complex is emerging. Sarcoglycan appears to be an important, independent mediator of dystrophic pathology in both skeletal muscle and heart. The absence of sarcoglycan leads to alterations of membrane permeability and apoptosis, two shared features of a number of dystrophies. beta-sarcoglycan and delta-sarcoglycan may form the core of the sarcoglycan subcomplex with alpha- and gamma-sarcoglycan less tightly associated to this core. The relationship of epsilon-sarcoglycan to the dystrophin-glycoprotein complex remains unclear. Animals lacking alpha-, gamma- and delta-sarcoglycan have been described and provide excellent opportunities for further investigation of the function of sarcoglycan. Dystrophin with dystroglycan and laminin may be a mechanical link between the actin cytoskeleton and the extracellular matrix. By positioning itself in close proximity to dystrophin and dystroglycan, sarcoglycan may function to couple mechanical and chemical signals in striated muscle. Sarcoglycan may be an independent signaling or regulatory module whose position in the membrane is determined by dystrophin but whose function is carried out independent of the dystrophin-dystroglycan-laminin axis.

  6. Reduction of a 4q35-encoded nuclear envelope protein in muscle differentiation

    SciTech Connect

    Ostlund, Cecilia; Guan, Tinglu; Figlewicz, Denise A.; Hays, Arthur P.; Worman, Howard J.; Gerace, Larry; Schirmer, Eric C.

    2009-11-13

    Muscular dystrophy and peripheral neuropathy have been linked to mutations in genes encoding nuclear envelope proteins; however, the molecular mechanisms underlying these disorders remain unresolved. Nuclear envelope protein p19A is a protein of unknown function encoded by a gene at chromosome 4q35. p19A levels are significantly reduced in human muscle as cells differentiate from myoblasts to myotubes; however, its levels are not similarly reduced in all differentiation systems tested. Because 4q35 has been linked to facioscapulohumeral muscular dystrophy (FSHD) and some adjacent genes are reportedly misregulated in the disorder, levels of p19A were analyzed in muscle samples from patients with FSHD. Although p19A was increased in most cases, an absolute correlation was not observed. Nonetheless, p19A downregulation in normal muscle differentiation suggests that in the cases where its gene is inappropriately re-activated it could affect muscle differentiation and contribute to disease pathology.

  7. Muscle diseases: the muscular dystrophies.

    PubMed

    McNally, Elizabeth M; Pytel, Peter

    2007-01-01

    Dystrophic muscle disease can occur at any age. Early- or childhood-onset muscular dystrophies may be associated with profound loss of muscle function, affecting ambulation, posture, and cardiac and respiratory function. Late-onset muscular dystrophies or myopathies may be mild and associated with slight weakness and an inability to increase muscle mass. The phenotype of muscular dystrophy is an endpoint that arises from a diverse set of genetic pathways. Genes associated with muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, and the sarcomere and Z band, as well as nuclear membrane components. Because muscle has such distinctive structural and regenerative properties, many of the genes implicated in these disorders target pathways unique to muscle or more highly expressed in muscle. This chapter reviews the basic structural properties of muscle and genetic mechanisms that lead to myopathy and muscular dystrophies that affect all age groups.

  8. Cone rod dystrophies.

    PubMed

    Hamel, Christian P

    2007-01-01

    Cone rod dystrophies (CRDs) (prevalence 1/40,000) are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP), also called the rod cone dystrophies (RCDs) resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7). Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far). The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs), CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs), and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs). It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is always advised. Currently

  9. Congenital myopathies and muscular dystrophies.

    PubMed

    Gilbreath, Heather R; Castro, Diana; Iannaccone, Susan T

    2014-08-01

    The congenital muscular dystrophies (CMD) and myopathies (CM) are a diverse group of diseases that share features such as early onset of symptoms (in the first year of life), genetic causes, and high risks for restrictive lung disease and orthopedic deformities. Understanding for disease mechanism is available and a fairly well-structured genotype-phenotype correlation for all the CMDs and CMs is now available. To best illustrate the clinical spectrum and diagnostic algorithm for these diseases, this article presents 5 cases, including Ullrich congenital muscular dystrophy, nemaline myopathy, centronuclear myopathy, merosin deficiency congenital muscular dystrophy, and core myopathy.

  10. Congenital myopathies and muscular dystrophies.

    PubMed

    Gilbreath, Heather R; Castro, Diana; Iannaccone, Susan T

    2014-08-01

    The congenital muscular dystrophies (CMD) and myopathies (CM) are a diverse group of diseases that share features such as early onset of symptoms (in the first year of life), genetic causes, and high risks for restrictive lung disease and orthopedic deformities. Understanding for disease mechanism is available and a fairly well-structured genotype-phenotype correlation for all the CMDs and CMs is now available. To best illustrate the clinical spectrum and diagnostic algorithm for these diseases, this article presents 5 cases, including Ullrich congenital muscular dystrophy, nemaline myopathy, centronuclear myopathy, merosin deficiency congenital muscular dystrophy, and core myopathy. PMID:25037085

  11. Clinical Trials in Retinal Dystrophies.

    PubMed

    Grob, Seanna R; Finn, Avni; Papakostas, Thanos D; Eliott, Dean

    2016-01-01

    Research development is burgeoning for genetic and cellular therapy for retinal dystrophies. These dystrophies are the focus of many research efforts due to the unique biology and accessibility of the eye, the transformative advances in ocular imaging technology that allows for in vivo monitoring, and the potential benefit people would gain from success in the field - the gift of renewed sight. Progress in the field has revealed the immense complexity of retinal dystrophies and the challenges faced by researchers in the development of this technology. This study reviews the current trials and advancements in genetic and cellular therapy in the treatment of retinal dystrophies and also discusses the current and potential future challenges. PMID:26957839

  12. Fuchs’ corneal dystrophy

    PubMed Central

    Eghrari, Allen O; Gottsch, John D

    2010-01-01

    Fuchs’ corneal dystrophy (FCD) is a progressive, hereditary disease of the cornea first described a century ago by the Austrian ophthalmologist Ernst Fuchs. Patients often present in the fifth to sixth decade of life with blurry morning vision that increases in duration as the disease progresses. Primarily a condition of the posterior cornea, characteristic features include the formation of focal excrescences of Descemet membrane termed ‘guttae’, loss of endothelial cell density and end-stage disease manifested by corneal edema and the formation of epithelial bullae. Recent advances in our understanding of the genetic and pathophysiological mechanisms of the disease, as well as the application of new imaging modalities and less invasive surgical procedures, present new opportunities for improved outcomes among patients with FCD. PMID:20625449

  13. What Are the Treatments for Muscular Dystrophy?

    MedlinePlus

    ... Resources and Publications What are the treatments for muscular dystrophy? Skip sharing on social media links Share this: ... available to stop or reverse any form of muscular dystrophy (MD). Instead, certain therapies and medications aim to ...

  14. Molecular genetics and clinical aspects of inherited disorders of nerve and muscle.

    PubMed

    Harding, A E

    1992-10-01

    Rapid progress has been made in elucidating the molecular genetic basis of several neuromuscular disorders in the past year. Candidate genes have been identified or analysed in hereditary motor and sensory neuropathy (HMSN) type I, X-linked bulbospinal neuronopathy and non-dystrophic myotonic disorders, and further mutations causing amyloidosis have been identified. A familial amyotrophic lateral sclerosis (ALS) locus maps to chromosome 21 in some families, and the chronic childhood spinal muscular atrophy (SMA), facioscapulohumeral muscular dystrophy (FSHD) and malignant hyperthermia loci have been localized more precisely. PMID:1392132

  15. 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.

  16. Hypothalamic hypogonadism in myotonic dystrophy.

    PubMed

    Ulloa-Aguirre, A; Larrea, F; Shkurovich, M

    1981-06-01

    Hypothalamic-pituitary-ovarian axis function was assessed in a postpubertal female patient with myotonic dystrophy and secondary amenorrhea. The results suggested a hypothalamic basis for the amenorrhea, confirming previous reports regarding the nature of gonadal failure in women with this multisystemic disorder.

  17. 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...

  18. 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.

  19. Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration.

    PubMed

    Bakay, Marina; Wang, Zuyi; Melcon, Gisela; Schiltz, Louis; Xuan, Jianhua; Zhao, Po; Sartorelli, Vittorio; Seo, Jinwook; Pegoraro, Elena; Angelini, Corrado; Shneiderman, Ben; Escolar, Diana; Chen, Yi-Wen; Winokur, Sara T; Pachman, Lauren M; Fan, Chenguang; Mandler, Raul; Nevo, Yoram; Gordon, Erynn; Zhu, Yitan; Dong, Yibin; Wang, Yue; Hoffman, Eric P

    2006-04-01

    Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cell-specific perturbations of the mRNA transcriptome in terminally differentiated cells. To test this model, we studied 125 human muscle biopsies from 13 diagnostic groups (125 U133A, 125 U133B microarrays), including EDMD patients with LMNA and emerin mutations. A Visual and Statistical Data Analyzer (VISDA) algorithm was used to statistically model cluster hierarchy, resulting in a tree of phenotypic classifications. Validations of the diagnostic tree included permutations of U133A and U133B arrays, and use of two probe set algorithms (MAS5.0 and MBEI). This showed that the two nuclear envelope defects (EDMD LMNA, EDMD emerin) were highly related disorders and were also related to fascioscapulohumeral muscular dystrophy (FSHD). FSHD has recently been hypothesized to involve abnormal interactions of chromatin with the nuclear envelope. To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle. A high proportion of top-ranked and validated transcripts were components of the same transcriptional regulatory pathway involving Rb1 and MyoD during muscle regeneration (CRI-1, CREBBP, Nap1L1, ECREBBP/p300), where each was specifically upregulated in EDMD. Using a muscle regeneration time series (27 time points) we develop a transcriptional model for downstream consequences of LMNA and emerin mutations. We propose that key interactions between the nuclear

  20. Genetics Home Reference: Emery-Dreifuss muscular dystrophy

    MedlinePlus

    ... Health Conditions Emery-Dreifuss muscular dystrophy Emery-Dreifuss muscular dystrophy Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Emery-Dreifuss muscular dystrophy is a condition that chiefly affects muscles used ...

  1. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    MedlinePlus

    ... Duchenne and Becker muscular dystrophy Duchenne and Becker muscular dystrophy Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Muscular dystrophies are a group of genetic conditions characterized by ...

  2. Neuromuscular Highlights-AAN 2005.

    PubMed

    Cheema, Zahid; Saperstein, David; Jackson, Carolyn; Newman, Daniel

    2006-06-01

    Summary of Neuromuscular Presentations at the 57 Annual AAN 2005 meeting in Miami Florida on topics of Facioscapulohumeral muscular dystrophy (FSHD), Duchenne muscular dystrophy (DMD), Diabetic Neuropathy, Charco Marie Tooth disease (CMT), Comparison of injected steroids versus Surgery for carpal tunnel syndrome, Rituximab in Anti-MAG associated polyneuropathy, Cannabis based medicine (CBM) in the treatment of neuropathic pain, utility of skin biopsy with intraepidermal nerve fiber density (IENFD) in sensory complaints, comparing sympathetic skin responses (SSRs) and skin biopsy in diagnosing small fiber sensory neuropathy, Chronic inflammatory demyelinating polyneuropathy (CIDP) clinical and electrophysiologic predictors, affect of limb warming in mild ulnar nerve conduction study (NCS) abnormalities, Tamoxifen affect in ALS, open label study of 3,4 DAP, Pyridostigmine and Ephedrine in fast channel syndrome, Mexilitine as an antimyotonia treatment in myotonic dystrophy (DM1), frontal lobe impairment evaluation in DM1 and DM2 patients and phenotype-genotype correlation in patients with dysferlinopathy. PMID:19078809

  3. Comparative study of thallium-201 single-photon emission computed tomography and electrocardiography in Duchenne and other types of muscular dystrophy

    SciTech Connect

    Yamamoto, S.; Matsushima, H.; Suzuki, A.; Sotobata, I.; Indo, T.; Matsuoka, Y.

    1988-04-01

    Single-photon emission computed tomography (SPECT) using thallium-201 was compared with 12-lead electrocardiography (ECG) in patients with Duchenne (29), facioscapulohumeral (7), limb-girdle (6) and myotonic (5) dystrophies, by dividing the left ventricular (LV) wall into 5 segments. SPECT showed thallium defects (37 patients, mostly in the posteroapical wall), malrotation (23), apical aneurysm (5) and dilatation (7). ECG showed abnormal QRS (36 patients), particularly as a posterolateral pattern (13). Both methods of assessment were normal in only 7 patients. The Duchenne type frequently showed both a thallium defect (particularly in the posteroapical wall) and an abnormal QRS (predominantly in the posterolateral wall); the 3 other types showed abnormalities over the 5 LV wall segments in both tests. The percent of agreement between the 2 tests was 64, 66, 70, 72 and 72 for the lateral, apical, anteroseptal, posterior and inferior walls, respectively. The 2 tests were discordant in 31% of the LV wall, with SPECT (+) but ECG (-) in 21% (mostly in the apicoinferior wall) and SPECT (-) but ECG (+) in 10% (mostly in the lateral wall). Some patients showed large SPECT hypoperfusion despite minimal electrocardiographic changes. ECG thus appeared to underestimate LV fibrosis and to reflect posteroapical rather than posterolateral dystrophy in its posterolateral QRS pattern. In this disease, extensive SPECT hypoperfusion was also shown, irrespective of clinical subtype and skeletal involvement.

  4. Hypothesis: neoplasms in myotonic dystrophy

    PubMed Central

    Hilbert, James E.; Martens, William; Thornton, Charles A.; Moxley, Richard T.; Greene, Mark H.

    2011-01-01

    Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities. PMID:19642006

  5. Cardiac transplantation in Becker muscular dystrophy.

    PubMed

    Quinlivan, R M; Dubowitz, V

    1992-01-01

    Becker muscular dystrophy is associated with abnormal cardiac features in about 75% of cases; up to one-third will develop ventricular dilatation leading to congestive cardiac failure. As this form of muscular dystrophy is relatively benign, failure to respond to medical treatment warrants assessment for cardiac transplantation.

  6. Corneal dystrophy in the dog and cat.

    PubMed

    Cooley, P L; Dice, P F

    1990-05-01

    Two types of epithelial dystrophy have been described in dogs, one each in the Boxer and Shetland Sheepdog breeds, both of which can be associated with corneal erosions. Medical therapy is recommended when erosions or tear film abnormalities are present. Stromal dystrophies documented in dogs appear to be a primary lipid deposition in various layers of the stroma, depending on the breed. Stromal dystrophies seldom lead to loss of vision, but vision loss has been observed in middle aged Airedale Terriers and aged Siberian Huskies. Treatment is usually unnecessary. The dog demonstrates two types of endothelial dystrophy, one of which (posterior polymorphous dystrophy in the American Cocker Spaniel) does not lead to corneal edema. Endothelial dystrophy observed in the Boston Terrier, Chihuahua, and other breeds is associated with progressive corneal edema, which can lead to bullous keratopathy and corneal erosions. Stromal and endothelial dystrophies, both of which are associated with rapid progression of corneal edema, occur rarely in the cat. Treatment of dystrophies with progressive corneal edema is symptomatic and palliative.

  7. Establishment of clonal myogenic cell lines from severely affected dystrophic muscles - CDK4 maintains the myogenic population

    PubMed Central

    2011-01-01

    Background A hallmark of muscular dystrophies is the replacement of muscle by connective tissue. Muscle biopsies from patients severely affected with facioscapulohumeral muscular dystrophy (FSHD) may contain few myogenic cells. Because the chromosomal contraction at 4q35 linked to FSHD is thought to cause a defect within myogenic cells, it is important to study this particular cell type, rather than the fibroblasts and adipocytes of the endomysial fibrosis, to understand the mechanism leading to myopathy. Results We present a protocol to establish clonal myogenic cell lines from even severely dystrophic muscle that has been replaced mostly by fat, using overexpression of CDK4 and the catalytic component of telomerase (human telomerase reverse transcriptase; hTERT), and a subsequent cloning step. hTERT is necessary to compensate for telomere loss during in vitro cultivation, while CDK4 prevents a telomere-independent growth arrest affecting CD56+ myogenic cells, but not their CD56- counterpart, in vitro. Conclusions These immortal cell lines are valuable tools to reproducibly study the effect of the FSHD mutation within myoblasts isolated from muscles that have been severely affected by the disease, without the confounding influence of variable amounts of contaminating connective-tissue cells. PMID:21798090

  8. Duchenne muscular dystrophy: current cell therapies

    PubMed Central

    Sienkiewicz, Dorota; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-01-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed. PMID:26136844

  9. The molecular genetics of the corneal dystrophies--current status.

    PubMed

    Klintworth, Gordon K

    2003-05-01

    The pertinent literature on inherited corneal diseases is reviewed in terms of the chromosomal localization and identification of the responsible genes. Disorders affecting the cornea have been mapped to human chromosome 1 (central crystalline corneal dystrophy, familial subepithelial corneal amyloidosis, early onset Fuchs dystrophy, posterior polymorphous corneal dystrophy), chromosome 4 (Bietti marginal crystalline dystrophy), chromosome 5 (lattice dystrophy types 1 and IIIA, granular corneal dystrophy types 1, 2 and 3, Thiel-Behnke corneal dystrophy), chromosome 9 (lattice dystrophy type II), chromosome 10 (Thiel-Behnke corneal dystrophy), chromosome 12 (Meesmann dystrophy), chromosome 16 (macular corneal dystrophy, fish eye disease, LCAT disease, tyrosinemia type II), chromosome 17 (Meesmann dystrophy, Stocker-Holt dystrophy), chromosome 20 (congenital hereditary endothelial corneal dystrophy types I and II, posterior polymorphous corneal dystrophy), chromosome 21 (autosomal dominant keratoconus) and the X chromosome (cornea verticillata, cornea farinata, deep filiform corneal dystrophy, keratosis follicularis spinulosa decalvans, Lisch corneal dystrophy). Mutations in nine genes (ARSC1, CHST6, COL8A2, GLA, GSN, KRT3, KRT12, M1S1and TGFBI [BIGH3]) account for some of the corneal diseases and three of them are associated with amyloid deposition in the cornea (GSN, M1S1, TGFBI) including most of the lattice corneal dystrophies (LCDs) [LCD types I, IA, II, IIIA, IIIB, IV, V, VI and VII] recognized by their lattice pattern of linear opacities. Genetic studies on inherited diseases affecting the cornea have provided insight into some of these disorders at a basic molecular level and it has become recognized that distinct clinicopathologic phenotypes can result from specific mutations in a particular gene, as well as some different mutations in the same gene. A molecular genetic understanding of inherited corneal diseases is leading to a better appreciation of the

  10. [Muscular Dystrophies Involving the Retinal Function].

    PubMed

    Jägle, H

    2016-03-01

    Muscular dystrophies are rare disorders, with an incidence of approx. 20 in 100 000. Some dystrophies also affect retinal or optic nerve function. In such cases, the ophthalmological findings may be critical for differential diagnosis or patient counseling. For example in Duchenne muscular dystrophy, where the alteration in retinal function seems to reflect cerebral involvement. Other important forms are mitochondrial and metabolic disorders, such as the Kearns-Sayre syndrome and the Refsum syndrome. Molecular genetic analysis has become a major tool for differential diagnosis, but may be complex and demanding. This article gives an overview of major muscular dystrophies involving retinal function and their genetic origin, in order to guide differential diagnosis.

  11. Genetics Home Reference: Fukuyama congenital muscular dystrophy

    MedlinePlus

    ... and walking. Fukuyama congenital muscular dystrophy also impairs brain development. People with this condition have a brain abnormality ... cobblestones). These changes in the structure of the brain lead to significantly delayed development of speech and motor skills and moderate to ...

  12. The Muscular Dystrophies: From Genes to Therapies

    PubMed Central

    Porter, Neil C; Bloch, Robert J

    2015-01-01

    The genetic basis of many muscular disorders, including many of the more common muscular dystrophies, is now known. Clinically, the recent genetic advances have improved diagnostic capabilities, but they have not yet provided clues about treatment or management. Thanks to better management strategies and therapeutic interventions, however, many patients with a muscular dystrophy are more active and are living longer. Physical therapists, therefore, are more likely to see a patient with a muscular dystrophy, so understanding these muscle disorders and their management is essential. Physical therapy offers the most promise in caring for the majority of patients with these conditions, because it is unlikely that advances in gene therapy will significantly alter their clinical treatment in the near future. This perspective covers some of the basic molecular biological advances together with the clinical manifestations of the muscular dystrophies and the latest approaches to their management. PMID:16305275

  13. Genetics Home Reference: Bietti crystalline dystrophy

    MedlinePlus

    ... on PubMed Central Mansour AM, Uwaydat SH, Chan CC. Long-term follow-up in Bietti crystalline dystrophy. ... VD, Zhang J, Gesualdo C, Corte MD, Chan CC, Fielding Hejtmancik J, Simonelli F. An atypical form ...

  14. Targeting latent TGFβ release in muscular dystrophy.

    PubMed

    Ceco, Ermelinda; Bogdanovich, Sasha; Gardner, Brandon; Miller, Tamari; DeJesus, Adam; Earley, Judy U; Hadhazy, Michele; Smith, Lucas R; Barton, Elisabeth R; Molkentin, Jeffery D; McNally, Elizabeth M

    2014-10-22

    Latent transforming growth factor-β (TGFβ) binding proteins (LTBPs) bind to inactive TGFβ in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGFβ release. We have found that the hinge region of human LTBP4 was also readily proteolysed and that proteolysis could be blocked by an antibody to the hinge region. Transgenic mice were generated to carry a bacterial artificial chromosome encoding the human LTBP4 gene. These transgenic mice displayed larger myofibers, increased damage after muscle injury, and enhanced TGFβ signaling. In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate and greater LTBP4 cleavage in vivo. Blocking LTBP4 cleavage may be a therapeutic strategy to reduce TGFβ release and activity and decrease inflammation and muscle damage in muscular dystrophy.

  15. Genetics Home Reference: vitelliform macular dystrophy

    MedlinePlus

    ... faces. Vitelliform macular dystrophy causes a fatty yellow pigment (lipofuscin) to build up in cells underlying the ... structures in these cells that contain light-sensing pigments. It is unclear why PRPH2 mutations affect only ...

  16. Reflex sympathetic dystrophy following traumatic myelopathy.

    PubMed

    Wainapel, S F

    1984-04-01

    Two cases of reflex sympathetic dystrophy in the upper extremity of patients with traumatic cervical spinal cord injuries are reported. Both patients had very incomplete lesions with early neurological recovery, suggesting an underlying central cord syndrome. Although reflex sympathetic dystrophy is often seen following stroke, it has only rarely been documented in traumatic myelopathy, and it should be considered in the differential diagnosis of unexplained pain syndromes in the extremities of paraplegic or quadriplegic patients. PMID:6728500

  17. Duchenne muscular dystrophy: the management of scoliosis

    PubMed Central

    Gardner, Adrian C.; Roper, Helen P.; Chikermane, Ashish A.; Tatman, Andrew J.

    2016-01-01

    This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group. PMID:27757431

  18. [Genetic diagnostic testing in inherited retinal dystrophies].

    PubMed

    Kohl, S; Biskup, S

    2013-03-01

    Inherited retinal dystrophies are clinically and genetically highly heterogeneous. They can be divided according to the clinical phenotype and course of the disease, as well as the underlying mode of inheritance. Isolated retinal dystrophies (i.e., retinitis pigmentosa, Leber's congenital amaurosis, cone and cone-rod dystrophy, macular dystrophy, achromatopsia, congenital stationary nightblindness) and syndromal forms (i.e., Usher syndrome, Bardet-Biedl syndrome) can be differentiated. To date almost 180 genes and thousands of distinct mutations have been identified that are responsible for the different forms of these blinding illnesses. Until recently, there was no adequate diagnostic genetic testing available. With the development of the next generation sequencing technologies, a comprehensive genetic screening analysis for all known genes for inherited retinal dystrophies has been established at reasonable costs and in appropriate turn-around times. Depending on the primary clinical diagnosis and the presumed mode of inheritance, different diagnostic panels can be chosen for genetic testing. Statistics show that in 55-80 % of the cases the genetic defect of the inherited retinal dystrophy can be identified with this approach, depending on the initial clinical diagnosis. The aim of any genetic diagnostics is to define the genetic cause of a given illness within the affected patient and family and thereby i) confirm the clinical diagnosis, ii) provide targeted genetic testing in family members, iii) enable therapeutic intervention, iv) give a prognosis on disease course and progression and v) in the long run provide the basis for novel therapeutic approaches and personalised medicine.

  19. Porcine models of muscular dystrophy.

    PubMed

    Selsby, Joshua T; Ross, Jason W; Nonneman, Dan; Hollinger, Katrin

    2015-01-01

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein dystrophin. This disease has been studied using a variety of animal models including fish, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression, limitations inherent to each model have slowed the clinical advancement of therapies, which necessitates the development of novel large-animal models. Several porcine dystrophin-deficient models have been identified, although disease severity may be so severe as to limit their potential contributions to the field. We have recently identified and completed the initial characterization of a natural porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs recapitulate many of the cardinal features of muscular dystrophy, have elevated serum creatine kinase activity, and preliminarily appear to display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From an animal handling perspective, these pigs can generally be treated normally, with the understanding that acute stress can lead to sudden death. In summary, the ability to create genetically modified pig models and the serendipitous discovery of genetic disease in the swine industry has resulted in the emergence of new animal tools to facilitate the critical objective of improving the quality and length of life for boys afflicted with such a devastating disease.

  20. FDA OKs 1st Drug to Treat Duchenne Muscular Dystrophy

    MedlinePlus

    ... html FDA OKs 1st Drug to Treat Duchenne Muscular Dystrophy Exondys 51 seems to fill unmet need for ... the first drug for a rare form of muscular dystrophy. Exondys 51 (eteplirsen) was granted accelerated approval to ...

  1. Differential diagnosis of Schnyder corneal dystrophy.

    PubMed

    Weiss, Jayne S; Khemichian, Arbi J

    2011-01-01

    Schnyder corneal dystrophy (SCD) is a rare corneal dystrophy characterized by abnormally increased deposition of cholesterol and phospholipids in the cornea leading to progressive vision loss. SCD is inherited as an autosomal dominant trait with high penetrance and has been mapped to the UBIAD1 gene on chromosome 1p36.3. Although 2/3 of SCD patients also have systemic hypercholesterolemia, the incidence of hypercholesterolemia is also increased in unaffected members of SCD pedigrees. Consequently, SCD is thought to result from a local metabolic defect in the cornea. The corneal findings in SCD are very predictable depending on the age of the individual, with initial central corneal haze and/or crystals, subsequent appearance of arcus lipoides in the third decade and formation of midperipheral haze in the late fourth decade. Because only 50% of affected patients have corneal crystals, the International Committee for Classification of Corneal Dystrophies recently changed the original name of this dystrophy from Schnyder crystalline corneal dystrophy to Schnyder corneal dystrophy. Diagnosis of affected individuals without crystalline deposits is often delayed and these individuals are frequently misdiagnosed. The differential diagnosis of the SCD patient includes other diseases with crystalline deposits such as cystinosis, tyrosinemia, Bietti crystalline dystrophy, hyperuricemia/gout, multiple myeloma, monoclonal gammopathy, infectious crystalline keratopathy, and Dieffenbachia keratitis. Depositions from drugs such as gold in chrysiasis, chlorpromazine, chloroquine, and clofazamine can also result in corneal deposits and are different from SCD. Diseases of systemic lipid metabolism that cause corneal opacification, such as lecithin-cholesterol acyltransferase deficiency, fish eye disease and Tangier disease, should also be considered although these are autosomal recessive disorders. PMID:21540632

  2. Unusual scapular winging - A case report.

    PubMed

    Dori, Zohar; Sarig Bahat, Hilla

    2016-08-01

    Scapular mobility has a central role in maintaining normal upper limb function. Scapular winging is characterized by a failure in the dynamic stabilization of the scapula against the thoracic wall resulting in a condition in which the medial border of the scapula is prominent. The following case describes a patient who was referred to physiotherapy due to abnormal scapular protrusion. The main findings of the physical examination showed weakness of the scapular stabilizers more prominent on the right side than of the left. Additionally, the physical examination demonstrated weakness of the abdominal muscles, hip adductors, and ankle dorsi-flexors, as well as some facial muscles. The electromyography results were inconclusive. Further examination led to clinical suspicion of Facioscapulohumeral Dystrophy (FSHD) as a diagnosis, which was confirmed by genetic testing. Facioscapulohumeral Dystrophy is characterized by symptoms related to motor function and in most cases becomes evident in patients in their 20s and 30s. The disease signs and symptoms are often identified in a clinical setting. Currently, there are no reports describing an effective treatment for the disease. However, physiotherapy, moderate physical exercise, counselling, and use of suitable aids and orthoses may help improve functionality and mobility. This case report aims to increase the awareness of musculoskeletal physiotherapists to this unique dystrophy, when encountering complex presentations with scapular winging. PMID:26759220

  3. [Congenital muscular dystrophies in children].

    PubMed

    Scavone-Mauro, Cristina; Barros, Graciela

    2013-09-01

    From the clinical and genetic point of view, congenital muscular dystrophies (CMD) are a heterogenic group of diseases within neuromuscular pathologies. The best known forms are: merosin deficiency CMD, collagen VI deficiency CMD, LMNA-related CMD, selenoprotein-related CMD (SEPN1) and alpha-dystroglycan-related CMD. They present with a broad spectrum of clinical phenotypes. Most of them are transmitted by recessive autosomal inheritance. The initial manifestations very often begin in infancy or in the neonatal period. There are clinical suspicions of the existence of hypotonia and paresis, and they are characterised by a dystrophic pattern in the muscular biopsy (muscle replaced by fibroadipose tissue, with necrosis and cell regeneration). Advances in the understanding of the molecular pathogenesis of CMD have made it possible to make further progress in the classification of the different subtypes. The aim of this review is to comment on the advances made in recent years as regards the classification of CMD in terms of genetics, the proteins involved and their clinical presentation.

  4. Genetics of Bietti Crystalline Dystrophy.

    PubMed

    Ng, Danny S C; Lai, Timothy Y Y; Ng, Tsz Kin; Pang, Chi Pui

    2016-01-01

    Bietti crystalline dystrophy (BCD) is an inherited retinal degenerative disease characterized by crystalline deposits in the retina, followed by progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and photoreceptors. CYP4V2 has been identified as the causative gene for BCD. The CYP4V2 gene belongs to the cytochrome P450 superfamily and encodes for fatty acid ω-hydroxylase of both saturated and unsaturated fatty acids. The CYP4V2 protein is localized most abundantly within the endoplasmic reticulum in the RPE and is postulated to play a role in the physiological lipid recycling system between the RPE and photoreceptors to maintain visual function. Electroretinographic assessments have revealed progressive dysfunction of rod and cone photoreceptors in patients with BCD. Several genotypes have been associated with more severe phenotypes based on clinical and electrophysiological findings. With the advent of multimodal imaging with spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics scanning laser ophthalmoscopy, more precise delineation of BCD severity and progression is now possible, allowing for the potential future development of targets for gene therapy. PMID:27228076

  5. Advances in gene therapy for muscular dystrophies

    PubMed Central

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments.

  6. Advances in gene therapy for muscular dystrophies

    PubMed Central

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments. PMID:27594988

  7. Dystroglycan induced muscular dystrophies - a review.

    PubMed

    Zhang, Q-Z

    2016-09-01

    Dystroglycanopathies are muscular dystrophies caused by mutations in genes involved the in O-linked glycosylation of α-dystroglycan. Severe forms of these conditions result in abnormalities in exhibit brain and ocular developmental too, in addition to muscular dystrophy. The full spectrum of developmental pathology is caused mainly by loss of dystroglycan from Bergmann glia. Moreover, cognitive deficits are constant features of severe forms of dystroglycanopathies. However, the precise molecular mechanism leading to neuronal dysfunction in these diseases is not fully known yet. The present review article will discuss the importance of dystroglycan in cerebellar development and associated pathological states. PMID:27649671

  8. Advances in gene therapy for muscular dystrophies.

    PubMed

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments. PMID:27594988

  9. Hypotrichosis with juvenile macular dystrophy: Portuguese case.

    PubMed

    Elfatoiki, Fatima Zahra; Cordoliani, Florance; Pascal Regane, Pascal; Afforitit-Demoge, Aude

    2016-01-01

    Hypotrichosis with juvenile macular dystrophy is a rare congenital disease mainly found in the Druze population of Northern Israel. This disorder is caused by the CDH3 mutation encoding P-cadherin, which is expressed in retinal pigment epithelium and hair follicles. An 11-year-old girl who was born to related Portuguese parents, had hypotrichosis since birth and macular dystrophy diagnosed at age 5. Fundus examination and fluorescein angiography revealed located macular pigmentary abnormalities. No molecular analysis was done. A fundus examination should be considered mandatory in the assessment of congenital hypotrichosis. PMID:27617529

  10. How the magnitude of clinical severity and recurrence risk affects reproductive decisions in adult males with different forms of progressive muscular dystrophy.

    PubMed Central

    Eggers, S; Zatz, M

    1998-01-01

    The reproductive history of 177 male patients affected with Becker (BMD) (n=69), limb-girdle (LGMD) (n=54), and facioscapulohumeral (FSHMD) (n=54) muscular dystrophy (MD) was analysed according to severity of the disease (BMD>LGMD>FSHMD) and magnitude of recurrence risk (RR) (high for FSHMD, intermediate for BMD, and low for LGMD). Additionally, 62 male patients were interviewed on psychosocial issues, in order to disentangle the factors influencing reproductive decisions among patients affected with MD. Among male adults, significantly more FSHMD than LGMD or BMD patients were married and had children. Age specific reproductive outcome was 0.31-0.32 for BMD, 0.51-0.62 for LGMD, and 0.58-1.02 for FSHMD, reflecting the influence of the disease's severity. High RRs did not significantly diminish reproduction after genetic counselling or correlate with less prospective desire for children. Instead, early onset, severity of the disease, and past reproductive history were found to diminish reproductive outcome after genetic counselling, and prospective family planning was also found to be influenced by past reproductive history as well as by emotional/sexual dysfunction with the opposite sex. PMID:9541101

  11. How the magnitude of clinical severity and recurrence risk affects reproductive decisions in adult males with different forms of progressive muscular dystrophy.

    PubMed

    Eggers, S; Zatz, M

    1998-03-01

    The reproductive history of 177 male patients affected with Becker (BMD) (n=69), limb-girdle (LGMD) (n=54), and facioscapulohumeral (FSHMD) (n=54) muscular dystrophy (MD) was analysed according to severity of the disease (BMD>LGMD>FSHMD) and magnitude of recurrence risk (RR) (high for FSHMD, intermediate for BMD, and low for LGMD). Additionally, 62 male patients were interviewed on psychosocial issues, in order to disentangle the factors influencing reproductive decisions among patients affected with MD. Among male adults, significantly more FSHMD than LGMD or BMD patients were married and had children. Age specific reproductive outcome was 0.31-0.32 for BMD, 0.51-0.62 for LGMD, and 0.58-1.02 for FSHMD, reflecting the influence of the disease's severity. High RRs did not significantly diminish reproduction after genetic counselling or correlate with less prospective desire for children. Instead, early onset, severity of the disease, and past reproductive history were found to diminish reproductive outcome after genetic counselling, and prospective family planning was also found to be influenced by past reproductive history as well as by emotional/sexual dysfunction with the opposite sex.

  12. The IC3D Classification of the Corneal Dystrophies

    PubMed Central

    Weiss, Jayne S.; Møller, H. U.; Lisch, Walter; Kinoshita, Shigeru; Aldave, Anthony J.; Belin, Michael W.; Kivelä, Tero; Busin, Massimo; Munier, Francis L.; Seitz, Berthold; Sutphin, John; Bredrup, Cecilie; Mannis, Mark J.; Rapuano, Christopher J.; Van Rij, Gabriel; Kim, Eung Kweon; Klintworth, Gordon K.

    2010-01-01

    Background The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. Purpose The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. Methods The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. Results This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. Conclusions The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d. PMID:19337156

  13. Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene

    PubMed Central

    Dandapat, Abhijit; Bosnakovski, Darko; Hartweck, Lynn M.; Arpke, Robert W.; Baltgalvis, Kristen A.; Vang, Derek; Baik, June; Darabi, Radbod; Perlingeiro, RitaC.R.; Hamra, F. Kent; Gupta, Kalpna; Lowe, Dawn A.; Kyba, Michael

    2014-01-01

    SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) is an enigmatic disease associated with epigenetic alterations in the subtelomeric heterochromatin of the D4Z4 macrosatellite repeat. Each repeat unit encodes DUX4, a gene that is normally silent in most tissues. Besides muscular loss, most patients suffer retinal vascular telangiectasias. To generate an animal model, we introduced a doxycycline-inducible transgene encoding DUX4and 3′genomic DNA into a euchromatic region of the mouse X chromosome. Without induction, DUX4 RNA was expressed at low levels in many tissues and animals displayed a variety of unexpected dominant leaky phenotypes, including male-specific lethality. Remarkably, rare live-born males expressed DUX4 RNA in the retina and presented a retinal vascular telangiectasia. By using doxycycline to induce DUX4 expression in satellite cells, we observed impaired myogenesis in vitro and in vivo. This mouse model, which shows pathologies due to FSHD-related D4Z4 sequences, is likely to be useful for testing anti-DUX4 therapies in FSHD. PMID:25176645

  14. Cardiomyopathy in becker muscular dystrophy: Overview

    PubMed Central

    Ho, Rady; Nguyen, My-Le; Mather, Paul

    2016-01-01

    Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed. PMID:27354892

  15. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  16. 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

  17. An unusual central retinal dystrophy associated with ichthyosis vulgaris.

    PubMed

    Saatci, O A; Ozbek, Z; Köse, S; Durak, I; Kavukçu, S

    2000-06-01

    A number of ichthyosis syndromes may have retinal abnormalities such as the retinitis pigmentosa-like diffuse rod-cone dystrophy in Refsum's syndrome and the maculopathy in Sjögren-Larsson syndrome. We present two sisters who have an unusual, almost identical, bilaterally symmetric central retinal dystrophy associated with ichthyosis vulgaris in the absence of other systemic disorders. We believe that this dystrophy has not been previously described in patients with any of the known varieties of ichthyosis.

  18. Cogan's microcystic dystrophy of the cornea: ultrastructure and photomicroscopy.

    PubMed Central

    Dark, A J

    1978-01-01

    Corneal biopsy specimens from 3 patients with Cogan's microcystic corneal dystrophy were examined by light and electron microscopy. Specimens were taken from corneas showing microcysts, geographic or map-like areas, and refractile striae. In all samples there is a bilaminate subepithelial layer of fibrogranular material, the friability of which is probably the basis for recurrent erosions in this disorder. Histochemical and ultrastructural findings provide further evidence that Cogan's dystrophy, the finger print/bleb dystrophy, and Meesmann's dystrophy should be regarded as separate entities. Images PMID:310689

  19. Risk estimates for neonatal myotonic dystrophy.

    PubMed Central

    Glånz, A; Fråser, F C

    1984-01-01

    Children who inherit the autosomal dominant gene for myotonic dystrophy from their mother rather than their father may develop the severe neonatal type rather than the late onset type. The families of 22 neonatal type probands and 59 late onset type probands were studied to determine the risk of occurrence and recurrence of the neonatal type. The frequency of the neonatal type in sibs of neonatal type probands was 29%, or 37% if cases of neonatal deaths are counted as affected. This is significantly higher than the 6% of the neonatal type found in the offspring of affected women not ascertained through a child with the neonatal type. These data suggest that certain women carrying the gene for myotonic dystrophy are predisposed to have children affected with the neonatal type rather than the late onset type. The female near relatives of these women do not seem to share this predisposition. The data should be useful for genetic counseling. PMID:6748014

  20. Reflex sympathetic dystrophy associated with antiepileptic drugs.

    PubMed

    Falasca, G F; Toly, T M; Reginato, A J; Schraeder, P L; O'Connor, C R

    1994-01-01

    Reflex sympathetic dystrophy syndrome (RSDS) complicating antiepileptic drug (AED) therapy is not well acknowledged in the neurologic literature. We report 4 patients with reflex sympathetic dystrophy that occurred while they were receiving AEDs. All patients had shoulder and hand involvement, which in 2 was bilateral, and 1 had ipsilateral foot involvement. Two patients did not respond to a change in AEDs, but all improved with a course of prednisone. One patient with phenobarbital (PB)-associated RSDS relapsed on inadvertent rechallenge with secobarbital. A review of the literature showed that several other fibrosing disorders are associated with AED administration, including Dupuytren's contractures, frozen shoulder, plantar and hand nodules, and Peyronie's disease. RSD associated with AEDs is important to recognize because it may result in permanent disability if treatment is delayed.

  1. Therapeutics Development in Myotonic Dystrophy Type I

    PubMed Central

    Foff, Erin Pennock; Mahadevan, Mani S.

    2011-01-01

    Myotonic dystrophy (DM1), the most common adult muscular dystrophy, is a multi-system, autosomal dominant genetic disorder caused by an expanded CTG repeat that leads to nuclear retention of a mutant RNA and subsequent RNA toxicity. Significant insights into the molecular mechanisms of RNA toxicity have led to the surprising possibility that treating DM1 is a viable prospect. In this review, we briefly present the clinical picture in DM1, and describe how the research in understanding the pathogenesis of RNA toxicity in DM1 has led to targeted approaches to therapeutic development at various steps in the pathogenesis of the disease. We discuss the promise and current limitations of each with an emphasis on RNA-based therapeutics and small molecules. We conclude with a discussion of the unmet need for clinical tools and outcome measures that are essential prerequisites to proceed in evaluating these potential therapies in clinical trials. PMID:21607985

  2. Limb Girdle Muscular Dystrophy (LGMD): Case Report

    PubMed Central

    Kalyan, Meenakshi; Gaikwad, Anu N.; Makadia, Ankit; Shah, Harshad

    2015-01-01

    We report a young male of autosomal recessive limb girdle muscular dystrophy (LGMD) with positive family history presented with gradual onset proximal muscle weakness in all four limbs since eight years and thinning of shoulders, arms and thighs. Neurological examination revealed atrophy of both shoulders with wasting of both deltoids thinning of thighs and pseudo hypertrophy of both calves, hypotonia in all four limbs. Gower’s sign was positive. Winging of scapula was present. Power was 3/5 at both shoulders, 4/5 at both elbows, 5/5 at both wrists, 3/5 at both hip joints, 3/5 at both knees, 5/5 at both ankles. All deep tendon reflexes and superficial reflexes were present with plantars bilateral flexors. Electromyography (EMG) showed myopathic pattern. He had elevated creatinine phosphokinase levels and muscle biopsy findings consistent with muscular dystrophy. PMID:25738022

  3. Dog Models for Blinding Inherited Retinal Dystrophies

    PubMed Central

    Komáromy, András M.

    2015-01-01

    Abstract Spontaneous canine models exist for several inherited retinal dystrophies. This review will summarize the models and indicate where they have been used in translational gene therapy trials. The RPE65 gene therapy trials to treat childhood blindness are a good example of how studies in dogs have contributed to therapy development. Outcomes in human clinical trials are compared and contrasted with the result of the preclinical dog trials. PMID:25671556

  4. Dog models for blinding inherited retinal dystrophies.

    PubMed

    Petersen-Jones, Simon M; Komáromy, András M

    2015-03-01

    Spontaneous canine models exist for several inherited retinal dystrophies. This review will summarize the models and indicate where they have been used in translational gene therapy trials. The RPE65 gene therapy trials to treat childhood blindness are a good example of how studies in dogs have contributed to therapy development. Outcomes in human clinical trials are compared and contrasted with the result of the preclinical dog trials.

  5. Dog models for blinding inherited retinal dystrophies.

    PubMed

    Petersen-Jones, Simon M; Komáromy, András M

    2015-03-01

    Spontaneous canine models exist for several inherited retinal dystrophies. This review will summarize the models and indicate where they have been used in translational gene therapy trials. The RPE65 gene therapy trials to treat childhood blindness are a good example of how studies in dogs have contributed to therapy development. Outcomes in human clinical trials are compared and contrasted with the result of the preclinical dog trials. PMID:25671556

  6. Muscular Dystrophies at Different Ages: Metabolic and Endocrine Alterations

    PubMed Central

    Cruz Guzmán, Oriana del Rocío; Chávez García, Ana Laura; Rodríguez-Cruz, Maricela

    2012-01-01

    Common metabolic and endocrine alterations exist across a wide range of muscular dystrophies. Skeletal muscle plays an important role in glucose metabolism and is a major participant in different signaling pathways. Therefore, its damage may lead to different metabolic disruptions. Two of the most important metabolic alterations in muscular dystrophies may be insulin resistance and obesity. However, only insulin resistance has been demonstrated in myotonic dystrophy. In addition, endocrine disturbances such as hypogonadism, low levels of testosterone, and growth hormone have been reported. This eventually will result in consequences such as growth failure and delayed puberty in the case of childhood dystrophies. Other consequences may be reduced male fertility, reduced spermatogenesis, and oligospermia, both in childhood as well as in adult muscular dystrophies. These facts all suggest that there is a need for better comprehension of metabolic and endocrine implications for muscular dystrophies with the purpose of developing improved clinical treatments and/or improvements in the quality of life of patients with dystrophy. Therefore, the aim of this paper is to describe the current knowledge about of metabolic and endocrine alterations in diverse types of dystrophinopathies, which will be divided into two groups: childhood and adult dystrophies which have different age of onset. PMID:22701119

  7. Hypothalamic-pituitary function in myotonic dystrophy.

    PubMed

    Mahler, C; Parizel, G

    1982-01-01

    Function of the hypothalamic-pituitary axis was investigated in seven patients with myotonic dystrophy (MD). HGH and ACTH secretion were normal. TSH response to TRH was impaired in about half the cases, without concomitant thyroid dysfunction. LH and FSH levels were often elevated, with inconsistent response to LH-RH stimulation, Gonadotrophin disturbances in MD have previously been attributed to a primary gonadal lesion, characteristically seen in this disease. High prolactin levels in six of our seven patients however suggest that gonadal failure may be also be due to hyperprolactinemia through the direct anti-gonadal effect of prolactin and its interference with hypothalamic-pituitary regulation of gonadotrophin secretion.

  8. Noncoding RNAs: Emerging Players in Muscular Dystrophies

    PubMed Central

    2014-01-01

    The fascinating world of noncoding RNAs has recently come to light, thanks to the development of powerful sequencing technologies, revealing a variety of RNA molecules playing important regulatory functions in most, if not all, cellular processes. Many noncoding RNAs have been implicated in regulatory networks that are determinant for skeletal muscle differentiation and disease. In this review, we outline the noncoding RNAs involved in physiological mechanisms of myogenesis and those that appear dysregulated in muscle dystrophies, also discussing their potential use as disease biomarkers and therapeutic targets. PMID:24729974

  9. Emerging Drugs for Duchenne Muscular Dystrophy

    PubMed Central

    Malik, Vinod; Rodino-Klapac, Louise; Mendell, Jerry R.

    2012-01-01

    Introduction Duchenne muscular dystrophy (DMD) is the most common, severe childhood form of muscular dystrophy. Treatment is limited to glucocorticoids that have the benefit of prolonging ambulation by approximately 2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efficacy with a minimal side effect profile. Areas covered Authors discuss different therapeutic strategies that have been used in pre-clinical and clinical settings. Expert opinion Multiple treatment approaches have emerged. Most attractive are molecular-based therapies that can express the missing dystrophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Other approaches include increasing the strength of muscles (myostatin inhibitors), reducing muscle fibrosis, and decreasing oxidative stress. Additional targets include inhibiting NF-κB to reduce inflammation, or promoting skeletal muscle blood flow and muscle contractility using phosphodiesterase inhibitors or nitric oxide (NO) donors. The potential for each of these treatment strategies to enter clinical trials is a central theme of discussion. The review emphasizes that the goal of treatment should be to find a product at least as good as glucocorticoids with a lower side effect profile or with a significant glucocorticoid sparing effect. PMID:22632414

  10. Congenital muscular dystrophy with inflammation: Diagnostic considerations

    PubMed Central

    Konkay, Kaumudi; Kannan, Meena Angamuthu; Lingappa, Lokesh; Uppin, Megha S.; Challa, Sundaram

    2016-01-01

    Background and Purpose: Muscle biopsy features of congenital muscular dystrophies (CMD) vary from usual dystrophic picture to normal or nonspecific myopathic picture or prominent fibrosis or striking inflammatory infiltrate, which may lead to diagnostic errors. A series of patients of CMD with significant inflammatory infiltrates on muscle biopsy were correlated with laminin α2 deficiency on immunohistochemistry (IHC). Material and Methods: Cryostat sections of muscle biopsies from the patients diagnosed as CMD on clinical and muscle biopsy features from 1996 to 2014 were reviewed with hematoxylin and eosin(H&E), enzyme and immunohistochemistry (IHC) with laminin α2. Muscle biopsies with inflammatory infiltrate were correlated with laminin α2 deficiency. Results: There were 65 patients of CMD, with inflammation on muscle biopsy in 16. IHC with laminin α2 was available in nine patients, of which six showed complete absence along sarcolemma (five presented with floppy infant syndrome and one with delayed motor milestones) and three showed discontinuous, and less intense staining. Conclusions: CMD show variable degrees of inflammation on muscle biopsy. A diagnosis of laminin α2 deficient CMD should be considered in patients of muscular dystrophy with inflammation, in children with hypotonia/delayed motor milestones. PMID:27570388

  11. Diagnostic Odyssey of Patients with Myotonic Dystrophy

    PubMed Central

    Hilbert, James E.; Ashizawa, Tetsuo; Day, John W.; Luebbe, Elizabeth A.; Martens, William B.; McDermott, Michael P.; Tawil, Rabi; Thornton, Charles A.; Moxley, Richard T.

    2013-01-01

    The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 ± 14.1 years in DM2 patients compared to 26.1 ± 13.2 years in DM1 (p<0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6%) compared to grip myotonia in DM1 (38.3%). Pain was reported as the first symptom in 11.1% of DM2 and 3.0% of DM1 patients (p<0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed. PMID:23807151

  12. Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies.

    PubMed

    Gerard, Xavier; Garanto, Alejandro; Rozet, Jean-Michel; Collin, Rob W J

    2016-01-01

    Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several technical challenges so far prevent a broad clinical application of this approach for other forms of IRD. Many of the mutations leading to these retinal diseases affect pre-mRNA splicing of the mutated genes . Antisense oligonucleotide (AON)-mediated splice modulation appears to be a powerful approach to correct the consequences of such mutations at the pre-mRNA level , as demonstrated by promising results in clinical trials for several inherited disorders like Duchenne muscular dystrophy, hypercholesterolemia and various types of cancer. In this mini-review, we summarize ongoing pre-clinical research on AON-based therapy for a few genetic subtypes of IRD , speculate on other potential therapeutic targets, and discuss the opportunities and challenges that lie ahead to translate splice modulation therapy for retinal disorders to the clinic.

  13. Oxidative stress and the pathogenesis of muscular dystrophies.

    PubMed

    Rando, Thomas A

    2002-11-01

    The muscular dystrophies represent a diverse group of diseases differing in underlying genetic basis, age of onset, mode of inheritance, and severity of progression, but they share certain common pathologic features. Most prominent among these features is the necrotic degeneration of muscle fibers. Although the genetic basis of many of the dystrophies has been known for over a decade and new disease genes continue to be discovered, the pathogenetic mechanisms leading to muscle cell death in the dystrophies remain a mystery. This review focuses on the oxidative stress theory, which states that the final common pathway of muscle cell death in these diseases involves oxidative damage.

  14. Benign muscular dystrophy: risk calculation in families with consanguinity.

    PubMed Central

    Wolff, G; Müller, C R; Grimm, T

    1989-01-01

    This report concerns two families in which the index patients are sporadic cases of a benign form of muscular dystrophy. In both families the sisters of the patients have married a close relative. The respective risks for a child of these consanguineous marriages being affected with either X linked Becker muscular dystrophy or autosomal recessive limb girdle muscular dystrophy is calculated using pedigree information, results of serum creatine kinase determinations, and also, in one family, results of DNA typing using RFLPs from the short arm of the X chromosome. PMID:2732990

  15. Acetazolamide for cystoid macular oedema in Bietti crystalline retinal dystrophy.

    PubMed

    Broadhead, Geoffrey K; Chang, Andrew A

    2014-04-01

    Bietti crystalline retinal dystrophy is a rare, inherited disorder whose hallmark is the presence of retinal crystal deposits associated with later chorioretinal degeneration. This condition may rarely be complicated by the development of cystoid macular oedema leading to rapid visual decline. Currently, treatment options for this complication of Bietti dystrophy are limited and the visual prognosis is poor. Here, we present a case of cystoid macular oedema associated with Bietti dystrophy that was successfully diagnosed using multimodal imaging techniques including optical coherence tomography and fluorescein angiography. These modalities confirmed the diagnosis of macular oedema and excluded other possible causes of oedema such as choroidal neovascularisation. In this patient, cystoid macular oedema was resolved with oral acetazolamide therapy, a treatment that has not been previously reported in this context. Acetazolamide treatment resulted in oedema resolution and improvement in visual function, and can be considered a therapeutic option for other patients with Bietti dystrophy who develop cystoid macular oedema.

  16. Macular pattern dystrophy and homonymous hemianopia in MELAS syndrome.

    PubMed

    Kamal-Salah, Radua; Baquero-Aranda, Isabel; Grana-Pérez, María Del Mar; García-Campos, Jose Manuel

    2015-03-12

    We report an unusual association of a pattern dystrophy of the retinal pigment epithelium and homonymous hemianopia in a woman diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome.

  17. Genetics Home Reference: limb-girdle muscular dystrophy

    MedlinePlus

    ... most common form of limb-girdle muscular dystrophy , accounting for about 30 percent of cases. Dysferlinopathy, also ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  18. Macular pattern dystrophy and homonymous hemianopia in MELAS syndrome.

    PubMed

    Kamal-Salah, Radua; Baquero-Aranda, Isabel; Grana-Pérez, María Del Mar; García-Campos, Jose Manuel

    2015-01-01

    We report an unusual association of a pattern dystrophy of the retinal pigment epithelium and homonymous hemianopia in a woman diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome. PMID:25766436

  19. Muscular dystrophy of mink: a new animal model.

    PubMed

    Hegreberg, G A; Hamilton, M J; Padgett, G A

    1976-04-01

    Muscular dystrophies comprise an important group of inherited disorders of man. Although the disease has been studied extensively, little is known about the underlying primary pathomechanisms. Consequently, treatment of patients is difficult and prognosis is poor. An animal model of muscular dystrophy is a useful research tool for approaching the basic problems of pathogenesis in muscle diseases. An inherited progressive muscular dystrophy of mink which resembles the amyotonic forms of human muscular dystrophy is currently under study. Clinically, the earliest sign is progressive muscular weakness and atrophy. Muscle enzyme activities in serum are usually elevated to pathologic levels. Urinary creatine/creatinine ratio is elevated. Pathologic changes are limited to skeletal muscle and are typical of those seen in amyotonic forms of human muscular dystrophy. These changes include variation in diameter size of muscle fibers, centralized nuclei, floccular and hyaline degeneration of scattered muscle fibers, increase in connective tissue in endomysial and perimysial areas, and regenerative attempts. Both type I and type II muscle fibers are involved in the disease process. Genetic studies indicate an autosomal recessive mode of inheritance. Although the primary defect in muscular dystrophy is traditionally thought to reside in skeletal muscle, recent studies have produced theories of primary involvement of other tissues and organ systems. These theories are presented and relationships to the traditional theory are discussed.

  20. Oculopharyngeal muscular dystrophy: a polyalanine myopathy.

    PubMed

    Brais, Bernard

    2009-01-01

    It has been 10 years since the identification of the first PABPN1 gene (GCN)(n)/polyalanine mutations responsible for oculopharyngeal muscular dystrophy (OPMD). These mutations have been found in most cases of OPMD diagnosed in more than 35 countries. Sequence analyses have shown that such mutations have occurred numerous times in human history. Although PABPN1 was found early on to be a component of the classic filamentous intranuclear inclusions (INIs), mRNA and other proteins also have been found to coaggregate in the INIs. It is still unclear if the INIs play a pathologic or a protective role. The generation of numerous cell and animal models of OPMD has led to greater insight into its complex molecular pathophysiology and identified the first candidate therapeutic molecules. This paper reviews basic and clinical research on OPMD, with special emphasis on recent developments in the understanding of its pathophysiology.

  1. Congenital, hypotonic-sclerotic muscular dystrophy.

    PubMed Central

    Furukawa, T; Toyokura, Y

    1977-01-01

    Four cases of congenital, hypotonic-sclerotic muscular dystrophy are presented. The patients showed clinically prominent features described by Ullrich, i.e. congenital muscle weakness, hypotonia, and hyperextensibility of distal joints, contractures of proximal joints, high-arched palate, hyperhidrosis, posterior protrusion of calcaneus, and no progression. Muscle biopsies revealed dystrophic changes. Ullrich suggested that this condition was a new entity, but the disease has received little attention. In the present cases superior intelligence and tendency to recurrent upper respiratory tract infections were stressed as characteristics of this disorder. Insufficient cellular immunity was suspected and this may contribute to the recurrent upper respiratory tract infections and pneumonia often observed. This disease is considered a distinct entity of multisystemic involvement inherited as an autosomal recessive trait. Images PMID:604494

  2. Neuromuscular function in limb girdle dystrophy.

    PubMed Central

    Belanger, A Y; McComas, A J

    1985-01-01

    The contractile properties of ankle dorsiflexor and plantarflexor muscles in 20 patients with limb girdle muscular dystrophy have been compared with those in matched controls. Twitch and voluntary torques were significantly smaller in the patient population and in nine patients it was impossible to record a twitch from tibialis anterior, a dorsiflexor muscle studied in detail. The disease process evidently ran a more rapid course in tibialis anterior than in plantarflexor muscles and this susceptibility was related to some aspect of the muscle other than its fibre type composition. Surviving fibres in dorsiflexor and plantarflexor muscles did not reveal evidence of excitation-contraction uncoupling; they exhibited normal post-activation potentiation and fatigue properties. Some patients were initially incapable of exciting their motor units maximally during voluntary contractions. A finding of possible pathogenetic significance was that one patient, with prominent calves, developed exceptionally large voluntary torque in his plantarflexor muscles. PMID:4087001

  3. Porcine Models of Muscular Dystrophy1

    PubMed Central

    Selsby, Joshua T.; Ross, Jason W.; Nonneman, Dan; Hollinger, Katrin

    2015-01-01

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein dystrophin. This disease has been studied using a variety of animal models including fish, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression, limitations inherent to each model have slowed the clinical advancement of therapies, which necessitates the development of novel large-animal models. Several porcine dystrophin-deficient models have been identified, although disease severity may be so severe as to limit their potential contributions to the field. We have recently identified and completed the initial characterization of a natural porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs recapitulate many of the cardinal features of muscular dystrophy, have elevated serum creatine kinase activity, and preliminarily appear to display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From an animal handling perspective, these pigs can generally be treated normally, with the understanding that acute stress can lead to sudden death. In summary, the ability to create genetically modified pig models and the serendipitous discovery of genetic disease in the swine industry has resulted in the emergence of new animal tools to facilitate the critical objective of improving the quality and length of life for boys afflicted with such a devastating disease. PMID:25991703

  4. Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication

    MedlinePlus

    ... 2013 March 2013 (historical) Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication A readily available ... effects of a promising experimental treatment for Duchenne muscular dystrophy (DMD), according to research partially funded by the ...

  5. NIH study shows increased risk for two types of myotonic muscular dystrophy

    Cancer.gov

    Adults with a form of muscular dystrophy called myotonic muscular dystrophy (MMD) may be at increased risk of developing cancer, according to a study by investigators at the National Cancer Institute (NCI), part of the National Institutes of Health.

  6. DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis

    PubMed Central

    Krom, Yvonne D.; Banerji, Christopher R. S.; Panamarova, Maryna; Moyle, Louise A.; den Hamer, Bianca; van der Maarel, Silvère M.

    2016-01-01

    ABSTRACT Skeletal muscle wasting in facioscapulohumeral muscular dystrophy (FSHD) results in substantial morbidity. On a disease-permissive chromosome 4qA haplotype, genomic and/or epigenetic changes at the D4Z4 macrosatellite repeat allows transcription of the DUX4 retrogene. Analysing transgenic mice carrying a human D4Z4 genomic locus from an FSHD-affected individual showed that DUX4 was transiently induced in myoblasts during skeletal muscle regeneration. Centromeric to the D4Z4 repeats is an inverted D4Z4 unit encoding DUX4c. Expression of DUX4, DUX4c and DUX4 constructs, including constitutively active, dominant-negative and truncated versions, revealed that DUX4 activates target genes to inhibit proliferation and differentiation of satellite cells, but that it also downregulates target genes to suppress myogenic differentiation. These transcriptional changes elicited by DUX4 in mouse have significant overlap with genes regulated by DUX4 in man. Comparison of DUX4 and DUX4c transcriptional perturbations revealed that DUX4 regulates genes involved in cell proliferation, whereas DUX4c regulates genes engaged in angiogenesis and muscle development, with both DUX4 and DUX4c modifing genes involved in urogenital development. Transcriptomic analysis showed that DUX4 operates through both target gene activation and repression to orchestrate a transcriptome characteristic of a less-differentiated cell state. PMID:27744317

  7. High Frequency Hearing Loss and Hyperactivity in DUX4 Transgenic Mice

    PubMed Central

    Dandapat, Abhijit; Perrin, Benjamin J.; Cabelka, Christine; Razzoli, Maria; Ervasti, James M.; Bartolomucci, Alessandro; Lowe, Dawn A.; Kyba, Michael

    2016-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is caused by mutations leading to ectopic expression of the transcription factor DUX4, and encompasses both muscle-related and non-muscle phenotypes. Mouse models bearing this gene represent valuable tools to investigate which pathologies are due to DUX4 expression, and how DUX4 leads to these pathologies. The iDUX4(2.7) mouse contains an X-linked doxycycline-inducible DUX4 gene that shows low level basal expression in the absence of doxycycline, leading to male lethality, generally in embryo, but always before 8 weeks of age. Here, we describe additional non-muscle phenotypes in this animal model. We find that iDUX4(2.7) female carriers are extremely hyperactive, spending large amounts of time ambulating and much less time resting. Rare 3-week old males, although hypophagic, runted and extremely fragile, are capable of high activity, but show periods of catatonic torpor in which animals appear dead and respiration is virtually absent. We also examine a non-muscle phenotype of interest to FSHD, high frequency hearing loss. We find that young iDUX4(2.7) females are significantly impaired in their ability to hear at frequencies above 8 kHz. These phenotypes make the iDUX4(2.7) mouse an attractive model in which to study non-muscle activities of DUX4. PMID:26978271

  8. The epigenetic regulator Smchd1 contains a functional GHKL-type ATPase domain.

    PubMed

    Chen, Kelan; Dobson, Renwick C J; Lucet, Isabelle S; Young, Samuel N; Pearce, F Grant; Blewitt, Marnie E; Murphy, James M

    2016-06-15

    Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic regulator that plays critical roles in gene regulation during development. Mutations in SMCHD1 were recently implicated in the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD), although the mechanistic basis remains of outstanding interest. We have previously shown that Smchd1 associates with chromatin via its homodimeric C-terminal hinge domain, yet little is known about the function of the putative GHKL (gyrase, Hsp90, histidine kinase, MutL)-type ATPase domain at its N-terminus. To formally assess the structure and function of Smchd1's ATPase domain, we have generated recombinant proteins encompassing the predicted ATPase domain and the adjacent region. Here, we show that the Smchd1 N-terminal region exists as a monomer and adopts a conformation resembling that of monomeric full-length heat shock protein 90 (Hsp90) protein in solution, even though the two proteins share only ∼8% overall sequence identity. Despite being monomeric, the N-terminal region of Smchd1 exhibits ATPase activity, which can be antagonized by the reaction product, ADP, or the Hsp90 inhibitor, radicicol, at a nanomolar concentration. Interestingly, introduction of an analogous mutation to that identified in SMCHD1 of an FSHD patient compromised protein stability, suggesting a possible molecular basis for loss of protein function and pathogenesis. Together, these results reveal important structure-function characteristics of Smchd1 that may underpin its mechanistic action at the chromatin level. PMID:27059856

  9. Interaction of atypical cadherin Fat1 with SoHo adaptor proteins CAP/ponsin and ArgBP2.

    PubMed

    Braun, Gerald S; Kuszka, Andrzej; Dau, Cécile; Kriz, Wilhelm; Moeller, Marcus J

    2016-03-25

    Mammalian Fat1 is a giant atypical cadherin/tumor suppressor involved in the regulation of cellular orientation, migration, and growth. Fat1 is implicated in the development of the brain, eye, and kidney. Altered expression or mutations of FAT1 are also associated with cancer and facioscapulohumeral muscular dystrophy (FSHD). Yet, the mechanistic functions of this pathway remain incompletely understood. Here, we report the identification of Sorbin-homology (SoHo) proteins as novel interaction partners of Fat1 by virtue of a yeast-two-hybrid screen. SoHo proteins play diverse roles as adaptor proteins in cell signaling, cell adhesion and sarcomere architecture, including altered expression in cancer and FSHD. Specifically, we found SoHo proteins CAP/ponsin-1 and -2 (Sorbs1) and ArgBP2 (Sorbs2) to interact with the cytoplasmic domain of Fat1. We mapped the interaction to a prolin-rich classic type II PXXP motif within Fat1 and to the three Src-homology (SH3) domains within SoHo proteins using mutant expression in yeast, pulldown assays, and cell culture. Functionally, endogenous ponsin-2 expression of NRK-52E cells at cellular leading edges was lost upon knockdown of Fat1. In summary, our data point to an interaction of Fat1 with SoHo proteins that is able to recruit SoHo proteins to sites of Fat1 expression. PMID:26903299

  10. High Frequency Hearing Loss and Hyperactivity in DUX4 Transgenic Mice.

    PubMed

    Dandapat, Abhijit; Perrin, Benjamin J; Cabelka, Christine; Razzoli, Maria; Ervasti, James M; Bartolomucci, Alessandro; Lowe, Dawn A; Kyba, Michael

    2016-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is caused by mutations leading to ectopic expression of the transcription factor DUX4, and encompasses both muscle-related and non-muscle phenotypes. Mouse models bearing this gene represent valuable tools to investigate which pathologies are due to DUX4 expression, and how DUX4 leads to these pathologies. The iDUX4(2.7) mouse contains an X-linked doxycycline-inducible DUX4 gene that shows low level basal expression in the absence of doxycycline, leading to male lethality, generally in embryo, but always before 8 weeks of age. Here, we describe additional non-muscle phenotypes in this animal model. We find that iDUX4(2.7) female carriers are extremely hyperactive, spending large amounts of time ambulating and much less time resting. Rare 3-week old males, although hypophagic, runted and extremely fragile, are capable of high activity, but show periods of catatonic torpor in which animals appear dead and respiration is virtually absent. We also examine a non-muscle phenotype of interest to FSHD, high frequency hearing loss. We find that young iDUX4(2.7) females are significantly impaired in their ability to hear at frequencies above 8 kHz. These phenotypes make the iDUX4(2.7) mouse an attractive model in which to study non-muscle activities of DUX4. PMID:26978271

  11. Modifier Genes and their effect on Duchenne Muscular Dystrophy

    PubMed Central

    Vo, Andy H.; McNally, Elizabeth M.

    2015-01-01

    Purpose of Review Recently, genetic pathways that modify the clinical severity of Duchenne Muscular Dystrophy have been identified. The pathways uncovered as modifiers are useful to predict prognosis and also elucidate molecular signatures that can be manipulated therapeutically. Recent Findings Modifiers have been identified using combinations of transcriptome and genome profiling. Osteopontin, encoded by the SPP1 gene, was found using gene expression profiling. LTBP4, encoding latent transforming growth factor β binding protein 4 was initially discovered using a genomewide screen in mice and then validated in cohorts of Duchenne Muscular Dystrophy patients. These two pathways converge in that they both regulate TGFβ. A third modifier, Anxa6 that specifies annexin A6, is a calcium binding protein has been identified using mouse models, and regulates the injury pathway and sarcolemmal resealing. Summary Genetic modifiers can serve as biomarkers for outcomes in Duchenne Muscular Dystrophy. Modifiers can alter strength and ambulation in muscular dystrophy, and these same features can be used as endpoints used in clinical trials. Moreover, because genetic modifiers can influence outcomes, these genetic markers should be considered when stratifying results in muscular dystrophy. PMID:26263473

  12. Neurocognitive Profiles in Duchenne Muscular Dystrophy and Gene Mutation Site

    PubMed Central

    D’Angelo, Maria Grazia; Lorusso, Maria Luisa; Civati, Federica; Comi, Giacomo Pietro; Magri, Francesca; Del Bo, Roberto; Guglieri, Michela; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo

    2011-01-01

    The presence of nonprogressive cognitive impairment is recognized as a common feature in a substantial proportion of patients with Duchenne muscular dystrophy. To investigate the possible role of mutations along the dystrophin gene affecting different brain dystrophin isoforms and specific cognitive profiles, 42 school-age children affected with Duchenne muscular dystrophy, subdivided according to sites of mutations along the dystrophin gene, underwent a battery of tests tapping a wide range of intellectual, linguistic, and neuropsychologic functions. Full-scale intelligence quotient was approximately 1 S.D. below the population average in the whole group of dystrophic children. Patients with Duchenne muscular dystrophy and mutations located in the distal portion of the dystrophin gene (involving the 140-kDa brain protein isoform, called Dp140) were generally more severely affected and expressed different patterns of strengths and impairments, compared with patients with Duchenne muscular dystrophy and mutations located in the proximal portion of the dystrophin gene (not involving Dp140). Patients with Duchenne muscular dystrophy and distal mutations demonstrated specific impairments in visuospatial functions and visual memory (which seemed intact in proximally mutated patients) and greater impairment in syntactic processing. PMID:22000308

  13. [Specific features of Becker Muscular Dystrophy patients and female carriers of Duchenne Muscular Dystrophy].

    PubMed

    Magot, A; Mercier, S; Péréon, Y

    2015-12-01

    Becker muscular dystrophy (BMD) was first described in 1955 and linked to the DMD gene in 1987. Compared to Duchenne muscular dystrophy (DMD), clinical onset of BMD usually occurs after the age of 12 and wheelchair is required after the age of 16. BMD is characterized by generalized weakness first affecting limb girdle muscles, hypertrophy of the calves and cardiomyopathy in males. Some patients have only mild symptoms such as cramps or elevated serum creatine kinases (SCK) throughout all their lives. SCK levels are usually elevated. Muscle biopsy (immunohistochemistry or immunoblotting) shows a dystrophic pattern with abnormal dystrophin staining. Diagnosis is confirmed by DMD gene sequencing. Deletions or duplications of one or several exons are identified in the majority of cases. A multidisciplinary approach is recommended for the care management of these patients with a particular attention to the cardiomyopathy, which is typically responsible for death but can be prevented by specific treatment. X-linked dilated cardiomyopathies linked to DMD gene are a phenotypic continuum of BMD. Some female carriers of DMD mutations exhibit clinical symptoms of variable severity, often milder and beginning later than in males. The cardiomyopathy is the most frequent feature that should be especially monitored in these patients. Genetic counselling should be systematically proposed. PMID:26773584

  14. The effects of myotonic dystrophy and Duchenne muscular dystrophy on the orofacial muscles and dentofacial morphology.

    PubMed

    Kiliaridis, S; Katsaros, C

    1998-12-01

    This article takes a closer view of two of the less rare myopathies, myotonic dystrophy (MyD) and Duchenne muscular dystrophy (DMD). A high prevalence of malocclusions was found among the patients affected by these diseases. The development of the malocclusions in MyD patients seems to be strongly related to the vertical aberration of their craniofacial growth due to the involvement of the masticator, muscles in association with the possibly less affected suprahyoid musculature. Thus, a new situation is established around the teeth transversely. The lowered tongue is not in a position to counterbalance the forces developed during the lowering of the mandible by the stretched facial musculature. This may affect the teeth transversely, decreasing the width of the palate and causing posterior crossbite. The lowered position of the mandible, in combination with the decreased biting forces, may permit an overeruption of the posterior teeth, with increased palatal vault height and development of anterior open bite. The development of the malocclusions in DMD patients also seems to be strongly related to the involvement of the orofacial muscles by the disease. However, the posterior crossbite is not developed owing to the narrow maxillary arch, as is the case in MyD patients. On the contrary, the posterior crossbite in DMD is due to the transversal expansion of the mandibular arch, possibly because of the decreased tonus of the masseter muscle near the molars, in combination with the enlarged hypotonic tongue and the predominance of the less affected orbicularis oris muscle.

  15. Targeting Fibrosis in Duchenne Muscular Dystrophy

    PubMed Central

    Zhou, Lan; Lu, Haiyan

    2010-01-01

    Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease affecting 1 in 3,500 live male births. It is an X-linked recessive disease caused by a defective dystrophin gene. The disease is characterized by progressive limb weakness, respiratory and cardiac failure and premature death. Fibrosis is a prominent pathological feature of muscle biopsies from patients with DMD. It directly causes muscle dysfunction and contributes to the lethal DMD phenotype. Although gene therapy and cell therapy may ultimately provide a cure for DMD, currently the disease is devastating, with no effective therapies. Recent studies have demonstrated that ameliorating muscle fibrosis may represent a viable therapeutic approach for DMD. By reducing scar formation, antifibrotic therapies may not only improve muscle function but also enhance muscle regeneration and promote gene and stem cell engraftment. Antifibrotic therapy may serve as a necessary addition to gene and cell therapies to treat DMD in the future. Therefore, understanding cellular and molecular mechanisms underlying muscle fibrogenesis associated with dystrophin deficiency is key to the development of effective antifibrotic therapies for DMD. PMID:20613637

  16. Congenital muscular dystrophy: from muscle to brain.

    PubMed

    Falsaperla, Raffaele; Praticò, Andrea D; Ruggieri, Martino; Parano, Enrico; Rizzo, Renata; Corsello, Giovanni; Vitaliti, Giovanna; Pavone, Piero

    2016-01-01

    Congenital muscular dystrophies (CMDs) are a wide group of muscular disorders that manifest with very early onset of muscular weakness, sometime associated to severe brain involvement.The histologic pattern of muscle anomalies is typical of dystrophic lesions but quite variable depending on the different stages and on the severity of the disorder.Recent classification of CMDs have been reported most of which based on the combination of clinical, biochemical, molecular and genetic findings, but genotype/phenotype correlation are in constant progression due to more diffuse utilization of the molecular analysis.In this article, the Authors report on CMDs belonging to the group of dystroglycanopathies and in particular on the most severe forms represented by the Fukuyama CMD, Muscle-Eye-Brain disease and Walker Walburg syndrome.Clinical diagnosis of infantile hypotonia is particularly difficult considering the different etiologic factors causing the lesions, the difficulty in localizing the involved CNS area (central vs. peripheral) and the limited role of the diagnostic procedures at this early age.The diagnostic evaluation is not easy mainly in differentiating the various types of CMDs, and represents a challenge for the neonatologists and pediatricians. Suggestions are reported on the way to reach a correct diagnosis with the appropriate use of the diagnostic means. PMID:27576556

  17. Optimizing Bone Health in Duchenne Muscular Dystrophy

    PubMed Central

    Buckner, Jason L.; Bowden, Sasigarn A.; Mahan, John D.

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA), as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA. PMID:26124831

  18. Autophagy in granular corneal dystrophy type 2.

    PubMed

    Choi, Seung-Il; Kim, Eung Kweon

    2016-03-01

    Autophagy is a lysosomal degradative process that is essential for cellular homeostasis and metabolic stress adaptation. Defective autophagy is involved in the pathogenesis of many diseases including granular corneal dystrophy type 2 (GCD2). GCD2 is an autosomal dominant disorder caused by substitution of histidine for arginine at codon 124 (R124H) in the transforming growth factor β-induced gene (TGFBI) on chromosome 5q31. Transforming growth factor β-induced protein (TGFBIp) is degraded by autophagy, but mutant-TGFBIp accumulates in autophagosomes and/or lysosomes, despite significant activation of basal autophagy, in GCD2 corneal fibroblasts. Furthermore, inhibition of autophagy induces cell death of GCD2 corneal fibroblasts through active caspase-3. As there is currently no pharmacological treatment for GCD2, development of novel therapies is required. A potential strategy for preventing cytoplasmic accumulation of mutant-TGFBIp in GCD2 corneal fibroblasts is to enhance mutant-TGFBIp degradation. This could be achieved by activation of the autophagic pathway. Here, we will consider the role and the potential therapeutic benefits of autophagy in GCD2, with focus on TGFBIp degradation, in light of the recently established role of autophagy in protein degradation.

  19. Measuring quality of life in muscular dystrophy

    PubMed Central

    Abresch, Richard T.; Biesecker, Barbara; Conway, Kristin Caspers; Heatwole, Chad; Peay, Holly; Scal, Peter; Strober, Jonathan; Uzark, Karen; Wolff, Jodi; Margolis, Marjorie; Blackwell, Angela; Street, Natalie; Montesanti, Angela; Bolen, Julie

    2015-01-01

    Objectives: The objectives of this study were to develop a conceptual model of quality of life (QOL) in muscular dystrophies (MDs) and review existing QOL measures for use in the MD population. Methods: Our model for QOL among individuals with MD was developed based on a modified Delphi process, literature review, and input from patients and patient advocacy organizations. Scales that have been used to measure QOL among patients with MD were identified through a literature review and evaluated using the COSMIN (Consensus-Based Standards for the Selection of Health Measurement Instruments) checklist. Results: The Comprehensive Model of QOL in MD (CMQM) captures 3 broad domains of QOL (physical, psychological, and social), includes factors influencing self-reported QOL (disease-related factors, support/resources, and expectations/aspirations), and places these concepts within the context of the life course. The literature review identified 15 QOL scales (9 adult and 6 pediatric) that have been applied to patients with MD. Very few studies reported reliability data, and none included data on responsiveness of the measures to change in disease progression, a necessary psychometric property for measures included in treatment and intervention studies. No scales captured all QOL domains identified in the CMQM model. Conclusions: Additional scale development research is needed to enhance assessment of QOL for individuals with MD. Item banking and computerized adaptive assessment would be particularly beneficial by allowing the scale to be tailored to each individual, thereby minimizing respondent burden. PMID:25663223

  20. Hyperkalaemia and selective hypoaldosteronism in myotonic dystrophy.

    PubMed

    Misra, Dolly; DeSilva, Shari; Fellerman, Herbert; Dufour, D Robert; Streeten, David H P; Nylen, Eric S

    2002-02-01

    Myotonic dystrophy (MyD) is a common genetic neuromuscular disorder in which chromosome 19 gives rise to an abnormal expansion of CTG-trinucleotide repeats. MyD is a highly variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being uncovered. Herein we present three unrelated cases with MyD with abnormally elevated serum potassium; 2 of the 3 cases presented clinically with cardiac dysrhythmias. Hyperkalaemic conditions such as renal failure, cortisol deficiency, pseudohyperkalaemia, and hyperkalaemic periodic paralysis were excluded. Further endocrine evaluation revealed baseline hypoaldosteronism associated with elevated renin activity. Perturbation of the renin-angiotensin-aldosterone system resulted in appropriately enhanced renin activity but with a subnormal aldosterone response, which appeared to be due to adrenal hyporesponsiveness. The treatment of all cases with fludrocortisone was without effect. Whether the apparent mineralocorticoid abnormality in MyD is due to associated hormonal perturbations (i.e. excessive ACTH responsiveness. elevated cytokines, elevated atrial natriuretic hormone, etc.), adrenal atrophy, and/or a manifestation of the underlying kinase dysfunction is uncertain, but merits further evaluation in view of the clinical consequence of hyperkalaemia.

  1. Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

    PubMed

    Banihani, Rudaina; Smile, Sharon; Yoon, Grace; Dupuis, Annie; Mosleh, Maureen; Snider, Andrea; McAdam, Laura

    2015-10-01

    Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5'untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy.

  2. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    PubMed

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy.

  3. Congenital myotonic dystrophy in Britain. I. Clinical aspects.

    PubMed Central

    Harper, P S

    1975-01-01

    A clinical and genetic study of congenital myotonic dystrophy in Britain has been carried out in 70 patients from 54 sibships. The clinical aspects are analysed here, and the existence of a syndrome clinically distinct from myotonic dystrophy of later onset is confirmed. Characteristic features included neonatal hypotonia, motor and mental retardation, and facial diplegia. A high incidence of talipes occurs at birth together with hydramnios and reduced fetal movements during pregnancy, factors suggesting prenatal onset of the disorder in many cases. Prolonged survival is the rule after infancy, but the occurrence of numerous neonatal deaths in the sibships suggests the existence of unrecognized cases dying in the neonatal period. PMID:1101835

  4. Dystrophin and muscular dystrophy: past, present, and future.

    PubMed

    O'Brien, K F; Kunkel, L M

    2001-01-01

    Duchenne muscular dystrophy was described in the medical literature in the early 1850s but the molecular basis of the disease was not determined until the late 1980s. The cloning of dystrophin led to the identification of a large complex of proteins that plays an important, although not yet well understood, role in muscle biology. Concomitant with the elucidation of the function of dystrophin and its associated proteins has been the pursuit of therapeutic options for muscular dystrophy. Although there is still no cure for this disorder, great advances are being made in the areas of gene introduction and cell transplant therapy. PMID:11592805

  5. Immobility reduces muscle fiber necrosis in dystrophin deficient muscular dystrophy.

    PubMed

    Kimura, S; Ikezawa, M; Nomura, K; Ito, K; Ozasa, S; Ueno, H; Yoshioka, K; Yano, S; Yamashita, T; Matuskura, M; Miike, T

    2006-08-01

    Duchenne/Becker muscular dystrophy is a progressive muscle disease, which is caused by the abnormality of dystrophin. Spina bifida is characterized by paralysis of the feet, with most of the upper extremities not being affected. We report here on the first case of Becker muscular dystrophy coinciding with spina bifida. The muscle biopsy specimens of the patient showed dystrophic changes in upper extremities, but clearly less in lower extremities. The results show that the restriction of excessive exercise is important for dystrophin deficiency disease. PMID:16516424

  6. Determinants of the incidence of Duchenne muscular dystrophy

    PubMed Central

    2015-01-01

    Duchenne muscular dystrophy (DMD), an X-linked disorder, is the most common muscular dystrophy with an incidence in boys of about 200 per million births. It presents in early childhood leading to death in early teens. Its relatively high incidence and severity have stimulated many studies from epidemiological to curative. Recent advances in molecular biology have opened up the possibility of carrier identification and potential reduction of the incidence of cases. This paper gives a population genetics model which can be used to predict the reduction in incidence. PMID:26697447

  7. Dupuytren's Contracture Cosegregation with Limb-Girdle Muscle Dystrophy

    PubMed Central

    Lace, Baiba; Inashkina, Inna; Micule, Ieva; Vasiljeva, Inta; Naudina, Maruta Solvita; Jankevics, Eriks

    2013-01-01

    Limb-girdle muscular dystrophies (LGMDs) is a heterogeneous group of muscular dystrophies that mostly affect the pelvic and shoulder girdle muscle groups. We report here a case of neuromuscular disease associated with Dupuytren's contracture, which has never been described before as cosegregating with an autosomal dominant type of inheritance. Dupuytren's contracture is a common disease, especially in Northern Europe. Comorbid conditions associated with Dupuytren's contracture are repetitive trauma to the hands, diabetes, and seizures, but it has never before been associated with neuromuscular disease. We hypothesize that patients may harbor mutations in genes with functions related to neuromuscular disease and Dupuytren's contracture development. PMID:24024053

  8. Torn apart: membrane rupture in muscular dystrophies and associated cardiomyopathies

    PubMed Central

    Lammerding, Jan; Lee, Richard T.

    2007-01-01

    Muscular dystrophies are often caused by mutations in cytoskeletal proteins that render cells more susceptible to strain-induced injury in mechanically active tissues such as skeletal or cardiac muscle. In this issue of the JCI, Han et al. report that dysferlin participates in membrane resealing in cardiomyocytes and that exercise results in increased membrane damage and disturbed cardiac function in dysferlin-deficient mice (see the related article beginning on page 1805). Thus, in addition to repetitive membrane damage, inadequate membrane repair may participate in the pathogenesis of muscular dystrophies and cardiomyopathies. PMID:17607350

  9. The adenine nucleotide translocase type 1 (ANT1): a new factor in mitochondrial disease.

    PubMed

    Sharer, J Daniel

    2005-09-01

    Mitochondrial disorders of oxidative phosphorylation (OXPHOS) comprise a growing list of potentially lethal diseases caused by mutations in either mitochondrial (mtDNA) or nuclear DNA (nDNA). Two such conditions, autosomal dominant progressive external ophthalmoplegia (adPEO) and Senger's Syndrome, are associated with dysfunction of the heart and muscle-specific isoform of the adenine nucleotide translocase (ANT1), a nDNA gene product that facilitates transport of ATP and ADP across the inner mitochondrial membrane. AdPEO is a mtDNA deletion disorder broadly characterized by pathology involving the eyes, skeletal muscle, and central nervous system. In addition to ANT1, mutations in at least two other nuclear genes, twinkle and POLG, have been shown to cause mtDNA destabilization associated with adPEO. Senger's syndrome is an autosomal recessive condition characterized by congenital heart defects, abnormalities of skeletal muscle mitochondria, cataracts, and elevated circulatory levels of lactic acid. This syndrome is associated with severe depletion of ANT1, which may be the result of an as yet unidentified ANT1-specific transcriptional or translational processing error. ANT1 has also been associated with a third condition, autosomal dominant facioscapulohumeral muscular dystrophy (FSHD), an adult onset disorder characterized by variable muscle weakness in the face, feet, shoulders, and hips. FSHD patients possess specific DNA deletions on chromosome 4, which appear to cause derepression of several nearby genes, including ANT1. Early development of FSHD may involve mitochondrial dysfunction and increased oxidative stress, possibly associated with overexpression of ANT1. PMID:16203679

  10. Gastrointestinal manifestations in myotonic muscular dystrophy

    PubMed Central

    Bellini, Massimo; Biagi, Sonia; Stasi, Cristina; Costa, Francesco; Mumolo, Maria Gloria; Ricchiuti, Angelo; Marchi, Santino

    2006-01-01

    Myotonic dystrophy (MD) is characterized by myotonic phenomena and progressive muscular weakness. Involvement of the gastrointestinal tract is frequent and may occur at any level. The clinical manifestations have previously been attributed to motility disorders caused by smooth muscle damage, but histologic evidence of alterations has been scarce and conflicting. A neural factor has also been hypothesized. In the upper digestive tract, dysphagia, heartburn, regurgitation and dyspepsia are the most common complaints, while in the lower tract, abdominal pain, bloating and changes in bowel habits are often reported. Digestive symptoms may be the first sign of dystrophic disease and may precede the musculo-skeletal features. The impairment of gastrointestinal function may be sometimes so gradual that the patients adapt to it with little awareness of symptoms. In such cases routine endoscopic and ultrasonographic evaluations are not sufficient and targeted techniques (electrogastrography, manometry, electromyography, functional ultrasonography, scintigraphy, etc.) are needed. There is a low correlation between the degree of skeletal muscle involvement and the presence and severity of gastrointestinal disturbances whereas a positive correlation with the duration of the skeletal muscle disease has been reported. The drugs recommended for treating the gastrointestinal complaints such as prokinetic, anti-dyspeptic drugs and laxatives, are mainly aimed at correcting the motility disorders. Gastrointestinal involvement in MD remains a complex and intriguing condition since many important problems are still unsolved. Further studies concentrating on genetic aspects, early diagnostic techniques and the development of new therapeutic strategies are needed to improve our management of the gastrointestinal manifestations of MD. PMID:16609987

  11. Sudomotor function in sympathetic reflex dystrophy.

    PubMed

    Birklein, F; Sittl, R; Spitzer, A; Claus, D; Neundörfer, B; Handwerker, H O

    1997-01-01

    Sudomotor functions were studied in 27 patients suffering from reflex sympathetic dystrophy (RSD) according to the criteria established by Bonica (18 women, 9 men; mean age 50 +/- 12.3 years; median duration of disease 8 weeks, range 2-468 weeks). To measure local sweating rates, two small chambers (5 cm2) were affixed to corresponding areas of hairy skin on the affected and unaffected limbs. Dry nitrogen gas was passed through the chambers (270 ml/min) and evaporation was recorded at both devices with hygrometers. Thermoregulatory sweating (TST) was induced by raising body temperature (intake of 0.5 1 hot tea and infra-red irradiation). Local sweating was also induced through an axon reflex (QSART) by transcutaneous iontophoretic application of carbachol (5 min, 1 mA). In addition, skin temperature was measured on the affected and unaffected side by infra-red thermography. Mean skin temperature was significantly higher on the affected side (P < 0.003). In spite of the temperature differences, there was no difference in basal sweating on the affected and unaffected side. However, both methods of sudomotor stimulation lead to significantly greater sweating responses on the affected compared to the unaffected side (TST: P < 0.05, QSART: P < 0.004). Latency to onset of sweating was significantly shorter on the affected side under both test conditions (P < 0.04 and P < 0.003, respectively). Sweat responses were not correlated to absolute skin temperature but were probably related to the increased blood flow on the affected side. Our findings imply a differential disturbance of vasomotor and sudomotor mechanisms in affected skin. Whereas vasoconstrictor activity is apparently lowered, sudomotor output is either unaltered or may even be enhanced.

  12. Sudomotor function in sympathetic reflex dystrophy.

    PubMed

    Birklein, F; Sittl, R; Spitzer, A; Claus, D; Neundörfer, B; Handwerker, H O

    1997-01-01

    Sudomotor functions were studied in 27 patients suffering from reflex sympathetic dystrophy (RSD) according to the criteria established by Bonica (18 women, 9 men; mean age 50 +/- 12.3 years; median duration of disease 8 weeks, range 2-468 weeks). To measure local sweating rates, two small chambers (5 cm2) were affixed to corresponding areas of hairy skin on the affected and unaffected limbs. Dry nitrogen gas was passed through the chambers (270 ml/min) and evaporation was recorded at both devices with hygrometers. Thermoregulatory sweating (TST) was induced by raising body temperature (intake of 0.5 1 hot tea and infra-red irradiation). Local sweating was also induced through an axon reflex (QSART) by transcutaneous iontophoretic application of carbachol (5 min, 1 mA). In addition, skin temperature was measured on the affected and unaffected side by infra-red thermography. Mean skin temperature was significantly higher on the affected side (P < 0.003). In spite of the temperature differences, there was no difference in basal sweating on the affected and unaffected side. However, both methods of sudomotor stimulation lead to significantly greater sweating responses on the affected compared to the unaffected side (TST: P < 0.05, QSART: P < 0.004). Latency to onset of sweating was significantly shorter on the affected side under both test conditions (P < 0.04 and P < 0.003, respectively). Sweat responses were not correlated to absolute skin temperature but were probably related to the increased blood flow on the affected side. Our findings imply a differential disturbance of vasomotor and sudomotor mechanisms in affected skin. Whereas vasoconstrictor activity is apparently lowered, sudomotor output is either unaltered or may even be enhanced. PMID:9060012

  13. Axillary Brachial Plexus Blockade for the Reflex Sympathetic Dystrophy Syndrome.

    ERIC Educational Resources Information Center

    Ribbers, G. M.; Geurts, A. C. H.; Rijken, R. A. J.; Kerkkamp, H. E. M.

    1997-01-01

    Reflex sympathetic dystrophy syndrome (RSD) is a neurogenic pain syndrome characterized by pain, vasomotor and dystrophic changes, and often motor impairments. This study evaluated the effectiveness of brachial plexus blockade with local anaesthetic drugs as a treatment for this condition. Three patients responded well; three did not. (DB)

  14. Molecular genetics of infantile-onset retinal dystrophies.

    PubMed

    Moradi, P; Moore, A T

    2007-10-01

    Over the last decade there have been major advances in our understanding of the molecular pathology of inherited retinal dystrophies. This paper reviews recent advances in the identification of genetic mutations underlying infantile-onset inherited retinal disorders and considers how this knowledge may lead to novel therapeutic approaches.

  15. Objective Assessment of the Corneal Endothelium in Fuchs' Endothelial Dystrophy

    PubMed Central

    McLaren, Jay W.; Bachman, Lori A.; Kane, Katrina M.; Patel, Sanjay V.

    2014-01-01

    Purpose. To develop a standardized method of endothelial cell density (ECD) assessment in Fuchs' endothelial dystrophy that maximizes the sample area and uses the clearest endothelial cells in confocal images. Methods. The corneal endothelium of 51 eyes from 30 patients, with varying degrees of Fuchs' endothelial dystrophy, was examined using confocal microscopy. In two or three distinct images of the central endothelium, local contiguous cell density was determined using a variable frame method. The effective ECD was the product of the local cell density and the fraction of the image that was free of guttae. Two examiners assessed the severity of disease in each eye during slit-lamp examination and assigned a severity grade of 1 to 6. In a second group of 55 eyes with Fuchs' dystrophy from 30 patients, the clinical grade was predicted from the effective ECD and the regression coefficients of the first group and compared to the subjective clinical grade assigned by one examiner. Results. The effective ECD decreased linearly with subjective grade (r = −0.93, P < 0.001). The grade predicted from the effective ECD differed from the subjective clinical grade by −0.1 ± 0.8 (mean difference ± standard deviation). Conclusions. The effective ECD in confocal images provides an objective means of assessing the corneal endothelium in Fuchs' dystrophy and might be a useful tool in clinical studies. PMID:24508788

  16. Molecular genetics of infantile-onset retinal dystrophies.

    PubMed

    Moradi, P; Moore, A T

    2007-10-01

    Over the last decade there have been major advances in our understanding of the molecular pathology of inherited retinal dystrophies. This paper reviews recent advances in the identification of genetic mutations underlying infantile-onset inherited retinal disorders and considers how this knowledge may lead to novel therapeutic approaches. PMID:17914438

  17. Psychiatric and Cognitive Phenotype of Childhood Myotonic Dystrophy Type 1

    ERIC Educational Resources Information Center

    Douniol, Marie; Jacquette, Aurelia; Cohen, David; Bodeau, Nicolas; Rachidi, Linda; Angeard, Nathalie; Cuisset, Jean-Marie; Vallee, Louis; Eymard, Bruno; Plaza, Monique; Heron, Delphine; Guile, Jean-Marc

    2012-01-01

    Aim: To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1). Method: Twenty-eight individuals (15 females, 13 males) with childhood DM1 (mean age 17y, SD 4.6, range 7-24y) were assessed using standardized instruments and cognitive testing of general intelligence,…

  18. Occupational Potential in a Population with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Schkade, Janette K.; And Others

    1987-01-01

    Twenty-five males with Duchenne muscular dystrophy were tested to assess their potential for occupational activity. Tests measured possible sensory deficits, strength, endurance, and fatigue in response to sustained fine motor activity. Results indicate that, within limitations, persons with this diagnosis can engage in activity leading to skill…

  19. Poor Facial Affect Recognition among Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Hinton, V. J.; Fee, R. J.; De Vivo, D. C.; Goldstein, E.

    2007-01-01

    Children with Duchenne or Becker muscular dystrophy (MD) have delayed language and poor social skills and some meet criteria for Pervasive Developmental Disorder, yet they are identified by molecular, rather than behavioral, characteristics. To determine whether comprehension of facial affect is compromised in boys with MD, children were given a…

  20. Dasatinib as a treatment for Duchenne muscular dystrophy.

    PubMed

    Lipscomb, Leanne; Piggott, Robert W; Emmerson, Tracy; Winder, Steve J

    2016-01-15

    Identification of a systemically acting and universal small molecule therapy for Duchenne muscular dystrophy would be an enormous advance for this condition. Based on evidence gained from studies on mouse genetic models, we have identified tyrosine phosphorylation and degradation of β-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus, preventing tyrosine phosphorylation and degradation of β-dystroglycan presents itself as a potential therapeutic strategy. Using the dystrophic sapje zebrafish, we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy. Dasatinib, a potent and specific Src tyrosine kinase inhibitor, was found to decrease the levels of β-dystroglycan phosphorylation on tyrosine and to increase the relative levels of non-phosphorylated β-dystroglycan in sapje zebrafish. Furthermore, dasatinib treatment resulted in the improved physical appearance of the sapje zebrafish musculature and increased swimming ability as measured by both duration and distance of swimming of dasatinib-treated fish compared with control animals. These data suggest great promise for pharmacological agents that prevent the phosphorylation of β-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy.

  1. Phosphorylation of intact erythrocytes in human muscular dystrophy

    SciTech Connect

    Johnson, R.M.; Nigro, M.

    1986-04-01

    The uptake of exogenous /sup 32/Pi into the membrane proteins of intact erythrocytes was measured in 8 patients with Duchenne muscular dystrophy. No abnormalities were noted after autoradiographic analysis. This contrasts with earlier results obtained when isolated membranes were phosphorylated with gamma-(/sup 32/P)ATP, and suggests a possible reinterpretation of those experiments.

  2. The Child with Muscular Dystrophy in School. Revised.

    ERIC Educational Resources Information Center

    Schock, Nancy C.

    Practical information on children with muscular dystrophy is intended to help parents and teachers facilitate their inclusion in mainstreamed classrooms. Major topics addressed include the following: transportation arrangements; providing full information to the teacher regarding the child's specific abilities and physical limitations;…

  3. Muscle Weakness and Speech in Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

    Neel, Amy T.; Palmer, Phyllis M.; Sprouls, Gwyneth; Morrison, Leslie

    2015-01-01

    Purpose: We documented speech and voice characteristics associated with oculopharyngeal muscular dystrophy (OPMD). Although it is a rare disease, OPMD offers the opportunity to study the impact of myopathic weakness on speech production in the absence of neurologic deficits in a relatively homogeneous group of speakers. Methods: Twelve individuals…

  4. The Assessment of Intelligence in Boys with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Mearig, Judith S.

    1979-01-01

    Challenges assumptions and research procedures leading to the position that below-average intellectual potential is an integral part of Duchenne muscular dystrophy. A study of 58 boys (ages 5 to 18) from urban, suburban, and rural settings indicated IQ range of 59 to 131 and no evidence of significant verbal deficit (reported in earlier studies).…

  5. Phonological Awareness Skills in Young Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Waring, Phoebe; Woodyatt, Gail

    2011-01-01

    Substantial research has detailed the reading deficits experienced by children with Duchenne muscular dystrophy (DMD). Although phonological awareness (PA) is vital in reading development, little is known about PA in the DMD population. This pilot study describes the PA abilities of a group of five young children with DMD, comparing the results…

  6. Dysphagia in Duchenne Muscular Dystrophy Assessed by Validated Questionnaire

    ERIC Educational Resources Information Center

    Archer, Sally K.; Garrod, Rachel; Hart, Nicholas; Miller, Simon

    2013-01-01

    Background: Duchenne muscular dystrophy (DMD) leads to progressive muscular weakness and death, most typically from respiratory complications. Dysphagia is common in DMD; however, the most appropriate swallowing assessments have not been universally agreed and the symptoms of dysphagia remain under-reported. Aims: To investigate symptoms of…

  7. Swallow Characteristics in Patients with Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

    Palmer, Phyllis M.; Neel, Amy T.; Sprouls, Gwyneth; Morrison, Leslie

    2010-01-01

    Purpose: This prospective investigation evaluates oral weakness and its impact on swallow function, weight, and quality of life in patients with oculopharyngeal muscular dystrophy (OPMD). Method: Intraoral pressure, swallow pressure, and endurance were measured using an Iowa Oral Performance Instrument in participants with OPMD and matched…

  8. Mutations in IMPG1 Cause Vitelliform Macular Dystrophies

    PubMed Central

    Manes, Gaël; Meunier, Isabelle; Avila-Fernández, Almudena; Banfi, Sandro; Le Meur, Guylène; Zanlonghi, Xavier; Corton, Marta; Simonelli, Francesca; Brabet, Philippe; Labesse, Gilles; Audo, Isabelle; Mohand-Said, Saddek; Zeitz, Christina; Sahel, José-Alain; Weber, Michel; Dollfus, Hélène; Dhaenens, Claire-Marie; Allorge, Delphine; De Baere, Elfride; Koenekoop, Robert K.; Kohl, Susanne; Cremers, Frans P.M.; Hollyfield, Joe G.; Sénéchal, Audrey; Hebrard, Maxime; Bocquet, Béatrice; Ayuso García, Carmen; Hamel, Christian P.

    2013-01-01

    Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507∗). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD. PMID:23993198

  9. Sleep-Wake Cycle and Daytime Sleepiness in the Myotonic Dystrophies.

    PubMed

    Romigi, A; Albanese, M; Liguori, C; Placidi, F; Marciani, M G; Massa, R

    2013-01-01

    Myotonic dystrophy is the most common type of muscular dystrophy in adults and is characterized by progressive myopathy, myotonia, and multiorgan involvement. Two genetically distinct entities have been identified, myotonic dystrophy type 1 (DM1 or Steinert's Disease) and myotonic dystrophy type 2 (DM2). Myotonic dystrophies are strongly associated with sleep dysfunction. Sleep disturbances in DM1 are common and include sleep-disordered breathing (SDB), periodic limb movements (PLMS), central hypersomnia, and REM sleep dysregulation (high REM density and narcoleptic-like phenotype). Interestingly, drowsiness in DM1 seems to be due to a central dysfunction of sleep-wake regulation more than SDB. To date, little is known regarding the occurrence of sleep disorders in DM2. SDB (obstructive and central apnoea), REM sleep without atonia, and restless legs syndrome have been described. Further polysomnographic, controlled studies are strongly needed, particularly in DM2, in order to clarify the role of sleep disorders in the myotonic dystrophies.

  10. Automated measurement of retinal blood vessel tortuosity

    NASA Astrophysics Data System (ADS)

    Joshi, Vinayak; Reinhardt, Joseph M.; Abramoff, Michael D.

    2010-03-01

    Abnormalities in the vascular pattern of the retina are associated with retinal diseases and are also risk factors for systemic diseases, especially cardiovascular diseases. The three-dimensional retinal vascular pattern is mostly formed congenitally, but is then modified over life, in response to aging, vessel wall dystrophies and long term changes in blood flow and pressure. A characteristic of the vascular pattern that is appreciated by clinicians is vascular tortuosity, i.e. how curved or kinked a blood vessel, either vein or artery, appears along its course. We developed a new quantitative metric for vascular tortuosity, based on the vessel's angle of curvature, length of the curved vessel over its chord length (arc to chord ratio), number of curvature sign changes, and combined these into a unidimensional metric, Tortuosity Index (TI). In comparison to other published methods this method can estimate appropriate TI for vessels with constant curvature sign and vessels with equal arc to chord ratios, as well. We applied this method to a dataset of 15 digital fundus images of 8 patients with Facioscapulohumeral muscular dystrophy (FSHD), and to the other publically available dataset of 60 fundus images of normal cases and patients with hypertensive retinopathy, of which the arterial and venous tortuosities have also been graded by masked experts (ophthalmologists). The method produced exactly the same rank-ordered list of vessel tortuosity (TI) values as obtained by averaging the tortuosity grading given by 3 ophthalmologists for FSHD dataset and a list of TI values with high ranking correlation with the ophthalmologist's grading for the other dataset. Our results show that TI has potential to detect and evaluate abnormal retinal vascular structure in early diagnosis and prognosis of retinopathies.

  11. The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease.

    PubMed

    Minnerop, Martina; Weber, Bernd; Schoene-Bake, Jan-Christoph; Roeske, Sandra; Mirbach, Sandra; Anspach, Christian; Schneider-Gold, Christiane; Betz, Regina C; Helmstaedter, Christoph; Tittgemeyer, Marc; Klockgether, Thomas; Kornblum, Cornelia

    2011-12-01

    Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T(1)/T(2)/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (P(corrected) < 0.05). We further examined the association of structural brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were

  12. Satellite Cells in Muscular Dystrophy - Lost in Polarity.

    PubMed

    Chang, Natasha C; Chevalier, Fabien P; Rudnicki, Michael A

    2016-06-01

    Recent findings employing the mdx mouse model for Duchenne muscular dystrophy (DMD) have revealed that muscle satellite stem cells play a direct role in contributing to disease etiology and progression of DMD, the most common and severe form of muscular dystrophy. Lack of dystrophin expression in DMD has critical consequences in satellite cells including an inability to establish cell polarity, abrogation of asymmetric satellite stem-cell divisions, and failure to enter the myogenic program. Thus, muscle wasting in dystrophic mice is not only caused by myofiber fragility but is exacerbated by intrinsic satellite cell dysfunction leading to impaired regeneration. Despite intense research and clinical efforts, there is still no effective cure for DMD. In this review we highlight recent research advances in DMD and discuss the current state of treatment and, importantly, how we can incorporate satellite cell-targeted therapeutic strategies to correct satellite cell dysfunction in DMD.

  13. Gene Therapy for Muscular Dystrophies: Progress and Challenges

    PubMed Central

    Oh, Donghoon

    2010-01-01

    Muscular dystrophies are groups of inherited progressive diseases of the muscle caused by mutations of diverse genes related to normal muscle function. Although there is no current effective treatment for these devastating diseases, various molecular strategies have been developed to restore the expressions of the associated defective proteins. In preclinical animal models, both viral and nonviral vectors have been shown to deliver recombinant versions of defective genes. Antisense oligonucleotides have been shown to modify the splicing mechanism of mesenger ribonucleic acid to produce an internally deleted but partially functional dystrophin in an experimental model of Duchenne muscular dystrophy. In addition, chemicals can induce readthrough of the premature stop codon in nonsense mutations of the dystrophin gene. On the basis of these preclinical data, several experimental clinical trials are underway that aim to demonstrate efficacy in treating these devastating diseases. PMID:20944811

  14. [Myotonic dystrophy and bundle-branch re-entrant tachycardia].

    PubMed

    Ramírez, Carlos J; Rodríguez, Diego A; Velasco, Víctor M; Rosas, Fernando

    2002-10-01

    We report the case of a 37-year-old man diagnosed with myotonic dystrophy who presented atrial fibrillation with high ventricular rate. While being treated with amiodarone, he suffered cardiac arrest. The electrophysiological study disclosed bundle-branch reentrant ventricular tachycardia and ventricular fibrillation. Catheter ablation of the right bundle branch was performed and a bicameral defibrillator was implanted. The mechanisms and treatment of arrhythmias in these patients are discussed. PMID:12383397

  15. NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy.

    PubMed

    Goody, Michelle F; Kelly, Meghan W; Reynolds, Christine J; Khalil, Andre; Crawford, Bryan D; Henry, Clarissa A

    2012-01-01

    Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex- or integrin alpha7-deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin alpha

  16. Reflex sympathetic dystrophy in the hands: clinical and scintigraphic criteria

    SciTech Connect

    Holder, L.E.; Mackinnon, S.E.

    1984-08-01

    In an attempt to establish specific scintigraphic criteria for the reflex sympathetic dystrophy syndrome (RSD) as defined by a group of specialized hand surgeons, 145 consecutive patients, 23 of whom had clinical RSD, underwent three phase radionuclide bone scanning (TPBS). Specific patterns for positive radionuclide angiogram, blood pool, and delayed images were established. The delayed images were sensitive (96%), specific (97%), and had a valuable negative predictive value (99%). It was concluded that TPBS could provide an objective marker for RSD.

  17. Prenatal diagnosis of congenital myopathies and muscular dystrophies.

    PubMed

    Massalska, D; Zimowski, J G; Bijok, J; Kucińska-Chahwan, A; Łusakowska, A; Jakiel, G; Roszkowski, T

    2016-09-01

    Congenital myopathies and muscular dystrophies constitute a genetically and phenotypically heterogeneous group of rare inherited diseases characterized by muscle weakness and atrophy, motor delay and respiratory insufficiency. To date, curative care is not available for these diseases, which may severely affect both life-span and quality of life. We discuss prenatal diagnosis and genetic counseling for families at risk, as well as diagnostic possibilities in sporadic cases. PMID:27197572

  18. Creatine monohydrate as a therapeutic aid in muscular dystrophy.

    PubMed

    Pearlman, Jared P; Fielding, Roger A

    2006-02-01

    In recent years, dietary supplementation with creatine has been shown to enhance neuromuscular function in several diseases. Recent studies have suggested that creatine can be beneficial in patients with muscular dystrophy and other mitochondrial cytopathies, and may attenuate sarcopenia and facilitate rehabilitation of disuse atrophy. Though the mechanisms are still unknown, creatine has been shown to decrease cytoplasmic Ca2+ levels and increase intramuscular and cerebral phosphocreatine stores, providing potential musculoskeletal and neuroprotective effects. PMID:16536185

  19. [Effectiveness of sodium selenite in experimental liver dystrophy].

    PubMed

    Danik, L M

    1976-01-01

    The effect of sodium selenite on the cholepoietic function of the liver in rats with acute dystrophy induced by carbon tetrachloride was studied. When used in doses of 1 and 10 gamma/100 g the drug was found to normalize the intensity of bile secretion, synthesis and secretion of bile acids and that of bilirubin, as well as excretion of cholesterol. This was attended by a rise of the cholate-cholesterol ratio. PMID:1278354

  20. Reflex sympathetic dystrophies and algodystrophies: historical and pathogenic considerations.

    PubMed

    Procacci, P; Maresca, M

    1987-11-01

    This paper reviews the historical development of the concepts of 'sympathy' of organs and of the sympathetic nervous system. In particular, the afferent function of the sympathetic system is discussed. The attention is focussed on sympathetic reflex dystrophies, known in some European schools as 'algodystrophies'. The pathogenic mechanisms of these affections, especially of causalgia, are discussed, considering the importance of peripheral damage to nerves, lateralisation of pain, 'mirror phenomena', and the relationship between peripheral and central mechanisms of pain.

  1. Differential isoform expression and selective muscle involvement in muscular dystrophies.

    PubMed

    Huovinen, Sanna; Penttilä, Sini; Somervuo, Panu; Keto, Joni; Auvinen, Petri; Vihola, Anna; Huovinen, Sami; Pelin, Katarina; Raheem, Olayinka; Salenius, Juha; Suominen, Tiina; Hackman, Peter; Udd, Bjarne

    2015-10-01

    Despite the expression of the mutated gene in all muscles, selective muscles are involved in genetic muscular dystrophies. Different muscular dystrophies show characteristic patterns of fatty degenerative changes by muscle imaging, even to the extent that the patterns have been used for diagnostic purposes. However, the underlying molecular mechanisms explaining the selective involvement of muscles are not known. To test the hypothesis that different muscles may express variable amounts of different isoforms of muscle genes, we applied a custom-designed exon microarray containing probes for 57 muscle-specific genes to assay the transcriptional profiles in sets of human adult lower limb skeletal muscles. Quantitative real-time PCR and whole transcriptome sequencing were used to further analyze the results. Our results demonstrate significant variations in isoform and gene expression levels in anatomically different muscles. Comparison of the known patterns of selective involvement of certain muscles in two autosomal dominant titinopathies and one autosomal dominant myosinopathy, with the isoform and gene expression results, shows a correlation between the specific muscles involved and significant differences in the level of expression of the affected gene and exons in these same muscles compared with some other selected muscles. Our results suggest that differential expression levels of muscle genes and isoforms are one determinant in the selectivity of muscle involvement in muscular dystrophies.

  2. Mutation hot spots in 5q31-linked corneal dystrophies.

    PubMed Central

    Korvatska, E; Munier, F L; Djemaï, A; Wang, M X; Frueh, B; Chiou, A G; Uffer, S; Ballestrazzi, E; Braunstein, R E; Forster, R K; Culbertson, W W; Boman, H; Zografos, L; Schorderet, D F

    1998-01-01

    Mutations in the BIGH3 gene on chromosome 5q31 cause four distinct autosomal dominant diseases of the human cornea: granular (Groenouw type I), Reis-Bücklers, lattice type I, and Avellino corneal dystrophies. All four diseases are characterized by both progressive accumulation of corneal deposits and eventual loss of vision. We have identified a specific recurrent missense mutation for each type of dystrophy, in 10 independently ascertained families. Genotype analysis with microsatellite markers surrounding the BIGH3 locus was performed in these 10 families and in 5 families reported previously. The affected haplotype could be determined in 10 of the 15 families and was different in each family. These data indicate that R555W, R124C, and R124H mutations occurred independently in several ethnic groups and that these mutations do not reflect a putative founder effect. Furthermore, this study confirms the specific importance of the R124 and R555 amino acids in the pathogenesis of autosomal dominant corneal dystrophies linked to 5q. PMID:9463327

  3. Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

    PubMed

    Banihani, Rudaina; Smile, Sharon; Yoon, Grace; Dupuis, Annie; Mosleh, Maureen; Snider, Andrea; McAdam, Laura

    2015-10-01

    Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5'untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy. PMID:25660133

  4. [Structural changes in sarcolemma with E-avitaminosis dystrophy].

    PubMed

    Tugai, V A; Litvinenko, O O

    1977-01-01

    Sorption properties of sarcolemma preparations isolated from skeletal muscles of normal and E-avitaminous rabbits were studied relative to organic ions. Analysis of isotherms of sarcolemma equilibrium binding of neutral red cations and turquoise direct lightfast "K" anions made it possible to determine the number of positively and negetively charged sorption centres, which fix the mentioned dyes. With E-avitaminous muscular dystrophy the number of the centres increases considerably. A larger number of the positively charged centres fixing the surquoise dye are found both in the control and in case of dystrophy. The calcium ions prevent the neutral red sorption and intensify the turquoise direct sorption. In the sarcolemma preparations isolated from the muscles of the E-avitaminous rabbits the content of calcium ions is almost twice as high and the number of sulphydryl groups is 30-40% less as compare to the normal level. The data presented evidence for structural changes in sarcolemma with E-avitaminous muscular dystrophy.

  5. Lipogenesis mitigates dysregulated sarcoplasmic reticulum calcium uptake in muscular dystrophy.

    PubMed

    Paran, Christopher W; Zou, Kai; Ferrara, Patrick J; Song, Haowei; Turk, John; Funai, Katsuhiko

    2015-12-01

    Muscular dystrophy is accompanied by a reduction in activity of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) that contributes to abnormal Ca(2+) homeostasis in sarco/endoplasmic reticulum (SR/ER). Recent findings suggest that skeletal muscle fatty acid synthase (FAS) modulates SERCA activity and muscle function via its effects on SR membrane phospholipids. In this study, we examined muscle's lipid metabolism in mdx mice, a mouse model for Duchenne muscular dystrophy (DMD). De novo lipogenesis was ~50% reduced in mdx muscles compared to wildtype (WT) muscles. Gene expressions of lipogenic and other ER lipid-modifying enzymes were found to be differentially expressed between wildtype (WT) and mdx muscles. A comprehensive examination of muscles' SR phospholipidome revealed elevated phosphatidylcholine (PC) and PC/phosphatidylethanolamine (PE) ratio in mdx compared to WT mice. Studies in primary myocytes suggested that defects in key lipogenic enzymes including FAS, stearoyl-CoA desaturase-1 (SCD1), and Lipin1 are likely contributing to reduced SERCA activity in mdx mice. Triple transgenic expression of FAS, SCD1, and Lipin1 (3TG) in mdx myocytes partly rescued SERCA activity, which coincided with an increase in SR PE that normalized PC/PE ratio. These findings implicate a defect in lipogenesis to be a contributing factor for SERCA dysfunction in muscular dystrophy. Restoration of muscle's lipogenic pathway appears to mitigate SERCA function through its effects on SR membrane composition.

  6. Degeneration of Neuromuscular Junction in Age and Dystrophy

    PubMed Central

    Rudolf, Rüdiger; Khan, Muzamil Majid; Labeit, Siegfried; Deschenes, Michael R.

    2014-01-01

    Functional denervation is a hallmark of aging sarcopenia as well as of muscular dystrophy. It is thought to be a major factor reducing skeletal muscle mass, particularly in the case of sarcopenia. Neuromuscular junctions (NMJs) serve as the interface between the nervous and skeletal muscular systems, and thus they may receive pathophysiological input of both pre- and post-synaptic origin. Consequently, NMJs are good indicators of motor health on a systemic level. Indeed, upon sarcopenia and dystrophy, NMJs morphologically deteriorate and exhibit altered characteristics of primary signaling molecules, such as nicotinic acetylcholine receptor and agrin. Since a remarkable reversibility of these changes can be observed by exercise, there is significant interest in understanding the molecular mechanisms underlying synaptic deterioration upon aging and dystrophy and how synapses are reset by the aforementioned treatments. Here, we review the literature that describes the phenomena observed at the NMJ in sarcopenic and dystrophic muscle as well as to how these alterations can be reversed and to what extent. In a second part, the current information about molecular machineries underlying these processes is reported. PMID:24904412

  7. Molecular Signatures of Membrane Protein Complexes Underlying Muscular Dystrophy*

    PubMed Central

    Turk, Rolf; Hsiao, Jordy J.; Smits, Melinda M.; Ng, Brandon H.; Pospisil, Tyler C.; Jones, Kayla S.; Campbell, Kevin P.; Wright, Michael E.

    2016-01-01

    Mutations in genes encoding components of the sarcolemmal dystrophin-glycoprotein complex (DGC) are responsible for a large number of muscular dystrophies. As such, molecular dissection of the DGC is expected to both reveal pathological mechanisms, and provides a biological framework for validating new DGC components. Establishment of the molecular composition of plasma-membrane protein complexes has been hampered by a lack of suitable biochemical approaches. Here we present an analytical workflow based upon the principles of protein correlation profiling that has enabled us to model the molecular composition of the DGC in mouse skeletal muscle. We also report our analysis of protein complexes in mice harboring mutations in DGC components. Bioinformatic analyses suggested that cell-adhesion pathways were under the transcriptional control of NFκB in DGC mutant mice, which is a finding that is supported by previous studies that showed NFκB-regulated pathways underlie the pathophysiology of DGC-related muscular dystrophies. Moreover, the bioinformatic analyses suggested that inflammatory and compensatory mechanisms were activated in skeletal muscle of DGC mutant mice. Additionally, this proteomic study provides a molecular framework to refine our understanding of the DGC, identification of protein biomarkers of neuromuscular disease, and pharmacological interrogation of the DGC in adult skeletal muscle https://www.mda.org/disease/congenital-muscular-dystrophy/research. PMID:27099343

  8. Warming up Improves Speech Production in Patients with Adult Onset Myotonic Dystrophy

    ERIC Educational Resources Information Center

    de Swart, B.J.M.; van Engelen, B.G.M.; Maassen, B.A.M.

    2007-01-01

    This investigation was conducted to study whether warming up decreases myotonia (muscle stiffness) during speech production or causes adverse effects due to fatigue or exhaustion caused by intensive speech activity in patients with adult onset myotonic dystrophy. Thirty patients with adult onset myotonic dystrophy (MD) and ten healthy controls…

  9. Meeting the Assistive Technology Needs of Students with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Heller, Kathryn Wolff; Mezei, Peter J.; Avant, Mary Jane Thompson

    2009-01-01

    Students with Duchenne muscular dystrophy (DMD) have a degenerative disease that requires ongoing changes in assistive technology (AT). The AT team needs to be knowledgeable about the disease and its progression in order to meet these students' changing needs in a timely manner. The unique needs of students with Duchenne muscular dystrophy in…

  10. Segmental myofiber necrosis in myotonic dystrophy - An immunoperoxidase study of immunoglobulins in skeletal muscle.

    PubMed Central

    Silver, M. M.; Banerjee, D.; Hudson, A. J.

    1983-01-01

    Because serum immunoglobulin G levels are low in patients with myotonic dystrophy, it was hypothesized that it might be catabolized within abnormal muscle fibers. Accordingly, immunohistochemical stains for immunoglobulins were performed on muscle sections derived at biopsy or autopsy from patients with myotonic dystrophy, other forms of muscular dystrophy, nondystrophic muscle disease, or normal muscle. Positive staining for immunoglobulins was found only in necrotic segments of myofibers (in 7 of 19 dystrophic and 6 of 27 nondystrophic subjects), and it is believed that the staining was due to nonspecific diffusion. However, staining reactions distinguished between incipient necrosis and artifactual contraction bands and allowed us to study segmental myofiber necrosis, comparing its frequency in the various muscle diseases. Segmental myofiber necrosis was present in 4 of 16 cases of myotonic dystrophy. The relevance of this finding to the clinical and morphologic features of myotonic dystrophy is discussed. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:6351629

  11. Trends with corticosteroid use in males with Duchenne muscular dystrophy born 1982-2001.

    PubMed

    Fox, Deborah J; Kumar, Anil; West, Nancy A; DiRienzo, A Gregory; James, Katherine A; Oleszek, Joyce

    2015-01-01

    This study examines trends in corticosteroid use for males with Duchenne muscular dystrophy by birth year, race/ethnicity, and knowledge of Duchenne muscular dystrophy family history. Firstborn males (n = 521) selected from a population-based surveillance system of Duchenne muscular dystrophy were analyzed using Kaplan Meier and regression methods. Comparing males born 1982 to 1986 with males born 1997 to 2001, steroid use increased from 54% to 72% and mean age at steroid initiation decreased from 8.2 to 7.1 years. Hispanics and non-Hispanic Black males used steroids less frequently and delayed initiation compared to white males. Compared to males without a Duchenne muscular dystrophy family history, males with known family history were half as likely to use steroids. Duration of steroid use increased over time and age at initiation decreased. Racial/ethnic disparities exist for steroid use and should be addressed to improve outcome and quality of life for boys with Duchenne muscular dystrophy.

  12. Continuous infusion propofol general anesthesia for dental treatment in patients with progressive muscular dystrophy.

    PubMed

    Kawaai, Hiroyoshi; Tanaka, Kazuho; Yamazaki, Shinya

    2005-01-01

    Progressive muscular dystrophy may produce abnormal reactions to several drugs. There is no consensus of opinion regarding the continuous infusion of propofol in patients with progressive muscular dystrophy. We successfully treated 2 patients with progressive muscular dystrophy who were anesthetized with a continuous infusion of propofol. In case 1, a 19-year-old, 59-kg man with Becker muscular dystrophy and mental retardation was scheduled for dental treatment under general anesthesia. General anesthesia was maintained by a continuous infusion of 6-10 mg/kg propofol per hour and an inhalational mixture of 67% nitrous oxide and 33% oxygen. No complications were observed during or after the operation. In case 2, a 5-year-old, 11-kg boy with Fukuyama type congenital muscular dystrophy and slight mental retardation was scheduled for dental treatment under general anesthesia. General anesthesia was maintained with a continuous infusion of 6-12 mg/kg propofol per hour and an inhalational mixture of 0.5-1.5% sevoflurane in 67% nitrous oxide and 33% oxygen. No complications were observed during or after the operation. It is speculated that a continuous infusion of propofol in progressive muscular dystrophy does not cause malignant hyperthermia because serum levels of creatine phosphokinase and myoglobin decreased after our anesthetic management. Furthermore, our observations suggest that sevoflurane may have some advantages in patients with progressive type muscular dystrophies other than Duchenne muscular dystrophy and Becker muscular dystrophy. In conclusion, our cases suggest that a continuous infusion of propofol for the patients with progressive muscular dystrophy is a safe component of our anesthetic strategy. PMID:15859443

  13. New aspects on patients affected by dysferlin deficient muscular dystrophy

    PubMed Central

    Klinge, Lars; Aboumousa, Ahmed; Eagle, Michelle; Hudson, Judith; Sarkozy, Anna; Vita, Gianluca; Charlton, Richard; Roberts, Mark; Straub, Volker; Barresi, Rita; Lochmüller, Hanns

    2009-01-01

    Mutations in the dysferlin gene lead to limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal anterior compartment myopathy. A cohort of 36 patients affected by dysferlinopathy is described, in the first UK study of clinical, genetic, pathological and biochemical data. The diagnosis was established by reduction of dysferlin in the muscle biopsy and subsequent mutational analysis of the dysferlin gene. Seventeen mutations were novel; the majority of mutations were small deletions/insertions, and no mutational hotspots were identified. Sixty-one per cent of patients (22 patients) initially presented with limb girdle muscular dystrophy 2B, 31% (11 patients) with a Miyoshi phenotype, one patient with proximodistal mode of onset, one patient with muscle stiffness after exercise and one patient as a symptomatic carrier. A wider range of age of onset was noted than previously reported, with 25% of patients having first symptoms before the age of 13 years. Independent of the initial mode of presentation, in our cohort of patients the gastrocnemius muscle was the most severely affected muscle leading to an inability to stand on tiptoes, and lower limbs were affected more severely than upper limbs. As previous anecdotal evidence on patients affected by dysferlinopathy suggests good muscle prowess before onset of symptoms, we also investigated pre-symptomatic fitness levels of the patients. Fifty-three per cent of the patients were very active and sporty before the onset of symptoms which makes the clinical course of dysferlinopathy unusual within the different forms of muscular dystrophy and provides a challenge to understanding the underlying pathomechanisms in this disease. PMID:19528035

  14. [The reflex sympathetic dystrophy syndrome associated with breast cancer].

    PubMed

    Cobeta García, J C; López-Longo, F J; Monteagudo Sáez, I; Núñez Olarte, J M; Fernández García, J E; Rivera Redondo, J

    1990-05-01

    Reflex sympathetic dystrophy syndrome (RSDS) is a rare entity of unknown etiopathogenesis, associated to different precipitating factors such as malignant tumors of several localizations. A new clinical variety has been recently described which has been denominated palmar fasciitis and polyarthritis syndrome. We present here two patients with RSDS associated to breast cancer: one case presenting fasciitis and polyarthritis and another case also associated to polymyalgia rheumatica. We emphasize the importance of reducing the tumor mass in the treatment of this syndrome, as well as including it in the gammagraphic differential diagnosis of bone metastasis.

  15. Reflex sympathetic dystrophy: an enigmatic improvement with spinal manipulation

    PubMed Central

    Bortolotto, James

    2000-01-01

    Reflex Sympathetic Dystrophy (RSD) or complex regional pain syndrome, is an extremely painful and disabling condition commonly seen following trauma. Its early recognition and treatment is most critical for a favorable prognosis. Although its diagnosis and treatments vary, neuroblockade is the treatment of choice. Very little has been reported in the literature in regards to manipulation as an early treatment modality to improve joint mobility and reduce pain and future disability. This case report reviews one case presentation of RSD where dramatic results followed cervical spine manipulation.

  16. Clinical utility of serum biomarkers in Duchenne muscular dystrophy.

    PubMed

    Hathout, Yetrib; Seol, Haeri; Han, Meng Hsuan J; Zhang, Aiping; Brown, Kristy J; Hoffman, Eric P

    2016-01-01

    Assessments of disease progression and response to therapies in Duchenne muscular dystrophy (DMD) patients remain challenging. Current DMD patient assessments include complex physical tests and invasive procedures such as muscle biopsies, which are not suitable for young children. Defining alternative, less invasive and objective outcome measures to assess disease progression and response to therapy will aid drug development and clinical trials in DMD. In this review we highlight advances in development of non-invasive blood circulating biomarkers as a means to assess disease progression and response to therapies in DMD.

  17. Bone scintigraphy in the reflex sympathetic dystrophy syndrome

    SciTech Connect

    Kozin, F.; Soin, J.S.; Ryan, L.M.; Carrera, G.F.; Wortmann, R.L.

    1981-02-01

    Sixty-four consecutive patients were studied for possible reflex sympathetic dystrophy syndrome (RSDS). They were divided into five groups, based upon specific clinical criteria, and the radiographic and scintigraphic findings in each group were examined. Osteoporosis was the most common radiographic abnormality. Scintigraphic abnormalities were noted in 60% of RSDS patients but in only 7% of the others. These findings included increased blood flow and enhanced periarticular radionuclide activity in the affected extremity. The scan may reflect an active, potentially reversible disorder of local blood flow in RSDS. Furthermore, the scintigraphic patterns may be useful in the diagnosis and in predicting which patients are likely to respond to systemic steroid therapy.

  18. Complications of sodium hydroxide chemical matrixectomy: nail dystrophy, allodynia, hyperalgesia.

    PubMed

    Bostancı, Seher; Koçyiğit, Pelin; Güngör, Hilayda Karakök; Parlak, Nehir

    2014-11-01

    Ingrown toenails are seen most commonly in young adults, and they can seriously affect daily life. Partial nail avulsion with chemical matrixectomy, generally by using either sodium hydroxide or phenol, is one of the most effective treatment methods. Known complications of phenol matrixectomy are unpredictable tissue damage, prolonged postoperative drainage, increased secondary infection rates, periostitis, and poor cosmetic results. To our knowledge, there have been no reports about the complications related to sodium hydroxide matrixectomy. Herein, we describe three patients who developed nail dystrophy, allodynia, and hyperalgesia after sodium hydroxide matrixectomy.

  19. Evolution of Cellular Inclusions in Bietti’s Crystalline Dystrophy

    PubMed Central

    Furusato, Emiko; Cameron, J. Douglas; Chan, Chi-Chao

    2010-01-01

    Bietti’s crystalline dystrophy (BCD) consists of small, yellow-white, glistening intraretinal crystals in the posterior pole, tapetoretinal degeneration with atrophy of the retinal pigment epithelium (RPE) and “sclerosis” of the choroid; in addition, sparking yellow crystals in the superficial marginal cornea are also found in many patients. BCD is inherited as an autosomal-recessive trait (4q35-tel) and usually has its onset in the third decade of life. This review focuses on the ultrastructure of cellular crystals and lipid inclusions of BCD. PMID:21359135

  20. Dystrophie maculaire de Stargardt - à propos d'un cas

    PubMed Central

    El Ouafi, Aziz; Elmellaoui, Med; Lakataoui, Abdelkader

    2014-01-01

    La maladie de Stardardt est une dystrophie maculaire héréditaire rare d'apparition précoce caractérisée par une perte progressive de la vision centrale, mais avec une vision périphérique intacte, une légère perte de la vision des couleurs, une adaptation à l'obscurité retardée, et une atrophie maculaire avec ou sans taches paramaculaires et une dégénérescence de l’épithélium pigmentaire de la rétine. PMID:25422697

  1. Cardiac involvement in myotonic muscular dystrophy (Steinert's disease): a prospective study of 25 patients

    SciTech Connect

    Perloff, J.K.; Stevenson, W.G.; Roberts, N.K.; Cabeen, W.; Weiss, J.

    1984-11-01

    The presence, degree and frequency of disorders of cardiac conduction and rhythm and of regional or global myocardial dystrophy or myotonia have not previously been studied prospectively and systematically in the same population of patients with myotonic dystrophy. Accordingly, 25 adults with classic Steinert's disease underwent electrocardiography, 24-hour ambulatory electrocardiography, vectorcardiography, chest x-rays, echocardiography, electrophysiologic studies, and technetium-99m angiography. Clinically important cardiac manifestations of myotonic dystrophy reside in specialized tissues rather than in myocardium. Involvement is relatively specific, primarily assigned to the His-Purkinje system. The cardiac muscle disorder takes the form of dystrophy rather than myotonia, and is not selective, appearing with approximately equal distribution in all 4 chambers. Myocardial dystrophy seldom results in clinically overt ventricular failure, but may be responsible for atrial and ventricular arrhythmias. Since myotonic dystrophy is genetically transmitted, a primary biochemical defect has been proposed with complete expression of the gene toward striated muscle tissue, whether skeletal or cardiac. Specialized cardiac tissue and myocardium have close, if not identical, embryologic origins, so it is not surprising that the genetic marker affects both. Cardiac involvement is therefore an integral part of myotonic dystrophy, targeting particularly the infranodal conduction system, to a lesser extent the sinus node, and still less specifically, the myocardium.

  2. A personal overview of causalgia and other reflex dystrophies.

    PubMed Central

    Shumacker, H B

    1985-01-01

    This is a personal assessment of true major causalgia and the other reflex dystrophies, related but distinctly separate entities. The clinical picture of causalgia differs only in minor respects from that described by Mitchell over 120 years ago. Its management has, however, been clarified, largely through the extensive experiences of World War II. It is readily recognized and can be treated effectively by sympathetic blocks or sympathectomy together with active exercise. The other reflex dystrophies are far less understood. They appear to have a similar pattern in their early phase and to respond well to a program of exercise and control of edema--a regimen which, because of pain and paresis, cannot be carried out without sympathetic blocks or occasionally sympathectomy. When not recognized early and treated properly, the sympatomatology usually changes dramatically and treatment differs. Often control of edema and active use of the affected part are all that is necessary. Sometimes, in addition to these measures, sympathetic blocks or sympathectomy is required. Guidelines found useful in management are outlined. Puzzling features are discussed. PMID:3977427

  3. Vascular adrenergic receptor responses in skeletal muscle in myotonic dystrophy

    SciTech Connect

    Mechler, F.; Mastaglia, F.L.

    1981-02-01

    The pharmacological responses of vascular adrenergic receptors to intravenously administered epinephrine, phentolamine, and propranolol were assessed by measuring muscle blood flow (MBF) changes in the tibialis anterior muscle using the xenon 133 clearance technique and were compared in 8 normal subjects and 11 patients with myotonic dystrophy. In cases with advanced involvement of the muscle, the resting MBF was reduced and was not significantly altered by epinephrine before or after alpha- or beta-receptor blockade. In patients in whom the tibialis anterior muscle was normal or only minimally affected clinically, a paradoxical reduction in the epinephrine-induced increase in MBF was found after alpha blockade by phentolamine, and the epinephrine-induced MBF increase was not completely blocked by propranolol as in the normal subjects. These findings point to functional alteration in the properties of vascular adrenergic receptors in muscle in myotonic dystrophy. While this may be another manifestation of a widespread cell membrane defect in the disease, the possibility that the changes are secondary to the myotonic state cannot be excluded.

  4. Nitric oxide synthase deficiency and the pathophysiology of muscular dystrophy

    PubMed Central

    Tidball, James G; Wehling-Henricks, Michelle

    2014-01-01

    The secondary loss of neuronal nitric oxide synthase (nNOS) that occurs in dystrophic muscle is the basis of numerous, complex and interacting features of the dystrophic pathology that affect not only muscle itself, but also influence the interaction of muscle with other tissues. Many mechanisms through which nNOS deficiency contributes to misregulation of muscle development, blood flow, fatigue, inflammation and fibrosis in dystrophic muscle have been identified, suggesting that normalization in NO production could greatly attenuate diverse aspects of the pathology of muscular dystrophy through multiple regulatory pathways. However, the relative importance of the loss of nNOS from the sarcolemma versus the importance of loss of total nNOS from dystrophic muscle remains unknown. Although most current evidence indicates that nNOS localization at the sarcolemma is not required to achieve NO-mediated reductions of pathology in muscular dystrophy, the question remains open concerning whether membrane localization would provide a more efficient rescue from features of the dystrophic phenotype. PMID:25194047

  5. Splicing biomarkers of disease severity in myotonic dystrophy

    PubMed Central

    Nakamori, Masayuki; Sobczak, Krzysztof; Puwanant, Araya; Welle, Steve; Eichinger, Katy; Pandya, Shree; Dekdebrun, Jeannne; Heatwole, Chad R.; McDermott, Michael P.; Chen, Tian; Cline, Melissa; Tawil, Rabi; Osborne, Robert J.; Wheeler, Thurman M.; Swanson, Maurice; Moxley, Richard T.; Thornton, Charles A.

    2014-01-01

    Objective To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2). Methods In a discovery cohort we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM-associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides (ASOs) to reduce levels of toxic RNA. Results Forty-two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM-specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue. Interpretation Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy. PMID:23929620

  6. Altered cross-bridge properties in skeletal muscle dystrophies

    PubMed Central

    Guellich, Aziz; Negroni, Elisa; Decostre, Valérie; Demoule, Alexandre; Coirault, Catherine

    2014-01-01

    Force and motion generated by skeletal muscle ultimately depends on the cyclical interaction of actin with myosin. This mechanical process is regulated by intracellular Ca2+ through the thin filament-associated regulatory proteins i.e.; troponins and tropomyosin. Muscular dystrophies are a group of heterogeneous genetic affections characterized by progressive degeneration and weakness of the skeletal muscle as a consequence of loss of muscle tissue which directly reduces the number of potential myosin cross-bridges involved in force production. Mutations in genes responsible for skeletal muscle dystrophies (MDs) have been shown to modify the function of contractile proteins and cross-bridge interactions. Altered gene expression or RNA splicing or post-translational modifications of contractile proteins such as those related to oxidative stress, may affect cross-bridge function by modifying key proteins of the excitation-contraction coupling. Micro-architectural change in myofilament is another mechanism of altered cross-bridge performance. In this review, we provide an overview about changes in cross-bridge performance in skeletal MDs and discuss their ultimate impacts on striated muscle function. PMID:25352808

  7. Multifocal electroretinography in patients with Stargardt's macular dystrophy

    PubMed Central

    Kretschmann, U; Seeliger, M; Ruether, K; Usui, T; Apfelstedt-Sylla, E; Zrenner, E

    1998-01-01

    AIMS—To describe the topography of multifocal electroretinograms (ERGs) and to explore its diagnostic value in patients with Stargardt's macular dystrophy (SMD).
METHODS—51 patients with SMD were examined by means of the m-sequence technique to characterise the topography of electroretinographic responses in the central visual field. The results were compared with data from 30 normal volunteers.
RESULTS—In 49 of 51 patients with SMD, macular electroretinographic activity was markedly diminished or non-detectable. Towards more peripheral areas, ERG responses of the SMD patients approached those of normals. Implicit times were not markedly delayed at any eccentricity.
CONCLUSION—In contrast with Ganzfeld electroretinography, multifocal electroretinography is useful to detect foveal dysfunction in SMD. Areas of dysfunction were found to be usually larger than expected from psychophysical measurements and morphological alteration. In early stages of the disease it was possible to detect foveal dysfunction, even in patients lacking morphological fundus changes and with good visual acuity.

 Keywords: Stargardt's macular dystrophy; fundus flavimaculatus; electroretinography PMID:9602623

  8. 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.

  9. Dystrophin in frameshift deletion patients with Becker Muscular Dystrophy

    SciTech Connect

    Gangopadhyay, S.B.; Ray, P.N.; Worton, R.G.; Sherratt, T.G.; Heckmatt, J.Z.; Dubowitz, V.; Strong, P.N.; Miller, G. ); Shokeir, M. )

    1992-09-01

    In a previous study the authors identified 14 cases with Duchenne muscular dystrophy (DMD) or its milder variant, Becker muscular dystrophy (BMD), with a deletion of exons 3-7, a deletion that would be expected to shift the translational reading frame of the mRNA and give a severe phenotype. They have examined dystrophin and its mRNA from muscle biopsies of seven cases with either mild or intermediate phenotypes. In all cases they detected slightly lower-molecular-weight dystrophin in 12%-15% abundance relative to the normal. By sequencing amplified mRNA they have found that exon 2 is spliced to exon 8, a splice that produces a frameshifted mRNA, and have found no evidence for alternate splicing that might be involved in restoration of dystrophin mRNA reading frame in the patients with a mild phenotype. Other transcriptional and posttranscriptional mechanisms such as cryptic promoter, ribosomal frameshifting, and reinitiation are suggested that might play some role in restoring the reading frame. 34 refs., 5 figs. 1 tab.

  10. Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy.

    PubMed

    De Arcangelis, Valeria; Strimpakos, Georgios; Gabanella, Francesca; Corbi, Nicoletta; Luvisetto, Siro; Magrelli, Armando; Onori, Annalisa; Passananti, Claudio; Pisani, Cinzia; Rome, Sophie; Severini, Cinzia; Naro, Fabio; Mattei, Elisabetta; Di Certo, Maria Grazia; Monaco, Lucia

    2016-01-01

    Numerous therapeutic approaches for Duchenne and Becker Muscular Dystrophy (DMD and BMD), the most common X-linked muscle degenerative disease, have been proposed. So far, the only one showing a clear beneficial effect is the use of corticosteroids. Recent evidence indicates an improvement of dystrophic cardiac and skeletal muscles in the presence of sustained cGMP levels secondary to a blocking of their degradation by phosphodiesterase five (PDE5). Due to these data, we performed a study to investigate the effect of the specific PDE5 inhibitor, tadalafil, on dystrophic skeletal muscle function. Chronic pharmacological treatment with tadalafil has been carried out in mdx mice. Behavioral and physiological tests, as well as histological and biochemical analyses, confirmed the efficacy of the therapy. We then performed a microarray-based genomic analysis to assess the pattern of gene expression in muscle samples obtained from the different cohorts of animals treated with tadalafil. This scrutiny allowed us to identify several classes of modulated genes. Our results show that PDE5 inhibition can ameliorate dystrophy by acting at different levels. Tadalafil can lead to (1) increased lipid metabolism; (2) a switch towards slow oxidative fibers driven by the up-regulation of PGC-1α; (3) an increased protein synthesis efficiency; (4) a better actin network organization at Z-disk.

  11. Drug screening in a zebrafish model of Duchenne muscular dystrophy.

    PubMed

    Kawahara, Genri; Karpf, Jeremy A; Myers, Jennifer A; Alexander, Matthew S; Guyon, Jeffrey R; Kunkel, Louis M

    2011-03-29

    Two known zebrafish dystrophin mutants, sapje and sapje-like (sap(c/100)), represent excellent small-animal models of human muscular dystrophy. Using these dystrophin-null zebrafish, we have screened the Prestwick chemical library for small molecules that modulate the muscle phenotype in these fish. With a quick and easy birefringence assay, we have identified seven small molecules that influence muscle pathology in dystrophin-null zebrafish without restoration of dystrophin expression. Three of seven candidate chemicals restored normal birefringence and increased survival of dystrophin-null fish. One chemical, aminophylline, which is known to be a nonselective phosphodiesterase (PDE) inhibitor, had the greatest ability to restore normal muscle structure and up-regulate the cAMP-dependent PKA pathway in treated dystrophin-deficient fish. Moreover, other PDE inhibitors also reduced the percentage of affected sapje fish. The identification of compounds, especially PDE inhibitors, that moderate the muscle phenotype in these dystrophin-null zebrafish validates the screening protocol described here and may lead to candidate molecules to be used as therapeutic interventions in human muscular dystrophy. PMID:21402949

  12. The Intriguing Regulators of Muscle Mass in Sarcopenia and Muscular Dystrophy

    PubMed Central

    Sakuma, Kunihiro; Aoi, Wataru; Yamaguchi, Akihiko

    2014-01-01

    Recent advances in our understanding of the biology of muscle have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle mass and increased intramuscular fibrosis occur in both sarcopenia and muscular dystrophy. Several regulators (mammalian target of rapamycin, serum response factor, atrogin-1, myostatin, etc.) seem to modulate protein synthesis and degradation or transcription of muscle-specific genes during both sarcopenia and muscular dystrophy. This review provides an overview of the adaptive changes in several regulators of muscle mass in both sarcopenia and muscular dystrophy. PMID:25221510

  13. Dexmedetomidine and fentanyl combination for procedural sedation in a case of Duchenne muscular dystrophy

    PubMed Central

    Kulshrestha, Ashish; Bajwa, Sukhminder Jit Singh; Singh, Amarjit; Kapoor, Vinod

    2011-01-01

    Duchenne muscular dystrophy, an X-linked disorder characterized by progressive muscle weakness, is the most common muscular dystrophy among children leading to death before the end of third decade. Anesthesia in such patients pose a great challenge due to various complications associated with it. The dreaded metabolic and clinical complications occur due to various inhalational anesthetics and succinylcholine in this subset of patients. We are reporting a child with diagnosed Duchenne muscular dystrophy who underwent excision of dentigerous cyst in oral cavity under procedural sedation with combination of dexmedetomidine and fentanyl and thus administration of general anesthesia was avoided. PMID:25885395

  14. Translating golden retriever muscular dystrophy microarray findings to novel biomarkers for cardiac/skeletal muscle function in Duchenne Muscular Dystrophy

    PubMed Central

    Galindo, Cristi L.; Soslow, Jonathan H.; Brinkmeyer-Langford, Candice L.; Gupte, Manisha; Smith, Holly M.; Sengsayadeth, Seng; Sawyer, Douglas B.; Benson, D. Woodrow; Kornegay, Joe N.; Markham, Larry W.

    2016-01-01

    Background In Duchenne muscular dystrophy (DMD), abnormal cardiac function is typically preceded by a decade of skeletal muscle disease. Molecular reasons for differences in onset and progression of these muscle groups are unknown. Human biomarkers are lacking. Methods We analyzed cardiac and skeletal muscle microarrays from normal and golden retriever muscular dystrophy (GRMD) dogs (ages 6, 12, or 47+ months) to gain insight into muscle dysfunction and to identify putative DMD biomarkers. These biomarkers were then measured using human DMD blood samples. Results We identified GRMD candidate genes that might contribute to the disparity between cardiac and skeletal muscle disease, focusing on brain-derived neurotropic factor (BDNF) and osteopontin (OPN/SPP1). BDNF was elevated in cardiac muscle of younger GRMD but was unaltered in skeletal muscle, while SPP1 was increased only in GRMD skeletal muscle. In human DMD, circulating levels of BDNF were inversely correlated with ventricular function and fibrosis, while SPP1 levels correlated with skeletal muscle function. Conclusion These results highlight gene expression patterns that could account for differences in cardiac and skeletal disease in GRMD. Most notably, animal model-derived data were translated to DMD and support use of BDNF and SPP1 as biomarkers for cardiac and skeletal muscle involvement, respectively. PMID:26672735

  15. Serum profiling identifies novel muscle miRNA and cardiomyopathy-related miRNA biomarkers in Golden Retriever muscular dystrophy dogs and Duchenne muscular dystrophy patients.

    PubMed

    Jeanson-Leh, Laurence; Lameth, Julie; Krimi, Soraya; Buisset, Julien; Amor, Fatima; Le Guiner, Caroline; Barthélémy, Inès; Servais, Laurent; Blot, Stéphane; Voit, Thomas; Israeli, David

    2014-11-01

    Duchenne muscular dystrophy (DMD) is a fatal, X-linked neuromuscular disease that affects 1 boy in 3500 to 5000 boys. The golden retriever muscular dystrophy dog is the best clinically relevant DMD animal model. Here, we used a high-thoughput miRNA sequencing screening for identification of candidate serum miRNA biomarkers in golden retriever muscular dystrophy dogs. We confirmed the dysregulation of the previously described muscle miRNAs, miR-1, miR-133, miR-206, and miR-378, and identified a new candidate muscle miRNA, miR-95. We identified two other classes of dysregulated serum miRNAs in muscular dystrophy: miRNAs belonging to the largest known miRNA cluster that resides in the imprinting DLK1-DIO3 genomic region and miRNAs associated with cardiac disease, including miR-208a, miR-208b, and miR-499. No simple correlation was identified between serum levels of cardiac miRNAs and cardiac functional parameters in golden retriever muscular dystrophy dogs. Finally, we confirmed a dysregulation of miR-95, miR-208a, miR-208b, miR-499, and miR-539 in a small cohort of DMD patients. Given the interspecies conservation of miRNAs and preliminary data in DMD patients, these newly identified dysregulated miRNAs are strong candidate biomarkers for DMD patients.

  16. Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

    PubMed

    Cotta, Ana; Carvalho, Elmano; da-Cunha-Júnior, Antonio Lopes; Paim, Júlia Filardi; Navarro, Monica M; Valicek, Jaquelin; Menezes, Miriam Melo; Nunes, Simone Vilela; Xavier Neto, Rafael; Takata, Reinaldo Issao; Vargas, Antonio Pedro

    2014-09-01

    Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype.

  17. [Reflex dystrophy following so-called whiplash injury of the cervical spine].

    PubMed

    Bühring, M

    1984-01-01

    In bad cases of whiplash injury of the cervical spine the post-accidental course is complicated by pain, vegetative dysfunctional syndromes and by psychic and psychiatric disorders over many years. There is no satisfactory concept to understand the pathophysiology of these processes. The paper deals with the possibility of a reflex dystrophy. Sympathetic reflex dystrophy syndromes are seen principally in patients with joint, tendon or vascular lesions. In case of whiplash injury, it would concern the cervical spine itself as well as visceral organs including the central nervous system. For the CNS the lymphostatic encephalopathy is a well defined entity. Above all, a reflex dystrophy develops on the basis of a special personality structure. In case of psychic and psychiatric complaints after whiplash injury patients with a so called Sudeck-personality should not be suspected to aggravate; in contrast, especially in these patients complications by reflex dystrophy are credible. Consequences for the assessment and for rehabilitation are discussed. PMID:6475217

  18. Stakeholder cooperation to overcome challenges in orphan medicine development: the example of Duchenne muscular dystrophy.

    PubMed

    Straub, Volker; Balabanov, Pavel; Bushby, Kate; Ensini, Monica; Goemans, Nathalie; De Luca, Annamaria; Pereda, Alejandra; Hemmings, Robert; Campion, Giles; Kaye, Edward; Arechavala-Gomeza, Virginia; Goyenvalle, Aurelie; Niks, Erik; Veldhuizen, Olav; Furlong, Pat; Stoyanova-Beninska, Violeta; Wood, Matthew J; Johnson, Alex; Mercuri, Eugenio; Muntoni, Francesco; Sepodes, Bruno; Haas, Manuel; Vroom, Elizabeth; Aartsma-Rus, Annemieke

    2016-07-01

    Duchenne muscular dystrophy is a rare, progressive, muscle-wasting disease leading to severe disability and premature death. Treatment is currently symptomatic, but several experimental therapies are in development. Implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive information about the natural history of the disease are essential for regulatory approval of any treatment. However, for Duchenne muscular dystrophy and other rare diseases, these requirements are not always in place when potential therapies enter the clinical trial phase. A cooperative effort of stakeholders in Duchenne muscular dystrophy-including representatives from patients' groups, academia, industry, and regulatory agencies-is aimed at addressing this shortfall by identifying strategies to overcome challenges, developing the tools needed, and collecting relevant data. An open and constructive dialogue among European stakeholders has positively affected development of treatments for Duchenne muscular dystrophy; this approach could serve as a paradigm for development of treatments for rare diseases in general. PMID:27302365

  19. Defective (U-14 C) palmitic acid oxidation in Duchenne muscular dystrophy

    SciTech Connect

    Carroll, J.E.; Norris, B.J.; Brooke, M.H.

    1985-01-01

    Compared with normal skeletal muscle, muscle from patients with Duchenne dystrophy had decreased (U-14 C) palmitic acid oxidation. (1-14 C) palmitic acid oxidation was normal. These results may indicate a defect in intramitochondrial fatty acid oxidation.

  20. Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.

    PubMed

    Momma, Kazunari; Noguchi, Satoru; Malicdan, May Christine V; Hayashi, Yukiko K; Minami, Narihiro; Kamakura, Keiko; Nonaka, Ikuya; Nishino, Ichizo

    2012-01-01

    Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45-48 in DMD gene. All patients having rimmed vacuoles showed milder clinical features compared to those without rimmed vacuoles. Interestingly, the rimmed vacuoles in Becker muscular dystrophy muscles seem to represent autophagic vacuoles and are also associated with polyubiquitinated protein aggregates. These findings support the notion that rimmed vacuoles can appear in Becker muscular dystrophy, and may be related to the chronic changes in muscle pathology induced by certain mutations in the DMD gene.

  1. Complementary and Alternative Medicine for Duchenne and Becker Muscular Dystrophies: Characteristics of Users and Caregivers

    PubMed Central

    Zhu, Yong; Romitti, Paul A.; Conway, Kristin M.; Andrews, Jennifer; Liu, Ke; Meaney, F. John; Street, Natalie; Puzhankara, Soman; Druschel, Charlotte M.; Matthews, Dennis J.

    2015-01-01

    BACKGROUND Complementary and alternative medicine is frequently used in the management of chronic pediatric diseases, but little is known about its use by those with Duchenne or Becker muscular dystrophy. METHODS Complementary and alternative medicine use by male patients with Duchenne or Becker muscular dystrophy and associations with characteristics of male patients and their caregivers were examined through interviews with 362 primary caregivers identified from the Muscular Dystrophy Surveillance, Tracking, and Research Network. RESULTS Overall, 272 of the 362 (75.1%) primary caregivers reported that they had used any complementary and alternative medicine for the oldest Muscular Dystrophy Surveillance, Tracking, and Research Network male in their family. The most commonly reported therapies were from the mind-body medicine domain (61.0%) followed by those from the biologically based practice (39.2%), manipulative and body-based practice (29.3%), and whole medical system (6.9%) domains. Aquatherapy, prayer and/or blessing, special diet, and massage were the most frequently used therapies. Compared with nonusers, male patients who used any therapy were more likely to have an early onset of symptoms and use a wheel chair; their caregivers were more likely to be non-Hispanic white. Among domains, associations were observed with caregiver education and family income (mind-body medicines [excluding prayer and/or blessing only] and whole medical systems) and Muscular Dystrophy Surveillance, Tracking, and Research Network site (biologically based practices and mind-body medicines [excluding prayer and/or blessing only]). CONCLUSIONS Complementary and alternative medicine use was common in the management of Duchenne and Becker muscular dystrophies among Muscular Dystrophy Surveillance, Tracking, and Research Network males. This widespread use suggests further study to evaluate the efficacy of integrating complementary and alternative medicine into treatment regimens for

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

    SciTech Connect

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

    1995-08-28

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

  3. Decreased Insulin Receptors but Normal Glucose Metabolism in Duchenne Muscular Dystrophy

    NASA Astrophysics Data System (ADS)

    de Pirro, Roberto; Lauro, Renato; Testa, Ivano; Ferretti, Ginofabrizio; de Martinis, Carlo; Dellantonio, Renzo

    1982-04-01

    Compared to matched controls, 17 patients with Duchenne muscular dystrophy showed decreased insulin binding to monocytes due to decreased receptor concentration. These patients showed no signs of altered glucose metabolism and retrospective analysis of the clinical records of a further 56 such patients revealed no modification in carbohydrate metabolism. These data suggest that reduced insulin receptor number does not produce overt modifications of glucose metabolism in Duchenne muscular dystrophy.

  4. A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber's congenital amaurosis.

    PubMed

    Ugur Iseri, Sibel A; Durlu, Yusuf K; Tolun, Aslihan

    2010-10-01

    Cone-rod dystrophies are inherited retinal dystrophies that are characterized by progressive degeneration of cones and rods, causing an early decrease in central visual acuity and colour vision defects, followed by loss of peripheral vision in adolescence or early adult life. Both genetic and clinical heterogeneity are well known. In a family with autosomal recessive cone-rod dystrophy, genetic analyses comprising genome scan with microsatellite markers, fine mapping and candidate gene approach resulted in the identification of a homozygous missense GUCY2D mutation. This is the first GUCY2D mutation associated with autosomal recessive cone-rod dystrophy rather than Leber's congenital amaurosis (LCA), a severe disease leading to childhood blindness. This study hence establishes GUCY2D, which is a common cause for both recessive LCA and dominant cone-rod dystrophy, as a good candidate for autosomal recessive cone-rod dystrophy. PMID:20517349

  5. Pathophysiology of Corneal Dystrophies: From Cellular Genetic Alteration to Clinical Findings.

    PubMed

    Sacchetti, Marta; Macchi, Ilaria; Tiezzi, Alessandro; La Cava, Maurizio; Massaro-Giordano, Giacomina; Lambiase, Alessandro

    2016-02-01

    Corneal dystrophies are a heterogeneous group of bilateral, inherited, rare diseases characterized by slowly progressive corneal opacities, that lead to visual impairment. Most of them have an autosomal dominant pattern of inheritance with variable expressivity, but new mutations have been described. Many corneal dystrophies have been genetically characterized and the specific gene mutations identified, such as for the epithelial-stromal TGFBI dystrophies. Current classification systems identified four main groups of corneal dystrophies based on clinical, histologic, and genetic information. Diagnosis is performed during a routine ophthalmic examination that shows typical cellular abnormalities of the corneal epithelium, stroma, or endothelium. Disease progression should be carefully monitored to decide the proper clinical management. The treatment of corneal dystrophies is variable, depending on symptoms, clinical course, severity, and type of dystrophy. Management aimed to reduce symptoms and to improve vision, includes different surgical approaches. Novel cellular and genetic therapeutic approaches are under evaluation. J. Cell. Physiol. 231: 261-269, 2016. © 2015 Wiley Periodicals, Inc. PMID:26104822

  6. Muscular dystrophy in the Japanese Spitz: an inversion disrupts the DMD and RPGR genes.

    PubMed

    Atencia-Fernandez, Sabela; Shiel, Robert E; Mooney, Carmel T; Nolan, Catherine M

    2015-04-01

    An X-linked muscular dystrophy, with deficiency of full-length dystrophin and expression of a low molecular weight dystrophin-related protein, has been described in Japanese Spitz dogs. The aim of this study was to identify the causative mutation and develop a specific test to identify affected cases and carrier animals. Gene expression studies in skeletal muscle of an affected animal indicated aberrant expression of the Duchenne muscular dystrophy (dystrophin) gene and an anomaly in intron 19 of the gene. Genome-walking experiments revealed an inversion that interrupts two genes on the X chromosome, the Duchenne muscular dystrophy gene and the retinitis pigmentosa GTPase regulator gene. All clinically affected dogs and obligate carriers that were tested had the mutant chromosome, and it is concluded that the inversion is the causative mutation for X-linked muscular dystrophy in the Japanese Spitz breed. A PCR assay that amplifies mutant and wild-type alleles was developed and proved capable of identifying affected and carrier individuals. Unexpectedly, a 7-year-old male animal, which had not previously come to clinical attention, was shown to possess the mutant allele and to have a relatively mild form of the disease. This observation indicates phenotypic heterogeneity in Japanese Spitz muscular dystrophy, a feature described previously in humans and Golden Retrievers. With the availability of a simple, fast and accurate test for Japanese Spitz muscular dystrophy, detection of carrier animals and selected breeding should help eliminate the mutation from the breed.

  7. [Respiratory and intensive care aspects of muscular dystrophies].

    PubMed

    Ambrosi, X; Lamothe, L; Heming, N; Orlikowski, D

    2015-12-01

    Among the various myopathies, Duchenne muscular dystrophy represents the myopathy with the most stereotypical respiratory evolution. This progressive respiratory failure is going to develop in a parallel way of motor deficit, conducting patients to mechanical ventilation at the end of their second decade. In the absence of curative therapeutics, respiratory cares like home ventilation and prevention of respiratory complications, in a systematic and organized way, allowed to decrease the morbidity and the mortality of these patients. It is not exceptional to meet patients with life expectancy of which overtakes about forty. Besides axial stabilization, cough assistance techniques and swallowing disorders management need to be associated to mechanical ventilation. Invasive techniques of ventilation as tracheostomy keep their place in this pathology even if alternative techniques allowing full day non-invasive ventilation were generalized these last years. PMID:26773587

  8. Negative expansion of the myotonic dystrophy unstable sequence

    SciTech Connect

    Abeliovich, D.; Lerer, I.; Pashut-Lavon, I.; Shmueli, E. ); Raas-Rothschild, A.; Frydman, M. )

    1993-06-01

    The authors have analyzed the unstable fragment of the myotonic dystrophy (DM) gene in a pregnancy at 50% risk for DM. The affected father in this family had a 3.0-kb expansion of the DM unstable region. The fetus inherited the mutated gene, but with an expansion of 0.5 kb. This case represented a counseling problem in light of the absence of data concerning [open quotes]negative expansion[close quotes]. Analysis of the DM gene in 17 families with 72 affected individuals revealed four more cases of negative expansions, all of them in paternal transmissions. The possible significance of this finding is discussed. 21 refs., 3 figs., 3 tabs.

  9. Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy.

    PubMed

    Pessina, Patrizia; Kharraz, Yacine; Jardí, Mercè; Fukada, So-ichiro; Serrano, Antonio L; Perdiguero, Eusebio; Muñoz-Cánoves, Pura

    2015-06-01

    Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component. PMID:25981413

  10. Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy.

    PubMed

    Pessina, Patrizia; Kharraz, Yacine; Jardí, Mercè; Fukada, So-ichiro; Serrano, Antonio L; Perdiguero, Eusebio; Muñoz-Cánoves, Pura

    2015-06-01

    Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component.

  11. Anesthetic management of a myotonic dystrophy patient with paraganglionoma.

    PubMed

    Subramaniam, Ashwin; Grauer, Robert; Beilby, David; Tiruvoipati, Ravindranath

    2016-11-01

    Myotonic dystrophy (DM), though rare, can significantly complicate anesthesia due to muscular and extra-muscular involvement. When this condition is compounded by a pheochromocytoma, anesthetizing such patients becomes extra challenging. We present a case report of a 61-year-old lady with congenital DM, with the whole gamut of associated features, was diagnosed with a noradrenaline secreting paraganglionoma following investigation of refractory hypertension. We anesthetized her for an open resection of the lesion. The conduct of anesthesia and recovery of this patient is described. Our experience suggests that anesthetizing these patients though challenging can be safely managed with relaxant general anesthesia and epidural analgesia with meticulous care pre, intra and post-surgical intervention. PMID:27687340

  12. [Keratoconus, the most common corneal dystrophy. Can keratoplasty be avoided?].

    PubMed

    Arne, Jean Louis; Fournié, Pierre

    2011-01-01

    Keratoconus is the most common form of corneal dystrophy. It consists of a non inflammatory progressive thinning process that leads to conical ectasia of the cornea, causing high myopia and astigmatism. In more advanced cases, opacities can be seen at the apex of the cone. Traditional conservative management of keratoconus begins with spectacle correction and contact lenses. Surgery is recommended when a stable contact lens fit fails to provide adequate vision. Keratoplasty was long the only surgical treatment, but recent years have seen the introduction of new surgical options:--Collagen cross-linking stiffens the cornea and can halt disease progression;--Intrastromal corneal rings can reduce astigmatism and improve visual acuity;--Intraocular lenses are valuable additional options for the correction of refractive errors. Currently, keratoplasty is mainly restricted to patients with opacities of the central cornea. PMID:22039707

  13. Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy.

    PubMed

    Madej-Pilarczyk, A; Kochański, A

    2016-01-01

    Emery-Dreifuss muscular dystrophy (EDMD), a rare inherited disease, is characterized clinically by humero-peroneal muscle atrophy and weakness, multijoint contractures, spine rigidity and cardiac insufficiency with conduction defects. There are at least six types of EDMD known so far, of which five have been associated with mutations in genes encoding nuclear proteins. The majority of the EDMD cases described so far are of the emerinopathy (EDMD1) kind, with a recessive X-linked mode of inheritance, or else laminopathy (EDMD2), with an autosomal dominant mode of inheritance. In the work described here, the authors have sought to describe the history by which EDMD came to be distinguished as a separate entity, as well as the clinical and genetic characteristics of the disease, the pathophysiology of lamin-related muscular diseases and, finally, therapeutic issues, prevention and ethical aspects. PMID:27179216

  14. Duchenne muscular dystrophy drugs face tough path to approval.

    PubMed

    Hodgkinson, L; Sorbera, L; Graul, A I

    2016-03-01

    Highly anticipated as new disease-modifying treatments for Duchenne muscular dystrophy (DMD), therapeutics by BioMarin Pharmaceutical (Kyndrisa™; drisapersen) and Sarepta Therapeutics (eteplirsen; AVI-4658) both recently received negative FDA reviews and are now facing battles for approval in the U.S. At present, BioMarin is committed to working with the FDA to forge a pathway to approval following the failure of its NDA, while Sarepta awaits the formal decision on its NDA, which is expected by late May 2016. Despite the critical nature of both reviews, analysts consider that there is still a narrow possibility of approval of both drugs. According to Consensus forecasts from Thomson Reuters Cortellis for Competitive Intelligence, Kyndrisa is forecast to achieve sales of USD 533.71 million in 2021. PMID:27186594

  15. Oropharyngeal dysphagia in myotonic dystrophy type 1: a systematic review.

    PubMed

    Pilz, Walmari; Baijens, Laura W J; Kremer, Bernd

    2014-06-01

    A systematic review was conducted to investigate the pathophysiology of and diagnostic procedures for oropharyngeal dysphagia in myotonic dystrophy (MD). The electronic databases Embase, PubMed, and The Cochrane Library were used. The search was limited to English, Dutch, French, German, Spanish, and Portuguese publications. Sixteen studies met the inclusion criteria. Two independent reviewers assessed the methodological quality of the included articles. Swallowing assessment tools, the corresponding protocols, the studies' outcome measurements, and main findings are summarized and presented. The body of literature on pathophysiology of swallowing in dysphagic patients with MD type 1 remains scant. The included studies are heterogeneous with respect to design and outcome measures and hence are not directly comparable. More importantly, most studies had methodological problems. These are discussed in detail and recommendations for further research on diagnostic examinations for swallowing disorders in patients with MD type 1 are provided.

  16. A case of myotonic dystrophy with electrolyte imbalance.

    PubMed

    Ko, Weon-Jin; Kim, Kwang-Yeol; Kim, So-Mi; Hong, Seung-Jae; Lee, Sang-Hoon; Song, Ran; Yang, Hyung-In; Lee, Yeon-Ah

    2013-07-01

    Type 1 myotonic dystrophy (DM1) is an autosomal-dominant inherited disorder with a multisystem involvement, caused by an abnormal expansion of the CTG sequence of the dystrophic myotonia protein kinase (DMPK) gene. DM1 is a variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being reported. But, Electrolytes imbalance is a very rare condition in patients with DM1 yet. Herein we present a 42-yr-old Korean male of DM1 with abnormally elevated serum sodium and potassium. The patient had minimum volume of maximally concentrated urine without water loss. It was only cured by normal saline hydration. The cause of hypernatremia was considered by primary hypodipsia. Hyperkalemic conditions such as renal failure, pseudohyperkalemia, cortisol deficiency and hyperkalemic periodic paralysis were excluded. Further endocrine evaluation suggested selective hyperreninemic hypoaldosteronism as a cause of hyperkalemia.

  17. [Muscular spasms associated with a reflex sympathetic dystrophy].

    PubMed

    Tola, M A; Gutiérrez, J M; Llamazares, O; Yugueros, I

    1996-10-01

    The appearance of involuntary movements in the clinical course of reflex sympathetic dystrophy (DSR) constitutes a rare clinical entity. In this context, the most frequent changes in movements are muscle spasms and focal dystonia, although postural tremor, muscle weakness and rhythmic myoclonus have also been described. The disorder is more frequent in young women and in the lower limbs. It may have a focal, segmental, multifocal, hemicorporal or symmetrical distribution. It is almost always secondary to local trauma. The pathogenesis and most effective treatment are unknown. We present the case of a 62 year old woman with muscle spasms of both legs and feet as a complication of spontaneously appearing DSR. The electromyogram showed continuous non-rhythmic discharges with morphologically normal motor unit potentials in both anterior tibial muscles. The clinical course and symptomatic improvement following treatment with benzodiazepine seems to suggest that the disorder is of central origin. PMID:8983730

  18. Evidence for a chronic axonal atrophy in oculopharyngeal "muscular dystrophy".

    PubMed

    Probst, A; Tackmann, W; Stoeckli, H R; Jerusalem, F; Ulrich, J

    1982-01-01

    We report on morphometric investigations of peripheral nerves in a woman, who died at the age of 69, presenting the classical symptoms of oculopharyngeal muscular dystrophy (OPMD) and a typical family history with several members (males and females) affected over three generations. Evidence for chronic axonal atrophy was found in peripheral nerves and especially in oculomotor nerves with severe axon loss in endomysial nerve twigs of extraocular, laryngeal, and tongue muscles. Whereas limb muscles presented features of neurogenic atrophy, severe changes of "myopathic" type were evident in extrinsic eye muscles, laryngeal constrictor, tongue, and diaphragma. However, we interpreted these changes as neurogenic in origin in view of the severe denervation found in those muscles. Our findings suggest that OPMD is a disease of primary neurogenic origin rather than a primary myopathic disorder. PMID:7124348

  19. Dropped-head in recessive oculopharyngeal muscular dystrophy.

    PubMed

    Garibaldi, Matteo; Pennisi, Elena Maria; Bruttini, Mirella; Bizzarri, Veronica; Bucci, Elisabetta; Morino, Stefania; Talerico, Caterina; Stoppacciaro, Antonella; Renieri, Alessandra; Antonini, Giovanni

    2015-11-01

    A 69-year-old woman presented a dropped head, caused by severe neck extensor weakness that had started two years before. She had also developed a mild degree of dysphagia, rhinolalia, eyelid ptosis and proximal limb weakness during the last months. EMG revealed myopathic changes. Muscle MRI detected fatty infiltration in the posterior neck muscles and tongue. Muscle biopsy revealed fiber size variations, sporadic rimmed vacuoles, small scattered angulated fibers and a patchy myofibrillar network. Genetic analysis revealed homozygous (GCN)11 expansions in the PABPN1 gene that were consistent with recessive oculopharyngeal muscular dystrophy (OPMD). There are a few reports of the recessive form, which has a later disease onset with milder symptoms and higher clinical variability than the typical dominantly inherited form. This patient, who is the first Italian and the eighth worldwide reported case of recessive OPMD, is also the first case of OPMD with dropped-head syndrome, which thus expands the clinical phenotype of recessive OPMD.

  20. Muscle exercise in limb girdle muscular dystrophies: pitfall and advantages.

    PubMed

    Siciliano, Gabriele; Simoncini, Costanza; Giannotti, Stefano; Zampa, Virna; Angelini, Corrado; Ricci, Giulia

    2015-05-01

    Different genetic mutations underlying distinct pathogenic mechanisms have been identified as cause of muscle fibers degeneration and strength loss in limb girdle muscular dystrophies (LGMD). As a consequence, exercise tolerance is affected in patients with LGMD, either as a direct consequence of the loss of muscle fibers or secondary to the sedentary lifestyle due to the motor impairment. It has been debated for many years whether or not muscle exercise is beneficial or harmful for patients with myopathic disorders. In fact, muscular exercise would be considered in helping to hinder the loss of muscle tissue and strength. On the other hand, muscle structural defects in LGMD can result in instability of the sarcolemma, making it more likely to induce muscle damage as a consequence of intense muscle contraction, such as that performed during eccentric training. Several reports have suggested that supervised aerobic exercise training is safe and may be considered effective in improving oxidative capacity and muscle function in patients with LGMD, such as LGMD2I, LGMD2L, LGMD2A. More or less comfortable investigation methods applied to assess muscle function and structure can be useful to detect the beneficial effects of supervised training in LGMD. However, it is important to note that the available trials assessing muscle exercise in patients with LGMD have often involved a small number of patients, with a wide clinical heterogeneity and a different experimental design. Based on these considerations, resistance training can be considered part of the rehabilitation program for patients with a limb-girdle type of muscular dystrophy, but it should be strictly supervised to assess its effects and prevent possible development of muscle damage. PMID:26155063

  1. Current and emerging treatment strategies for Duchenne muscular dystrophy.

    PubMed

    Mah, Jean K

    2016-01-01

    Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing. Precise characterization of the DMD mutation is important for genetic counseling and individualized treatment. Current standard of care includes the use of corticosteroids to prolong ambulation and to delay the onset of secondary complications. Early use of cardioprotective agents, noninvasive positive pressure ventilation, and other supportive strategies has improved the life expectancy and health-related quality of life for many young adults with DMD. New emerging treatment includes viral-mediated microdystrophin gene replacement, exon skipping to restore the reading frame, and nonsense suppression therapy to allow translation and production of a modified dystrophin protein. Other potential therapeutic targets involve upregulation of compensatory proteins, reduction of the inflammatory cascade, and enhancement of muscle regeneration. So far, data from DMD clinical trials have shown limited success in delaying disease progression; unforeseen obstacles included immune response against the generated mini-dystrophin, inconsistent evidence of dystrophin production in muscle biopsies, and failure to demonstrate a significant improvement in the primary outcome measure, as defined by the 6-minute walk test in some studies. The long-term safety and efficacy of emerging treatments will depend on the selection of appropriate clinical end points and sensitive biomarkers to detect meaningful changes in disease progression. Correction of the underlying

  2. Dysphagia in Duchenne muscular dystrophy: practical recommendations to guide management

    PubMed Central

    Toussaint, Michel; Davidson, Zoe; Bouvoie, Veronique; Evenepoel, Nathalie; Haan, Jurn; Soudon, Philippe

    2016-01-01

    Abstract Purpose: Duchenne muscular dystrophy (DMD) is a rapidly progressive neuromuscular disorder causing weakness of the skeletal, respiratory, cardiac and oropharyngeal muscles with up to one third of young men reporting difficulty swallowing (dysphagia). Recent studies on dysphagia in DMD clarify the pathophysiology of swallowing disorders and offer new tools for its assessment but little guidance is available for its management. This paper aims to provide a step-by-step algorithm to facilitate clinical decisions regarding dysphagia management in this patient population. Methods: This algorithm is based on 30 years of clinical experience with DMD in a specialised Centre for Neuromuscular Disorders (Inkendaal Rehabilitation Hospital, Belgium) and is supported by literature where available. Results: Dysphagia can worsen the condition of ageing patients with DMD. Apart from the difficulties of chewing and oral fragmentation of the food bolus, dysphagia is rather a consequence of an impairment in the pharyngeal phase of swallowing. By contrast with central neurologic disorders, dysphagia in DMD accompanies solid rather than liquid intake. Symptoms of dysphagia may not be clinically evident; however laryngeal food penetration, accumulation of food residue in the pharynx and/or true laryngeal food aspiration may occur. The prevalence of these issues in DMD is likely underestimated. Conclusions: There is little guidance available for clinicians to manage dysphagia and improve feeding for young men with DMD. This report aims to provide a clinical algorithm to facilitate the diagnosis of dysphagia, to identify the symptoms and to propose practical recommendations to treat dysphagia in the adult DMD population.Implications for RehabilitationLittle guidance is available for the management of dysphagia in Duchenne dystrophy.Food can penetrate the vestibule, accumulate as residue or cause aspiration.We propose recommendations and an algorithm to guide management of

  3. [Genetic Diagnosis and Molecular Therapies for Duchenne Muscular Dystrophy].

    PubMed

    Takeshima, Yasuhiro

    2015-10-01

    Duchenne muscular dystrophy (DMD) is the most common form of inherited muscle disease and is characterized by progressive muscle wasting, ultimately resulting in the death of patients in their twenties or thirties. DMD is characterized by a deficiency of the muscle dystrophin as a result of mutations in the dystrophin gene. Currently, no effective treatment for DMD is available. Promising molecular therapies which are mutation-specific have been developed. Transformation of an out-of-frame mRNA into an in-frame dystrophin message by inducing exon skipping is considered one of the approaches most likely to lead to success. We demonstrated that the intravenous administration of the antisense oligonucleotide against the splicing enhancer sequence results in exon skipping and production of the dystrophin protein in DMD case for the first time. After extensive studies, anti-sense oligonucleotides comprising different monomers have undergone clinical trials and provided favorable results, enabling improvements in ambulation of DMD patients. Induction of the read-through of nonsense mutations is expected to produce dystrophin in DMD patients with nonsense mutations, which are detected in 19% of DMD cases. The clinical effectiveness of gentamicin and PTC124 has been reported. We have demonstrated that arbekacin-mediated read-through can markedly ameliorate muscular dystrophy in vitro. We have already begun a clinical trial of nonsense mutation read-through therapy using arbekacin. Some of these drug candidates are planned to undergo submission for approval to regulatory agencies in the US and EU. We hope that these molecular therapies will contribute towards DMD treatment. PMID:26897856

  4. Current and emerging treatment strategies for Duchenne muscular dystrophy

    PubMed Central

    Mah, Jean K

    2016-01-01

    Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing. Precise characterization of the DMD mutation is important for genetic counseling and individualized treatment. Current standard of care includes the use of corticosteroids to prolong ambulation and to delay the onset of secondary complications. Early use of cardioprotective agents, noninvasive positive pressure ventilation, and other supportive strategies has improved the life expectancy and health-related quality of life for many young adults with DMD. New emerging treatment includes viral-mediated microdystrophin gene replacement, exon skipping to restore the reading frame, and nonsense suppression therapy to allow translation and production of a modified dystrophin protein. Other potential therapeutic targets involve upregulation of compensatory proteins, reduction of the inflammatory cascade, and enhancement of muscle regeneration. So far, data from DMD clinical trials have shown limited success in delaying disease progression; unforeseen obstacles included immune response against the generated mini-dystrophin, inconsistent evidence of dystrophin production in muscle biopsies, and failure to demonstrate a significant improvement in the primary outcome measure, as defined by the 6-minute walk test in some studies. The long-term safety and efficacy of emerging treatments will depend on the selection of appropriate clinical end points and sensitive biomarkers to detect meaningful changes in disease progression. Correction of the underlying

  5. Mutation in BAG3 Causes Severe Dominant Childhood Muscular Dystrophy

    PubMed Central

    Selcen, Duygu; Muntoni, Francesco; Burton, Barbara K.; MD, Elena Pegoraro; Sewry, Caroline; Bite, Anna V.; Engel, Andrew G.

    2008-01-01

    Objective Myofibrillar myopathies (MFM) are morphologically distinct but genetically heterogeneous muscular dystrophies in which disintegration of Z disks and then of myofibrils is followed by ectopic accumulation of multiple proteins. Cardiomyopathy, neuropathy, and dominant inheritance are frequent associated features. Mutations in αB-crystallin, desmin, myotilin, Zasp, or filamin-C can cause MFM, and were detected in 32/85 patients of the Mayo MFM cohort. Bag3, another Z-disk associated protein, has antiapoptotic properties and its targeted deletion in mice causes fulminant myopathy with early lethality. We therefore searched for mutations in BAG3 in 53 unrelated MFM patients. Methods We searched for mutations in BAG3 by direct sequencing and excluded polymorphism using allele-specific PCR in relatives and 200 control subjects. We analyzed structural changes in muscle by histochemistry, immunocytochemistry and electron microscopy, examined mobility of the mutant Bag3 by nondenaturing electrophoresis, and searched for abnormal aggregation of the mutant protein in COS-7 cells. Results We identified a heterozygous p.Pro209Leu mutation in three patients. All presented in childhood, had progressive limb and axial muscle weakness, and developed cardiomyopathy and severe respiratory insufficiency in their teens; two had rigid spines and one a peripheral neuropathy. Electron microscopy showed disintegration of Z disks, extensive accumulation of granular debris and larger inclusions, and apoptosis of 8% of the nuclei. On nondenaturing electrophoresis of muscle extracts, the Bag3 complex migrated faster in patient than control extracts, and expression of FLAG-labeled mutant and wild-type Bag3 in COS cells revealed abnormal aggregation of the mutant protein. Interpretation We conclude mutation in Bag3 defines a novel severe autosomal dominant childhood muscular dystrophy. PMID:19085932

  6. Evidence for meiotic drive at the myotonic dystrophy locus

    SciTech Connect

    Shaw, A.M.; Barnetson, R.A.; Phillips, M.F.

    1994-09-01

    Myotonic dystrophy (DM), an autosomal dominant disorder, is the most common form of adult muscular dystrophy, affecting at least 1 in 8000 of the population. It is a multisystemic disorder, primarily characterized by myotonia, muscle wasting and cataract. The molecular basis of DM is an expanded CTG repeat located within the 3{prime} untranslated region of a putative serine-threonine protein kinase on chromosome 19q13.3. DM exhibits anticipation, that is, with successive generations there is increasing disease severity and earlier age of onset. This mechanism and the fact that the origin of the disease has been attributed to one or a small number of founder chromosomes suggests that, in time, DM should die out. Meiotic drive has been described as a way in which certain alleles are transmitted to succeeding generations in preference to others: preferential transmission of large CTG alleles may account for their continued existence in the gene pool. There is evidence that a CTG allele with > 19 repeats may gradually increase in repeat number over many generations until it is sufficiently large to give a DM phenotype. We report a study of 495 transmissions from individuals heterozygous for the CTG repeat and with repeat numbers within the normal range (5-30). Alleles were simply classified as large or small relative to the other allele in an individual. Of 242 male meioses, 126 transmissions from parent to child were of the larger allele to their offspring (57.7%, p=0.014). This shows that there is strong evidence for meiotic drive favoring the transmission of the larger DM allele in unaffected individuals. Contrary to a previous report of meiotic drive in the male, we have shown that females preferentially transmit the larger DM allele. Taken together, the data suggest the occurrence of meiotic drive in both males and females in this locus.

  7. An ADAM9 mutation in canine cone-rod dystrophy 3 establishes homology with human cone-rod dystrophy 9

    PubMed Central

    Goldstein, Orly; Mezey, Jason G.; Boyko, Adam R.; Gao, Chuan; Wang, Wei; Bustamante, Carlos D.; Anguish, Lynne J.; Jordan, Julie Ann; Pearce-Kelling, Susan E.; Aguirre, Gustavo D.

    2010-01-01

    Purpose To identify the causative mutation in a canine cone-rod dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog. Methods Glen of Imaal Terriers were ascertained for crd3 phenotype by clinical ophthalmoscopic examination, and in selected cases by electroretinography. Blood samples from affected cases and non-affected controls were collected and used, after DNA extraction, to undertake a genome-wide association study using Affymetrix Version 2 Canine single nucleotide polymorphism chips and 250K Sty Assay protocol. Positional candidate gene analysis was undertaken for genes identified within the peak-association signal region. Retinal morphology of selected crd3-affected dogs was evaluated by light and electron microscopy. Results A peak association signal exceeding genome-wide significance was identified on canine chromosome 16. Evaluation of genes in this region suggested A Disintegrin And Metalloprotease domain, family member 9 (ADAM9), identified concurrently elsewhere as the cause of human cone-rod dystrophy 9 (CORD9), as a strong positional candidate for canine crd3. Sequence analysis identified a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein. Light and electron microscopy established that, as in ADAM9 knockout mice, the primary lesion in crd3 appears to be a failure of the apical microvilli of the retinal pigment epithelium to appropriately invest photoreceptor outer segments. By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present. Subsequently, both rod and cone function degenerate. Conclusions Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease

  8. A review of 18p deletions.

    PubMed

    Hasi-Zogaj, Minire; Sebold, Courtney; Heard, Patricia; Carter, Erika; Soileau, Bridgette; Hill, Annice; Rupert, David; Perry, Brian; Atkinson, Sidney; O'Donnell, Louise; Gelfond, Jon; Lancaster, Jack; Fox, Peter T; Hale, Daniel E; Cody, Jannine D

    2015-09-01

    Since 18p- was first described in 1963, much progress has been made in our understanding of this classic deletion condition. We have been able to establish a fairly complete picture of the phenotype when the deletion breakpoint occurs at the centromere, and we are working to establish the phenotypic effects when each gene on 18p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families with an 18p- diagnosis. In addition, establishing the molecular underpinnings of the condition will potentially suggest targets for molecular treatments. Thus, the next step is to establish the precise effects of specific gene deletions. As we look forward to deepening our understanding of 18p-, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our 18p- cohort closely as they age to determine the presence or absence of some of these diagnoses, including spinocerebellar ataxia (SCA), facioscapulohumeral muscular dystrophy (FSHD), and dystonia. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. Mouse models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development. PMID:26250845

  9. A Pilot Study of Fourier Domain Optical Coherence Tomography of Retinal Dystrophy Patients

    PubMed Central

    Lim, Jennifer I.; Tan, Ou; Fawzi, Amani A.; Hopkins, J. Jill; Gil-Flamer, John H.; Huang, David

    2009-01-01

    Purpose To characterize the macular anatomy of retinal dystrophy eyes using high-speed, high-resolution, Fourier-domain optical coherence tomography (FD-OCT). Design Case control study. Methods Patients with retinal dystrophy and normal age and gender matched controls underwent FD-OCT imaging using the RTVue™ (Optovue, Inc.), which has an axial resolution of 5 microns. Vertical and horizontal eight mm scans of 1,024 lines/cross-section were obtained. Based on boundaries manually drawn on computer displays of OCT cross-sections, the thicknesses of the retina, inner retinal layer (IRL) and outer retinal layer (ORL) were averaged over both 5 and 1.5 millimeters regions centered at the fovea. The inner retina layer (IRL) was the sum of nerve fiber layer (NFL), ganglion cell layer (GCL) and inner plexiform layer (IPL) thicknesses. Total retinal thickness (RT) was measured between the inner edges of the NFL and the retinal pigment epithelium. Outer retinal layer (ORL) thickness was calculated by subtracting IRL thickness from RT. Results 14 patients (7 retinal dystrophy patients and seven normal controls) underwent high resolution OCT imaging. Patients ranged in age from 33 to 84 years old. Retinal dystrophy diagnoses included retinitis pigmentosa (3), cone-rod degeneration (2), and Stargardt disease (2). The following thickness values reported are mean ± standard deviation. Mean foveal RT (foveal RT) averaged over a 1.5 mm area was 271.3+/-23.3μ for normal patients and 159.2+/-48.0 μ for dystrophy (p<0.001) patients. Mean macular RT (macular RT), averaged over the central 5-mm area, was 292.8+/-8.1 μ for normal patients and 199.1+/-32.7μ for dystrophy patients (p<0.001). Mean macular IRL was 109.9 ± 6.4 for normals and 98.0 +/-20.6μ for dystrophy patients (p=0.02); mean macular ORL was 182.9+/-4.7 μ for normals and 101.1+/-18.8μ for dystrophy patients (p<0.001). Conclusion Eyes with retinal dystrophy had a small (11%) decrease in macular IRL and severe (45

  10. Identification of muscle-specific microRNAs in serum of muscular dystrophy animal models: promising novel blood-based markers for muscular dystrophy.

    PubMed

    Mizuno, Hideya; Nakamura, Akinori; Aoki, Yoshitsugu; Ito, Naoki; Kishi, Soichiro; Yamamoto, Kazuhiro; Sekiguchi, Masayuki; Takeda, Shin'ichi; Hashido, Kazuo

    2011-03-30

    Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder caused by mutations in the dystrophin gene, which encodes a cytoskeletal protein, dystrophin. Creatine kinase (CK) is generally used as a blood-based biomarker for muscular disease including DMD, but it is not always reliable since it is easily affected by stress to the body, such as exercise. Therefore, more reliable biomarkers of muscular dystrophy have long been desired. MicroRNAs (miRNAs) are small, ∼22 nucleotide, noncoding RNAs which play important roles in the regulation of gene expression at the post-transcriptional level. Recently, it has been reported that miRNAs exist in blood. In this study, we hypothesized that the expression levels of specific serum circulating miRNAs may be useful to monitor the pathological progression of muscular diseases, and therefore explored the possibility of these miRNAs as new biomarkers for muscular diseases. To confirm this hypothesis, we quantified the expression levels of miRNAs in serum of the dystrophin-deficient muscular dystrophy mouse model, mdx, and the canine X-linked muscular dystrophy in Japan dog model (CXMD(J)), by real-time PCR. We found that the serum levels of several muscle-specific miRNAs (miR-1, miR-133a and miR-206) are increased in both mdx and CXMD(J). Interestingly, unlike CK levels, expression levels of these miRNAs in mdx serum are little influenced by exercise using treadmill. These results suggest that serum miRNAs are useful and reliable biomarkers for muscular dystrophy.

  11. Peripheral nerve blocks as the sole anesthetic technique in a patient with severe Duchenne muscular dystrophy.

    PubMed

    Bang, Seung Uk; Kim, Yee Suk; Kwon, Woo Jin; Lee, Sang Mook; Kim, Soo Hyang

    2016-04-01

    General anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are associated with high risks of complications, including rhabdomyolysis, malignant hyperthermia, hemodynamic instability, and postoperative mechanical ventilation. Here, we describe peripheral nerve blocks as a safe approach to anesthesia in a patient with severe Duchenne muscular dystrophy who was scheduled to undergo surgery. A 22-year-old male patient was scheduled to undergo reduction and internal fixation of a left distal femur fracture. He had been diagnosed with Duchenne muscular dystrophy at 5 years of age, and had no locomotive capability except for that of the finger flexors and toe extensors. He had developed symptoms associated with dyspnea 5 years before and required intermittent ventilation. We blocked the femoral nerve, lateral femoral cutaneous nerve, and parasacral plexus under ultrasound on the left leg. The patient underwent a successful operation using peripheral nerve blocks with no complications. In conclusion general anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are unsafe approaches to anesthesia because of hemodynamic instability and respiratory depression. Peripheral nerve blocks are the best way to reduce the risks of critical complications, and are a safe and feasible approach to anesthesia in patients with severe Duchenne muscular dystrophy.

  12. 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.

  13. Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy.

    PubMed

    Körner, Zandra; Fontes-Oliveira, Cibely C; Holmberg, Johan; Carmignac, Virginie; Durbeej, Madeleine

    2014-05-01

    Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted.

  14. Developmental Defects in a Zebrafish Model for Muscular Dystrophies Associated with the Loss of Fukutin-Related Protein (FKRP)

    ERIC Educational Resources Information Center

    Thornhill, Paul; Bassett, David; Lochmuller, Hanns; Bushby, Kate; Straub, Volker

    2008-01-01

    A number of muscular dystrophies are associated with the defective glycosylation of [alpha]-dystroglycan and many are now known to result from mutations in a number of genes encoding putative or known glycosyltransferases. These diseases include severe forms of congenital muscular dystrophy (CMD) such as Fukuyama type congenital muscular dystrophy…

  15. [Principles of multidisciplinary management of Duchenne muscular dystrophy].

    PubMed

    Chabrol, B; Mayer, M

    2015-12-01

    Given the gradual progression observed in Duchenne muscular dystrophy, organization of care in multidisciplinary consultations is essential for optimal management of the different aspects of the disease. Drawing up a care plan is always preceded by a specific consultation for the announcement of the diagnosis with both the parents and the child. Explaining to the child the origin of his problems with simple words, telling him that why he experienced a particular symptom has been understood, is a fundamental step. The child needs to receive the information at different times of the disease following the rhythms of the disease stages, with an appropriate lead time. With the progress achieved in managing this disease, more than 90% of these children now live into adulthood. The switch from pediatric consultations to adult consultations, marking the transition from childhood management at adulthood, is a major challenge in the organization of care. Although today death occurs most often in adulthood, some children die in childhood. For the majority of teams who care for children, whatever the initial pathology may be, the notion of care continuity and accompaniment from the announcement of the disease to the terminal phase is essential. Increasing numbers of therapeutic trials have been developed over the past few years aiming to investigate children with DMD. However, they must not neglect the overall management of these patients and provide the best accompaniment possible.

  16. In vitro mapping of Myotonic Dystrophy (DM) gene promoter

    SciTech Connect

    Storbeck, C.J.; Sabourin, L.; Baird, S.

    1994-09-01

    The Myotonic Dystrophy Kinase (DMK) gene has been cloned and shared homology to serine/threonine protein kinases. Overexpression of this gene in stably transfected mouse myoblasts has been shown to inhibit fusion into myotubes while myoblasts stably transfected with an antisense construct show increased fusion potential. These experiments, along with data showing that the DM gene is highly expressed in muscle have highlighted the possibility of DMK being involved in myogenesis. The promoter region of the DM gene lacks a consensus TATA box and CAAT box, but harbours numerous transcription binding sites. Clones containing extended 5{prime} upstream sequences (UPS) of DMK only weakly drive the reporter gene chloramphenicol acetyl transferase (CAT) when transfected into C2C12 mouse myoblasts. However, four E-boxes are present in the first intron of the DM gene and transient assays show increased expression of the CAT gene when the first intron is present downstream of these 5{prime} UPS in an orientation dependent manner. Comparison between mouse and human sequence reveals that the regions in the first intron where the E-boxes are located are highly conserved. The mapping of the promoter and the importance of the first intron in the control of DMK expression will be presented.

  17. Reflex sympathetic dystrophy--a complex regional pain syndrome.

    PubMed

    Turner-Stokes, L

    2002-12-15

    Reflex sympathetic dystrophy (RSD) is a complex and poorly-understood condition characterized by: (a) pain and altered sensation; (b) motor disturbance and soft tissue change; (c) vasomotor and autonomic changes; and (d) psychosocial disturbance. Neurological symptoms typically do not conform to any particular pattern of nerve damage. Many different names have been ascribed to this condition and most recently the term 'complex regional pain syndrome' has been coined to emphasize the complex interaction of somatic, psychological and behavioural factors. Diagnostic criteria have been proposed by the International Association for the Study of Pain, but are still subject to debate. This review article describes the clinical features which may present as part of the condition, and the patho-physiology and pre-disposing factors so far identified. The evidence for effectiveness of different interventions is presented and a treatment approach outlined for inter-disciplinary management. While RSD is traditionally associated with pain in the extremities, the possibility is raised that the same process may underlie chronic pain syndromes affecting more central structures, such as testicular or pelvic pain.

  18. Severe metabolic acidosis in adult patients with Duchenne muscular dystrophy.

    PubMed

    Lo Cascio, Christian M; Latshang, Tsogyal D; Kohler, Malcolm; Fehr, Thomas; Bloch, Konrad E

    2014-01-01

    Duchenne muscular dystrophy (DMD) leads to progressive paresis, respiratory failure and premature death. Long-term positive pressure ventilation can improve quality of life and survival, but previously unrecognized complications may arise. We analyzed the characteristics of severe metabolic acidosis occurring in 8 of 55 DMD patients, of 20-36 years of age, observed over a 5-year period. All patients were on positive pressure ventilation and were being treated for chronic constipation. Before admission, they had had a reduced intake of fluids and food. Upon examination, they were severely ill, dyspneic and suffering from abdominal discomfort. Metabolic acidosis with a high anion gap was noted in 5 of the 8 patients and with a normal anion gap in the other 3. They all recovered after the administration of fluids and nutrition, the regulation of bowel movements and treatment with antibiotics, as appropriate. Metabolic acidosis is a life-threatening, potentially preventable complication in older DMD patients. Early recognition, subsequent administration of fluids, nutrition and antibiotics and regulation of bowel movements seem to be essential.

  19. [Social Cognitive Impairment in Myotonic Dystrophy Type 1].

    PubMed

    Kobayakawa, Mutsutaka

    2016-02-01

    Myotonic dystrophy type 1 (DM 1) is a heritable, multisystem disease that affects not only the muscles but also the brain. DM 1 is often accompanied by developmental behavioral disorders, such as autism spectrum disorders. The autistic traits in DM 1 may be related to social cognitive dysfunction. The social cognitive function of patients with DM 1 was examined with respect to facial emotion recognition and theory of mind, which is the specific cognitive ability to understand the mental states of other people. With respect to facial emotion recognition, the sensitivities to disgust and anger were lower among patients with DM 1 than among healthy subjects, and this difference could not be attributed to visual impairment. To examine the theory of mind ability, the "Reading the Mind in the Eyes" test and the faux pas recognition test were used. Patients with DM 1 were found to be impaired in both tests, but the results were not attributed to visual ability and lexical comprehension. The possible causes of social cognitive dysfunction in DM 1 are the l cerebral atrophy and white matter abnormalities in the temporal, frontal, and insular cortex. Dysfunctions in these areas may affect the emotional and theory of mind abilities in DM 1, which result in the behavioral and communication disorders.

  20. Tendon Extracellular Matrix Alterations in Ullrich Congenital Muscular Dystrophy

    PubMed Central

    Sardone, Francesca; Traina, Francesco; Bondi, Alice; Merlini, Luciano; Santi, Spartaco; Maraldi, Nadir Mario; Faldini, Cesare; Sabatelli, Patrizia

    2016-01-01

    Collagen VI (COLVI) is a non-fibrillar collagen expressed in skeletal muscle and most connective tissues. Mutations in COLVI genes cause two major clinical forms, Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). In addition to congenital muscle weakness, patients affected by COLVI myopathies show axial and proximal joint contractures and distal joint hypermobility, which suggest the involvement of the tendon function. We examined a peroneal tendon biopsy and tenocyte culture of a 15-year-old patient affected by UCMD with compound heterozygous COL6A2 mutations. In patient’s tendon biopsy, we found striking morphological alterations of tendon fibrils, consisting in irregular profiles and reduced mean diameter. The organization of the pericellular matrix of tenocytes, the primary site of collagen fibril assembly, was severely affected, as determined by immunoelectron microscopy, which showed an abnormal accumulation of COLVI and altered distribution of collagen I (COLI) and fibronectin (FBN). In patient’s tenocyte culture, COLVI web formation and cell surface association were severely impaired; large aggregates of COLVI, which matched with COLI labeling, were frequently detected in the extracellular matrix. In addition, metalloproteinase MMP-2, an extracellular matrix-regulating enzyme, was increased in the conditioned medium of patient’s tenocytes, as determined by gelatin zymography and western blot. Altogether, these data indicate that COLVI deficiency may influence the organization of UCMD tendon matrix, resulting in dysfunctional fibrillogenesis. The alterations of tendon matrix may contribute to the complex pathogenesis of COLVI related myopathies. PMID:27375477

  1. Catheter Ablation of Multiple Accessory Pathways in Duchenne Muscular Dystrophy

    PubMed Central

    Stöllberger, Claudia; Steger, Christine; Gatterer, Edmund

    2013-01-01

    A 23-year-old male with Duchenne muscular dystrophy (DMD) experienced self-limiting palpitations at age 19 years for the first time. Palpitations recurred not earlier than at age 23 years, and were attributed to narrow complex tachycardia, which could be terminated with adenosine. Since electrocardiography showed a delta-wave, Wolff-Parkinson-White (WPW) syndrome was diagnosed, ajmaline prescribed and radio-frequency catheter ablation of three accessory pathways carried out one week later. One day after ablation, however, a relapse of the supraventricular tachycardia occurred and was terminated with ajmaline. Re-entry tachycardia occurred a second time six days after ablation, and as before, it was stopped only with ajmaline. Despite administration of verapamil to prevent tachycardia, it occurred a third time four months after ablation. This case shows that cardiac involvement in DMD may manifest also as WPW-syndrome. In these patients, repeated radio-frequency catheter ablation of accessory pathways may be necessary to completely block the re-entry mechanism. PMID:23508228

  2. Duchenne Muscular Dystrophy Gene Therapy in the Canine Model

    PubMed Central

    2015-01-01

    Abstract Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model. PMID:25710459

  3. Muscle Activation during Gait in Children with Duchenne Muscular Dystrophy

    PubMed Central

    Vuillerot, Carole; Tiffreau, Vincent; Peudenier, Sylviane; Cuisset, Jean-Marie; Pereon, Yann; Leboeuf, Fabien; Delporte, Ludovic; Delpierre, Yannick; Gross, Raphaël

    2016-01-01

    The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD). Dynamic surface electromyography recordings (EMGs) of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF), vastus lateralis (VL), medial hamstrings (HS), tibialis anterior (TA) and gastrocnemius soleus (GAS) muscles was recorded and analysed quantitatively and qualitatively. The overall muscle activity in the children with DMD was significantly different from that of the control group. Percentage activation amplitudes of RF, HS and TA were greater throughout the gait cycle in the children with DMD and the timing of GAS activity differed from the control children. Significantly greater muscle coactivation was found in the children with DMD. There were no significant differences between sides. Since the motor command is normal in DMD, the hyper-activity and co-contractions likely compensate for gait instability and muscle weakness, however may have negative consequences on the muscles and may increase the energy cost of gait. Simple rehabilitative strategies such as targeted physical therapies may improve stability and thus the pattern of muscle activity. PMID:27622734

  4. Acceptance of the different denominations for reflex sympathetic dystrophy

    PubMed Central

    Alvarez-Lario, B; Aretxabala-Alciba..., I; Alegre-Lopez, J; Alonso-Valdiviels..., J

    2001-01-01

    OBJECTIVE—To elucidate the real impact in the medical literature of the different denominations for reflex sympathetic dystrophy (RSD).
METHODS—A search was performed through the Medline database (WinSPIRS, SilverPlatter International, NS), from 1995 to 1999, including the following descriptors: RSD, complex regional pain syndrome (CRPS), CRPS type I, algodystrophy, Sudeck, shoulder-hand syndrome, transient osteoporosis, causalgia, and CRPS type II.
RESULTS—The descriptor RSD was detected in 576 references, algodystrophy in 54, transient osteoporosis in 42, CRPS type I in 24, Sudeck in 16, and shoulder-hand syndrome in 11. One hundred records were obtained for the descriptor causalgia and five for CRPS type II. The descriptor RSD was detected in the title of 262 references, algodystrophy in 29, transient osteoporosis in 29, CRPS type I in 15, Sudeck in 3, shoulder-hand syndrome in 5, causalgia in 17, and CRPS type II in 3 references.
CONCLUSIONS—The new CRPS terminology has not effectively replaced the old one. RSD and causalgia are the most used denominations.

 PMID:11114289

  5. Diffusion tensor imaging study in Duchenne muscular dystrophy

    PubMed Central

    Fu, Ya; Dong, Yuru; Zhang, Chao; Sun, Yu; Zhang, Shu; Mu, Xuetao; Wang, Hong; Xu, Weihai

    2016-01-01

    Background Duchenne muscular dystrophy (DMD) is a progressive muscle disorder associated with an intellectual deficit which is non-progressive. The aim of this study was to investigate brain microstructural changes in DMD and to explore the relationship between such changes and cognitive impairment. Methods All participants (12 DMD patients, 14 age-matched healthy boys), intelligence quotients (IQs) [both full (FIQ) and verbal (VIQ)] were evaluated using the Wechsler intelligence scale for children China revised (WISC-CR) edition, and brain gray matter (GM) and white matter (WM) changes were mapped using diffusion tensor imaging (DTI) with fractional anisotropy (FA). The differences between groups were analyzed using the t-test and the association of cognition with neuroimaging parameters was evaluated using Pearson’s correlation coefficient. Results Compared to the normal controls, the DMD group had lower FIQ (82.0±15.39 vs. 120.21±16.06) and significantly lower splenium of corpus callosum (CC) FA values (P<0.05). Splenium of CC FA was positively correlated with VIQ (r=0.588, P=0.044). Conclusions There were microstructural changes of splenium of CC in DMD patients, which was associated with cognitive impairment. PMID:27127762

  6. The immune system in Duchenne muscular dystrophy: Friend or foe

    PubMed Central

    Villalta, S Armando; Rosenberg, Amy S; Bluestone, Jeffrey A

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a genetic disease caused by mutations in the X-linked dystrophin gene, resulting in reduced or absent protein production, subsequently leading to the structural instability of the dystroglycan complex (DGC), muscle degeneration, and early death in males. Thus, current treatments have been targeting the genetic defect either by bypassing the mutation through exon skipping or replacing the defective gene through gene therapy and stem cell approaches. However, what has been an underappreciated mediator of muscle pathology and, ultimately, of muscle degeneration and fibrotic replacement, is the prominent inflammatory response. Of potentially critical importance, however, is the fact that the elements mediating the inflammatory response also play an essential role in tissue repair. In this opinion piece, we highlight the detrimental and supportive immune parameters that occur as a consequence of the genetic disorder and discuss how changes to immunity can potentially ameliorate the disease intensity and be employed in conjunction with efforts to correct the genetic disorder. PMID:26481612

  7. miRNAs as serum biomarkers for Duchenne muscular dystrophy.

    PubMed

    Cacchiarelli, Davide; Legnini, Ivano; Martone, Julie; Cazzella, Valentina; D'Amico, Adele; Bertini, Enrico; Bozzoni, Irene

    2011-05-01

    Dystrophin absence in Duchenne muscular dystrophy (DMD) causes severe muscle degeneration. We describe that, as consequence of fibre damage, specific muscle-miRNAs are released in to the bloodstream of DMD patients and their levels correlate with the severity of the disease. The same miRNAs are abundant also in the blood of mdx mice and recover to wild-type levels in animals 'cured' through exon skipping. Even though creatine kinase (CK) blood levels have been utilized as diagnostic markers of several neuromuscular diseases, including DMD, we demonstrate that they correlate less well with the disease severity. Although the analysis of a larger number of patients should allow to obtain more refined correlations with the different stages of disease progression, we propose that miR-1, miR-133, and miR-206 are new and valuable biomarkers for the diagnosis of DMD and possibly also for monitoring the outcomes of therapeutic interventions in humans. Despite many different DMD therapeutic approaches are now entering clinical trials, a unifying method for assessing the benefit of different treatments is still lacking.

  8. Tendon Extracellular Matrix Alterations in Ullrich Congenital Muscular Dystrophy.

    PubMed

    Sardone, Francesca; Traina, Francesco; Bondi, Alice; Merlini, Luciano; Santi, Spartaco; Maraldi, Nadir Mario; Faldini, Cesare; Sabatelli, Patrizia

    2016-01-01

    Collagen VI (COLVI) is a non-fibrillar collagen expressed in skeletal muscle and most connective tissues. Mutations in COLVI genes cause two major clinical forms, Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). In addition to congenital muscle weakness, patients affected by COLVI myopathies show axial and proximal joint contractures and distal joint hypermobility, which suggest the involvement of the tendon function. We examined a peroneal tendon biopsy and tenocyte culture of a 15-year-old patient affected by UCMD with compound heterozygous COL6A2 mutations. In patient's tendon biopsy, we found striking morphological alterations of tendon fibrils, consisting in irregular profiles and reduced mean diameter. The organization of the pericellular matrix of tenocytes, the primary site of collagen fibril assembly, was severely affected, as determined by immunoelectron microscopy, which showed an abnormal accumulation of COLVI and altered distribution of collagen I (COLI) and fibronectin (FBN). In patient's tenocyte culture, COLVI web formation and cell surface association were severely impaired; large aggregates of COLVI, which matched with COLI labeling, were frequently detected in the extracellular matrix. In addition, metalloproteinase MMP-2, an extracellular matrix-regulating enzyme, was increased in the conditioned medium of patient's tenocytes, as determined by gelatin zymography and western blot. Altogether, these data indicate that COLVI deficiency may influence the organization of UCMD tendon matrix, resulting in dysfunctional fibrillogenesis. The alterations of tendon matrix may contribute to the complex pathogenesis of COLVI related myopathies. PMID:27375477

  9. Corneal haze in course of Fuchs' endothelial dystrophy.

    PubMed

    Pescosolido, N; Komaiha, C; Dapoto, L; Lenarduzzi, F; Nebbioso, M

    2012-07-01

    This article describes the observations obtained with confocal microscopy (CM) on the corneal structure in course of corneal edema in a patient with Fuchs endothelial corneal dystrophy (FD). The patient was a 40 year old male, suffering from second stage FD, in course of corneal edema and bullous keratopathy. The tissue structure was analyzed with CM confoscan CS4 (Nidek Technologies(®), Birmingham, UK) using the 40x mode. The CM has shown the presence of gaps due to corneal edema and a diffuse stromal hyper reflectivity related to the alteration of the extracellular matrix. It has also showed the presence of binucleate cells, assimilable to keratocytes, in cytokinesis which presented a typical fusiform aspect with two highly reflective nuclei awaiting cell division. The total number of cells was much lower than that of healthy control subjects of similar age, sex and race. The CM in this case suggests a significantly lower number of cells, presumably keratocytes, compared to normal range, but mostly it shows the presence of cells undergoing cytokinesis, which witnesses the active processes of collagenogenesis and possible vasculogenesis that represent early stages of loss of the normal corneal transparency. PMID:23007820

  10. Dropped-head in recessive oculopharyngeal muscular dystrophy.

    PubMed

    Garibaldi, Matteo; Pennisi, Elena Maria; Bruttini, Mirella; Bizzarri, Veronica; Bucci, Elisabetta; Morino, Stefania; Talerico, Caterina; Stoppacciaro, Antonella; Renieri, Alessandra; Antonini, Giovanni

    2015-11-01

    A 69-year-old woman presented a dropped head, caused by severe neck extensor weakness that had started two years before. She had also developed a mild degree of dysphagia, rhinolalia, eyelid ptosis and proximal limb weakness during the last months. EMG revealed myopathic changes. Muscle MRI detected fatty infiltration in the posterior neck muscles and tongue. Muscle biopsy revealed fiber size variations, sporadic rimmed vacuoles, small scattered angulated fibers and a patchy myofibrillar network. Genetic analysis revealed homozygous (GCN)11 expansions in the PABPN1 gene that were consistent with recessive oculopharyngeal muscular dystrophy (OPMD). There are a few reports of the recessive form, which has a later disease onset with milder symptoms and higher clinical variability than the typical dominantly inherited form. This patient, who is the first Italian and the eighth worldwide reported case of recessive OPMD, is also the first case of OPMD with dropped-head syndrome, which thus expands the clinical phenotype of recessive OPMD. PMID:26494409

  11. Myotonic Dystrophy-1 Complicated by Factor-V (Leiden) Mutation

    PubMed Central

    Finsterer, Josef; Stöllberger, Claudia

    2015-01-01

    Objectives. Presence of a factor-V Leiden mutation in a patient with myotonic dystrophy type 1 (DM1) has been reported only once. Here we report the second DM1 patient carrying a factor-V mutation who died from long-term complications of this mutation. Case Report. A 66-year-old DM1 patient with multi-organ-disorder syndrome developed a first deep venous thrombosis (DVT) and consecutive pulmonary embolism (PE) at age 50 y. Acetyl-salicylic acid was given. One year later he experienced a second DVT; that is why phenprocoumon was started. Despite anticoagulation, he experienced a third DVT bilaterally and a second PE bilaterally at 61 y; that is why a vena cava filter was additionally deployed. Despite therapeutic anticoagulation, he experienced a vena cava filter thrombosis at age 62 y. Genetic workup revealed a heterozygous factor-V mutation in addition to a CTG-repeat expansion of 500. As a consequence of PE he developed chronic obstructive pulmonary disease and experienced recurrent pulmonary infections, which were lastly responsible for decease at age 66 y despite intensive care measures. Conclusion. The heterozygous Leiden mutation may severely affect DM1 patients to such a degree that they die from its complications. If DM1 patients present with unusual manifestations, search for causes other than a CTG-repeat expansion is indicated. PMID:25918532

  12. Muscle Activation during Gait in Children with Duchenne Muscular Dystrophy.

    PubMed

    Ropars, Juliette; Lempereur, Mathieu; Vuillerot, Carole; Tiffreau, Vincent; Peudenier, Sylviane; Cuisset, Jean-Marie; Pereon, Yann; Leboeuf, Fabien; Delporte, Ludovic; Delpierre, Yannick; Gross, Raphaël; Brochard, Sylvain

    2016-01-01

    The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD). Dynamic surface electromyography recordings (EMGs) of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF), vastus lateralis (VL), medial hamstrings (HS), tibialis anterior (TA) and gastrocnemius soleus (GAS) muscles was recorded and analysed quantitatively and qualitatively. The overall muscle activity in the children with DMD was significantly different from that of the control group. Percentage activation amplitudes of RF, HS and TA were greater throughout the gait cycle in the children with DMD and the timing of GAS activity differed from the control children. Significantly greater muscle coactivation was found in the children with DMD. There were no significant differences between sides. Since the motor command is normal in DMD, the hyper-activity and co-contractions likely compensate for gait instability and muscle weakness, however may have negative consequences on the muscles and may increase the energy cost of gait. Simple rehabilitative strategies such as targeted physical therapies may improve stability and thus the pattern of muscle activity. PMID:27622734

  13. Synaptic protein dysregulation in myotonic dystrophy type 1

    PubMed Central

    Hernández-Hernández, Oscar; Sicot, Géraldine; Dinca, Diana M.; Huguet, Aline; Nicole, Annie; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève; Gomes-Pereira, Mário

    2013-01-01

    The toxicity of expanded transcripts in myotonic dystrophy type 1 (DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program. PMID:25003003

  14. Anesthetic and surgical complications in 219 cases of myotonic dystrophy.

    PubMed

    Mathieu, J; Allard, P; Gobeil, G; Girard, M; De Braekeleer, M; Bégin, P

    1997-12-01

    The objective of this study was to assess the frequency, type, and severity of perioperative complications after a first surgery under general anesthesia in patients with myotonic dystrophy (DM) and to measure the association with suspected risk factors. Numerous cases of perioperative complications in DM patients have been reported. Hazards have been associated with the use of thiopentone, suxamethonium, neostigmine, and halothane. A retrospective study of perioperative complications was conducted for 219 DM patients who had their first surgery under general anesthesia at the Chicoutimi Hospital. The overall frequency of complications was 8.2% (18 of 219). Most complications (16 of 18) were pulmonary, including five patients with acute ventilatory failure necessitating ventilatory support, four patients with atelectasis, and three patients with pneumonia. Using multivariate analysis, we found that the risk of perioperative pulmonary complications (PPC) was significantly higher after an upper abdominal surgery (odds ratio (OR), 24.4; 95% CI, 4.0 to 149.3) and for patients with a severe muscular disability, as assessed by the presence of proximal limb weakness (OR, 14.1; 95% CI, 1.5 to 134.4). The likelihood of PPC was not related to any specific anesthetic drug. Because of the increased risk of PPC, careful monitoring during the early postoperative period, protection of upper airways, chest physiotherapy, and incentive spirometry are mandatory in all symptomatic DM patients, particularly those with a severe muscular disability or those who have undergone an upper abdominal surgery.

  15. Muscle phenotypic variability in limb girdle muscular dystrophy 2 G.

    PubMed

    Paim, Julia F; Cotta, Ana; Vargas, Antonio P; Navarro, Monica M; Valicek, Jaquelin; Carvalho, Elmano; da-Cunha, Antonio L; Plentz, Estevão; Braz, Shelida V; Takata, Reinaldo I; Almeida, Camila F; Vainzof, Mariz

    2013-06-01

    Limb girdle muscular dystrophy type 2 G (LGMD2G) is caused by mutations in the telethonin gene. Only few families were described presenting this disease, and they are mainly Brazilians. Here, we identified one additional case carrying the same common c.157C > T mutation in the telethonin gene but with an atypical histopathological muscle pattern. In a female patient with a long duration of symptoms (46 years), muscle biopsy showed, in addition to telethonin deficiency, the presence of nemaline rods, type 1 fiber predominance, nuclear internalization, lobulated fibers, and mitochondrial paracrystalline inclusions. Her first clinical signs were identified at 8 years old, which include tiptoe walking, left lower limb deformity, and frequent falls. Ambulation loss occurred at 41 years old, and now, at 54 years old, she presented pelvic girdle atrophy, winging scapula, foot deformity with incapacity to perform ankle dorsiflexion, and absent tendon reflexes. The presence of nemaline bodies could be a secondary phenomenon, possibly associated with focal Z-line abnormalities of a long-standing disease. However, these new histopathological findings, characteristic of congenital myopathies, expand muscle phenotypic variability of telethoninopathy. PMID:23479141

  16. Actin-organising properties of the muscular dystrophy protein myotilin.

    PubMed

    von Nandelstadh, Pernilla; Grönholm, Mikaela; Moza, Monica; Lamberg, Arja; Savilahti, Harri; Carpén, Olli

    2005-10-15

    Myotilin is a sarcomeric Z-disc protein that binds F-actin directly and bundles actin filaments, although it does not contain a conventional actin-binding domain. Expression of mutant myotilin leads to sarcomeric alterations in the dominantly inherited limb-girdle muscular dystrophy 1A and in myofibrillar myopathy/desmin-related myopathy. Together, with previous in vitro studies, this indicates that myotilin has an important function in the assembly and maintenance of Z-discs. This study characterises further the interaction between myotilin and actin. Functionally important regions in myotilin were identified by actin pull-down and yeast two-hybrid assays and with a novel strategy that combines in vitro DNA transposition-based peptide insertion mutagenesis with phenotype analysis in yeast cells. The shortest fragment to bind actin was the second Ig domain together with a short C-terminal sequence. Concerted action of the first and second Ig domain was, however, necessary for the functional activity of myotilin, as verified by analysis of transposon mutants, actin binding and phenotypic effect in mammalian cells. Furthermore, the Ig domains flanked with N- and C-terminal regions were needed for actin-bundling, indicating that the mere actin-binding sequence was insufficient for the actin-regulating activity. None of the four known disease-associated mutations altered the actin-organising ability. These results, together with previous studies in titin and kettin, identify the Ig domain as an actin-binding unit.

  17. Retinal dystrophies, genomic applications in diagnosis and prospects for therapy.

    PubMed

    Nash, Benjamin M; Wright, Dale C; Grigg, John R; Bennetts, Bruce; Jamieson, Robyn V

    2015-04-01

    Retinal dystrophies (RDs) are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. This review aims to demonstrate the high degree of genetic complexity in both the causative disease genes and their associated phenotypes, highlighting the more common clinical manifestation of retinitis pigmentosa (RP). The review also provides insight to recent advances in genomic molecular diagnosis and gene and cell-based therapies for the RDs. PMID:26835369

  18. Compound loss of muscleblind-like function in myotonic dystrophy

    PubMed Central

    Lee, Kuang-Yung; Li, Moyi; Manchanda, Mini; Batra, Ranjan; Charizanis, Konstantinos; Mohan, Apoorva; Warren, Sonisha A; Chamberlain, Christopher M; Finn, Dustin; Hong, Hannah; Ashraf, Hassan; Kasahara, Hideko; Ranum, Laura P W; Swanson, Maurice S

    2013-01-01

    Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1−/−; Mbnl2−/− double knockouts (DKOs) are embryonic lethal, Mbnl1−/−; Mbnl2+/− mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1−/− knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease. PMID:24293317

  19. Motor unit remodelling in Duchenne muscular dystrophy. Electrophysiological assessment.

    PubMed

    Cruz Martínez, A; López-Terradas, J M

    1992-01-01

    Conventional EMG, motor and sensory conduction velocities, averaging analysis of MUPs, SFEMG, and muscle fiber conduction velocity in situ were performed in 14 boys with Duchenne muscular dystrophy (DD) aged 5 to 11 years. MUPs parameters study showed a striking increment of long duration MUPs followed by satellites and increase of polyphasic potentials of variable duration. The main findings in SFEMG examination were increment in fiber density of the motor unit, large MISI and presence of complex potentials of long duration in all patients. Muscle fiber conduction velocity in situ was significantly slower than in controls, with significant decrease in minimum conduction and increased variability (large SD) in propagation velocity values. Low conduction velocity of muscle fibers, long duration of polyphasics and MUPs followed by satellites, and large MISI were significantly related. These findings support the hypotheses which have suggested that the motor unit remodelling in DD is mainly myogenic. The abnormalities in muscle fiber conduction velocity in situ reflect an increased diameter variation of muscle fibers consistent with splitting fibers, small groups of regenerating and necrotic fibers, and fiber diameter variation found in histological studies. Thus, increased variability in fiber diameter may be the cause of complex and long duration MUPs in DD.

  20. Milder forms of muscular dystrophy associated with POMGNT2 mutations

    PubMed Central

    Endo, Yukari; Dong, Mingrui; Ogawa, Megumu; Hayashi, Yukiko K.; Kuru, Satoshi; Sugiyama, Kenji; Nagai, Shigehiro; Ozasa, Shiro; Nonaka, Ikuya; Nishino, Ichizo

    2015-01-01

    Objective: To determine the genetic variants in patients with dystroglycanopathy (DGP) and assess the pathogenicity of these variants. Methods: A total of 20 patients with DGP were identified by immunohistochemistry or Western blot analysis. Whole-exome sequencing (WES) was performed using patient samples. The pathogenicity of the variants identified was evaluated on the basis of the phenotypic recovery in a knockout (KO) haploid human cell line by transfection with mutated POMGNT2 cDNA and on the basis of the in vitro enzymatic activity of mutated proteins. Results: WES identified homozygous and compound heterozygous missense variants in POMGNT2 in 3 patients with the milder limb-girdle muscular dystrophy (LGMD) and intellectual disability without brain malformation. The 2 identified variants were located in the putative glycosyltransferase domain of POMGNT2, which affected its enzymatic activity. Mutated POMGNT2 cDNAs failed to rescue the phenotype of POMGNT2-KO cells. Conclusions: Novel variants in POMGNT2 are associated with milder forms of LGMD. The findings of this study expand the clinical and pathologic spectrum of DGP associated with POMGNT2 variants from the severest Walker-Warburg syndrome to the mildest LGMD phenotypes. The simple method to verify pathogenesis of variants may allow researchers to evaluate any variants present in all of the known causative genes and the variants in novel candidate genes to detect DGPs, particularly without using patients' specimens. PMID:27066570

  1. Retinal dystrophies, genomic applications in diagnosis and prospects for therapy

    PubMed Central

    Nash, Benjamin M.; Wright, Dale C.; Grigg, John R.; Bennetts, Bruce

    2015-01-01

    Retinal dystrophies (RDs) are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. This review aims to demonstrate the high degree of genetic complexity in both the causative disease genes and their associated phenotypes, highlighting the more common clinical manifestation of retinitis pigmentosa (RP). The review also provides insight to recent advances in genomic molecular diagnosis and gene and cell-based therapies for the RDs. PMID:26835369

  2. Functional muscle ischemia in Duchenne and Becker muscular dystrophy

    PubMed Central

    Thomas, Gail D.

    2013-01-01

    Duchenne and Becker muscular dystrophy (DMD/BMD) comprise a spectrum of devastating X-linked muscle wasting disease for which there is no treatment. DMD/BMD is caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that stabilizes the muscle membrane and also targets other proteins to the sarcolemma. Among these is the muscle-specific isoform of neuronal nitric oxide synthase (nNOSμ) which binds spectrin-like repeats within dystrophin's rod domain and the adaptor protein α-syntrophin. Dystrophin deficiency causes loss of sarcolemmal nNOSμ and reduces paracrine signaling of muscle-derived nitric oxide (NO) to the microvasculature, which renders the diseased muscle fibers susceptible to functional muscle ischemia during exercise. Repeated bouts of functional ischemia superimposed on muscle fibers already weakened by dystrophin deficiency result in use-dependent focal muscle injury. Genetic and pharmacologic strategies to boost nNOSμ-NO signaling in dystrophic muscle alleviate functional muscle ischemia and show promise as novel therapeutic interventions for the treatment of DMD/BMD. PMID:24391598

  3. Cerebro-oculo-muscular syndrome: a variant of Fukuyama congenital cerebromuscular dystrophy.

    PubMed

    Dambska, M; Wisniewski, K; Sher, J; Solish, G

    1982-01-01

    Familial occurrence of cerebral malformations with muscular dystrophy was described by Fukuyama as congenital cerebromuscular dystrophy. We have observed a new syndrome belonging to the same group in three siblings. These syndromes differ in the degree of CNS involvement and abnormalities in the eye. The main clinical characteristics of our cohort were dysmorphic face, hypotonia, areflexia, failure to thrive, corneal opacity, cataract, dysgenesis of the anterior chamber of the eye, and death within the 1st year of life. Hydrocephalus and agyria were verified by computed tomography. Neuropathologic examination demonstrated malformations of the CNS. The agyric hemispheres with polymicrogyria in several cortical segments and severe cortical disorganization in other segments represented the principal anomaly. Congenital muscular dystrophy was also found. The CNS anomalies demonstrated a long-lasting pathologic process extending to involve the eye and muscle, which is most likely an inborn error of metabolism with autosomal recessive inheritance.

  4. Modeling Myotonic Dystrophy 1 in C2C12 Myoblast Cells.

    PubMed

    Liang, Rui; Dong, Wei; Shen, Xiaopeng; Peng, Xiaoping; Aceves, Angie G; Liu, Yu

    2016-01-01

    Myotonic dystrophy 1 (DM1) is a common form of muscular dystrophy. Although several animal models have been established for DM1, myoblast cell models are still important because they offer an efficient cellular alternative for studying cellular and molecular events. Though C2C12 myoblast cells have been widely used to study myogenesis, resistance to gene transfection, or viral transduction, hinders research in C2C12 cells. Here, we describe an optimized protocol that includes daily maintenance, transfection and transduction procedures to introduce genes into C2C12 myoblasts and the induction of myocyte differentiation. Collectively, these procedures enable best transfection/transduction efficiencies, as well as consistent differentiation outcomes. The protocol described in establishing DM1 myoblast cell models would benefit the study of myotonic dystrophy, as well as other muscular diseases. PMID:27501221

  5. The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy.

    PubMed

    Marshall, Jamie L; Kwok, Yukwah; McMorran, Brian J; Baum, Linda G; Crosbie-Watson, Rachelle H

    2013-09-01

    Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and α7β1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein-replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important potential therapeutic target. Here, we review current protein-replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. PMID:23601082

  6. Utility of Cystatin C for Estimating Glomerular Filtration Rate in Patients With Muscular Dystrophy.

    PubMed

    Kimura, Koichi; Morita, Hiroyuki; Daimon, Masao; Horio, Masaru; Kawata, Takayuki; Nakao, Tomoko; Hirokawa, Megumi; Kitao, Ruriko; Watanabe, Daisuke; Komori, Tetsuo; Nagata, Tetsuya; Takeda, Shin'ichi; Komaki, Hirofumi; Segawa, Kazuhiko; Nakajima, Takashi; Takenaka, Katsu; Komuro, Issei

    2016-05-25

    Emerging concerns regarding heart failure, arrhythmia, and sudden death in patients with muscular dystrophy are of significant clinical importance. On the other hand, little attention has been paid to renal dysfunction because these patients have low serum creatinine levels. Serum cystatin C, unaffected by muscle quantity, is a potentially superior marker for estimating renal function. Here, we present cases with muscular dystrophy in which estimated glomerular filtration rate (GFR) by cystatin C (eGFRcys) provided good agreement with simultaneously measured GFR by inulin renal clearance (differences less than 20%). Sudden death with acute heart failure occurred in a patient with underlying renal dysfunction and elevated BNP. Neurologists and cardiologists should evaluate renal function using GFR with cystatin C in patients with muscular dystrophy.

  7. Enhanced autophagy as a potential mechanism for the improved physiological function by simvastatin in muscular dystrophy

    PubMed Central

    Whitehead, Nicholas P.

    2016-01-01

    ABSTRACT 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. PMID:26890413

  8. Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish.

    PubMed

    Plantié, Emilie; Migocka-Patrzałek, Marta; Daczewska, Małgorzata; Jagla, Krzysztof

    2015-01-01

    Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. Structurally, physiologically and biochemically, MDs affect different types of muscles and cause individual symptoms such that genetic and molecular pathways underlying their pathogenesis thus remain poorly understood. To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs. PMID:25859781

  9. Myotonia and flaccid dysarthria in patients with adult onset myotonic dystrophy

    PubMed Central

    de Swart, B J M; van Engelen, B G M; van de Kerkhof, J P B M; Maassen, B

    2004-01-01

    Objective: To specify and quantify possible defects in speech execution in patients with adult onset myotonic dystrophy. Methods: Studies on speech production were done on 30 mildly affected patients with myotonic dystrophy. Special attention was paid to myotonia. Because muscle activity can result in a decrease of myotonia, speech characteristics were measured before and after warm up. The possibility that warming up causes increased weakness was also assessed. Results: As with other motor skills, a warm up effect was found in speech production, resulting in an increase in repetition rate and a decrease in variability of repetition rate. Signs of fatigue did not occur. Conclusions: Warming up is valuable for patients with myotonic dystrophy in reducing the influence of myotonia on speech production. PMID:15377703

  10. Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy.

    PubMed

    Yamamoto, Guilherme L; Baratela, Wagner A R; Almeida, Tatiana F; Lazar, Monize; Afonso, Clara L; Oyamada, Maria K; Suzuki, Lisa; Oliveira, Luiz A N; Ramos, Ester S; Kim, Chong A; Passos-Bueno, Maria Rita; Bertola, Débora R

    2014-01-01

    Spondylometaphyseal dysplasia with cone-rod dystrophy is a rare autosomal-recessive disorder characterized by severe short stature, progressive lower-limb bowing, flattened vertebral bodies, metaphyseal involvement, and visual impairment caused by cone-rod dystrophy. Whole-exome sequencing of four individuals affected by this disorder from two Brazilian families identified two previously unreported homozygous mutations in PCYT1A. This gene encodes the alpha isoform of the phosphate cytidylyltransferase 1 choline enzyme, which is responsible for converting phosphocholine into cytidine diphosphate-choline, a key intermediate step in the phosphatidylcholine biosynthesis pathway. A different enzymatic defect in this pathway has been previously associated with a muscular dystrophy with mitochondrial structural abnormalities that does not have cartilage and/or bone or retinal involvement. Thus, the deregulation of the phosphatidylcholine pathway may play a role in multiple genetic diseases in humans, and further studies are necessary to uncover its precise pathogenic mechanisms and the entirety of its phenotypic spectrum.

  11. Erythrocytes in muscular dystrophy. Investigation with /sup 31/P nuclear magnetic resonance spectroscopy

    SciTech Connect

    Sarpel, G.; Lubansky, H.J.; Danon, M.J.; Omachi, A.

    1981-05-01

    Phosphorus 31 nuclear magnetic resonance (/sup 31/P NMR) signals were recorded from intact human erythrocytes for 16 hours. Total phosphate concentration, which was estimated as the sum of the individual /sup 31/P signals, was 25% lower in erythrocytes from men with myotonic dystrophy than in control erythrocytes. The inorganic-phosphate fraction contained the highest average phosphate concentration over the 16-hour period, and made the major contribution to the difference in total phosphate between the two groups. This result was not observed in erythrocytes from either women with myotonic dystrophy or patients with Duchenne's dystrophy and may be due to a change in cell membrane permeability to inorganic phosphate, which leads to lower steady-state concentrations of the intracellular phosphates.

  12. Erythrocytes in muscular dystrophy. Investigation with 31P nuclear magnetic resonance spectroscopy

    SciTech Connect

    Sarpel, G.; Lubansky, H.J.; Danon, M.J.; Omachi, A.

    1981-05-01

    Phosphorus 31 nuclear magnetic resonance (31P NMR) signals were recorded from intact human erythrocytes for 16 hours. Total phosphate concentration, which was estimated as the sum of the individual 31P signals, was 25% lower in erythrocytes from men with myotonic dystrophy than in control erythrocytes. The inorganic-phosphate fraction contained the highest average phosphate concentration over the 16-hour period, and made the major contribution to the difference in total phosphate between the two groups. This result was not observed in erythrocytes from either women with myotonic dystrophy or patients with Duchenne's dystrophy and may be due to a change in cell membrane permeability to inorganic phosphate, which lead to lower steady-state concentrations of the intracellular phosphates.

  13. Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish.

    PubMed

    Plantié, Emilie; Migocka-Patrzałek, Marta; Daczewska, Małgorzata; Jagla, Krzysztof

    2015-04-09

    Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. Structurally, physiologically and biochemically, MDs affect different types of muscles and cause individual symptoms such that genetic and molecular pathways underlying their pathogenesis thus remain poorly understood. To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs.

  14. Temporalis muscle hypertrophy and reduced skull eccentricity in Duchenne muscular dystrophy.

    PubMed

    Straathof, C S M; Doorenweerd, N; Wokke, B H A; Dumas, E M; van den Bergen, J C; van Buchem, M A; Hendriksen, J G M; Verschuuren, J J G M; Kan, H E

    2014-10-01

    Muscle hypertrophy and muscle weakness are well known in Duchenne muscular dystrophy. Decreased muscle force can have secondary effects on skeletal growth and development such as facial and dental morphology changes. In this study, we quantified temporal muscle thickness, circumference, and eccentricity of the skull and the head on T1-weighted magnetic resonance imaging (MRI) scans of the head of 15 Duchenne muscular dystrophy patients and 15 controls. Average temporal muscle thickness was significantly increased in patients (12.9 ± 5.2 mm) compared to controls (6.8 ± 1.4 mm) (P < .0001), whereas the shape of the skull was significantly rounder compared to controls. Temporal muscle thickness and skull eccentricity were significantly negatively correlated in patients, and positively in controls. Hypertrophy of the temporal muscles and changes in skull eccentricity appear to occur early in the course of Duchenne muscular dystrophy. Further studies in younger patients are needed to confirm a causal relationship.

  15. Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies.

    PubMed

    Lee, Kristy; Garg, Seema

    2015-04-01

    Inherited eye disorders are a significant cause of vision loss. Genetic testing can be particularly helpful for patients with inherited retinal dystrophies because of genetic heterogeneity and overlapping phenotypes. The need to identify a molecular diagnosis for retinal dystrophies is particularly important in the era of developing novel gene therapy-based treatments, such as the RPE65 gene-based clinical trials and others on the horizon, as well as recent advances in reproductive options. The introduction of massively parallel sequencing technologies has significantly advanced the identification of novel gene candidates and has expanded the landscape of genetic testing. In a relatively short time clinical medicine has progressed from limited testing options to a plethora of choices ranging from single-gene testing to whole-exome sequencing. This article outlines currently available genetic testing and factors to consider when selecting appropriate testing for patients with inherited retinal dystrophies.

  16. A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy.

    PubMed

    Hicks, Debbie; Sarkozy, A; Muelas, N; Koehler, K; Huebner, A; Hudson, G; Chinnery, P F; Barresi, R; Eagle, M; Polvikoski, T; Bailey, G; Miller, J; Radunovic, A; Hughes, P J; Roberts, R; Krause, S; Walter, M C; Laval, S H; Straub, V; Lochmüller, H; Bushby, K

    2011-01-01

    The limb-girdle muscular dystrophies are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, limb-girdle muscular dystrophy 2L and non-dysferlin Miyoshi muscular dystrophy. We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic single nucleotide polymorphism and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised serum creatine kinase values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20 s to 50 s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100,000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high serum creatine kinase and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult limb-girdle muscular

  17. Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ

    PubMed Central

    Gardner, Brandon B.; Gao, Quan Q.; Hadhazy, Michele; Vo, Andy H.; Wren, Lisa; Molkentin, Jeffery D.; McNally, Elizabeth M.

    2016-01-01

    Latent TGFβ binding proteins (LTBPs) regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFβ family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFβ and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFβ family ligand binding protein with the capacity to modify muscle disease through overexpression. PMID:27148972

  18. Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ.

    PubMed

    Lamar, Kay-Marie; Bogdanovich, Sasha; Gardner, Brandon B; Gao, Quan Q; Miller, Tamari; Earley, Judy U; Hadhazy, Michele; Vo, Andy H; Wren, Lisa; Molkentin, Jeffery D; McNally, Elizabeth M

    2016-05-01

    Latent TGFβ binding proteins (LTBPs) regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFβ family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFβ and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFβ family ligand binding protein with the capacity to modify muscle disease through overexpression.

  19. The Role of D4Z4-Encoded Proteins in the Osteogenic Differentiation of Mesenchymal Stromal Cells Isolated from Bone Marrow.

    PubMed

    de la Kethulle de Ryhove, Laurence; Ansseau, Eugénie; Nachtegael, Charlotte; Pieters, Karlien; Vanderplanck, Céline; Geens, Mieke; Sermon, Karen; Wilton, Steve D; Coppée, Frédérique; Lagneaux, Laurence; Belayew, Alexandra

    2015-11-15

    Facioscapulohumeral muscular dystrophy (FSHD) is associated with an activation of the double homeobox 4 (DUX4) gene, which we previously identified within the D4Z4 repeated elements in the 4q35 subtelomeric region. The pathological DUX4 mRNA is derived from the most distal D4Z4 unit and extends unexpectedly within the flanking pLAM region, which provides an intron and polyadenylation signal. The conditions that are required to develop FSHD are a permissive allele providing the polyadenylation signal and hypomethylation of the D4Z4 repeat array compared with the healthy muscle. The DUX4 protein is a 52-kDa transcription factor that initiates a large gene deregulation cascade leading to muscle atrophy, inflammation, differentiation defects, and oxidative stress, which are the key features of FSHD. DUX4 is a retrogene that is normally expressed in germline cells and is submitted to repeat-induced silencing in adult tissues. Since DUX4 mRNAs have been detected in human embryonic and induced pluripotent stem cells, we investigated whether they could also be expressed in human mesenchymal stromal cells (hMSCs). We found that DUX4 mRNAs were induced during the differentiation of hMSCs into osteoblasts and that this process involved DUX4 and new longer protein forms (58 and 70 kDa). A DUX4 mRNA with a more distant 5' start site was characterized that presented a 60-codon reading frame extension and encoded the 58-kDa protein. Transfections of hMSCs with an antisense oligonucleotide targeting DUX4 mRNAs decreased both the 52- and 58-kDa protein levels and confirmed their identity. Gain- and loss-of-function experiments in hMSCs suggested these DUX4 proteins had opposite roles in osteogenic differentiation as evidenced by the alkaline phosphatase activity and calcium deposition. Differentiation was delayed by the 58-kDa DUX4 expression and it was increased by 52-kDa DUX4. These data indicate a role for DUX4 protein forms in the osteogenic differentiation of h

  20. The natural history of congenital myotonic dystrophy: mortality and long term clinical aspects.

    PubMed Central

    Reardon, W; Newcombe, R; Fenton, I; Sibert, J; Harper, P S

    1993-01-01

    Although the genetic basis of the congenital form of myotonic dystrophy has recently been clarified, data as to outcome in terms of life expectancy and morbidity are scanty. Life table data based on a cohort of 115 patients with a confirmed diagnosis of congenital myotonic dystrophy are presented. The data suggest a 25% chance of death before 18 months of age and a 50% chance of survival into the mid-30s. The profile of disease and complications among survivors is also charted. PMID:8481038

  1. [Blood myoglobin in children with progressive muscular dystrophy and in carriers].

    PubMed

    Calandi, C; Baretti, S; Pacciani, G; Bagni, P; Borsotti, M; Tozzi, P; Adami Lami, C

    1984-12-01

    We studied the behaviour of serum myoglobin in 32 children affected by Duchenne muscular dystrophy, in 30 mothers (10 definite carriers and 20 possible carriers), in 5 sisters (possible carriers) and in 40 healthy women (control). The serum myoglobin was always increased in the patients affected by Duchenne muscular dystrophy; the greatest values were in the patients who were still ambulant, with a behaviour similar to creatine kinase. In the carriers the myoglobinemia showed a significant increase in definite carriers, while there was no significant difference between the possible carriers and the controls. PMID:6537549

  2. Cytokines and Chemokines as Regulators of Skeletal Muscle Inflammation: Presenting the Case of Duchenne Muscular Dystrophy

    PubMed Central

    De Bleecker, Jan L.

    2013-01-01

    Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary effects on muscle fiber damage control and tissue regeneration. In this review, current knowledge of cytokine and chemokine expression in Duchenne muscular dystrophy and its relevant animal disease models is listed, and implications for future therapeutic avenues are discussed. PMID:24302815

  3. Characteristics of corneal dystrophies: a review from clinical, histological and genetic perspectives

    PubMed Central

    Lin, Ze-Nan; Chen, Jie; Cui, Hong-Ping

    2016-01-01

    Corneal dystrophy is a common type of hereditary corneal diseases. It includes many types, which have varied pathology, histology and clinical manifestations. Recently, the examination techniques of ophthalmology and gene sequencing advance greatly, which do benefit to our understanding of these diseases. However, many aspects remain still unknown. And due to the poor knowledge of these diseases, the results of the treatments are not satisfoctory. The purpose of this review was to summarize the clinical, histological and genetic characteristics of different types of corneal dystrophies. PMID:27366696

  4. Median Canaliform Dystrophy of Heller occurring on thumb and great toe nails.

    PubMed

    Pathania, Vikas

    2016-04-01

    Median Canaliform Dystrophy of Heller is a rare but morphologically striking habit tic deformity of thumb nails characterized by midline longitudinal furrow with multiple transverse parallel lines. The proposed etiopathogenesis is repetitive trauma to the nail plate and cuticle, however some case reports have suggested familial occurrence and use of oral retinoids in its causation. Treatment is often prolonged and unsatisfactory, though some topical agents have been used successfully. We report a case of a young male patient presenting with Median Dystrophy of Heller affecting both Great thumb and toe nails simultaneously. PMID:27257330

  5. Two Cases of Endometrial Cancer in Twin Sisters with Myotonic Dystrophy

    PubMed Central

    2016-01-01

    We describe two cases of endometrial cancer (EC) occurring in nulligravid twin sisters with myotonic dystrophy. Both tested negative for Lynch syndrome and both were treated with laparoscopic hysterectomy with bilateral salpingooophorectomy and adjuvant radiotherapy. Although EC tends to run in families, the diagnosis in itself is not considered sufficient cause for screening or prophylactic measures in close relatives. However, the presence of additional risk factors, such as nulligravidity and myotonic dystrophy in the underlying cases, may call for extra vigilance in first-degree family members. PMID:27595026

  6. Technetium 99m-methylene diphosphonate bone scans in children with reflex neurovascular dystrophy

    SciTech Connect

    Laxer, R.M.; Allen, R.C.; Malleson, P.N.; Morrison, R.T.; Petty, R.E.

    1985-03-01

    Eleven children with reflex neurovascular dystrophy were investigated by technetium-labeled methylene diphosphonate bone scanning. Eight of 12 scans demonstrated abnormal findings, four showing diffusely decreased uptake and four diffusely increased uptake of the radionuclide in the affected site. Three scans showed normal findings initially, as did one previously abnormal scan when repeated in the asymptomatic patient 6 months later. Diffusely abnormal findings can be helpful in the diagnosis of childhood reflex neurovascular dystrophy, but a normal scan does not exclude the diagnosis.

  7. Emery-Dreifuss muscular dystrophy in the evaluation of decreased spinal mobility and joint contractures.

    PubMed

    Goncu, Kamil; Guzel, Rengin; Guler-Uysal, Fusun

    2003-12-01

    In this report we present three patients who had complaints primarily related to joints and flexibility. Two had no specific diagnosis and one was thought to have ankylosing spondylitis. Extensive evaluation revealed Emery-Dreifuss muscular dystrophy (EDMD) in all. EDMD is a muscular dystrophy where joint contractures and spinal limitation occur before any overt muscle weakness, and the syndrome may be combined with serious cardiac pathology. We wish to call the attention of professionals involved in rheumatology and physical medicine to the existence of this syndrome, which may only present with joint contractures and spinal limitation but which may end with fatal cardiac problems if not diagnosed in time.

  8. Splicing-correcting therapeutic approaches for retinal dystrophies: where endogenous gene regulation and specificity matter.

    PubMed

    Bacchi, Niccolò; Casarosa, Simona; Denti, Michela A

    2014-05-27

    Splicing is an important and highly regulated step in gene expression. The ability to modulate it can offer a therapeutic option for many genetic disorders. Antisense-mediated splicing-correction approaches have recently been successfully exploited for some genetic diseases, and are currently demonstrating safety and efficacy in different clinical trials. Their application for the treatment of retinal dystrophies could potentially solve a vast panel of cases, as illustrated by the abundance of mutations that could be targeted and the versatility of the technique. In this review, we will give an insight of the different therapeutic strategies, focusing on the current status of their application for retinal dystrophies.

  9. Evidence for linkage disequilibrium in chromosome 13-linked Duchenne-like muscular dystrophy

    SciTech Connect

    Othmane, K.B.; Speer, M.C.; Stauffer, J.

    1995-09-01

    Duchenne-like muscular dystrophy (DLMD) is an autosomal recessive Limb Girdle muscular dystrophy (LGMD2C) characterized by late age of onset, proximal muscle weakness leading to disability, high creatine kinase values, normal intelligence and normal dystrophin in muscle biopsy. We have shown previously that three DLMD families from Tunisia are linked to chromosome 13q12. To further localize the LGMD2C gene, we have investigated seven additional families (119 individuals). Both genotyping and two-point linkage analysis were performed as described elsewhere. 7 refs., 1 fig., 1 tab.

  10. Bilateral Atypical Granular Corneal Dystrophy Associated with Unilateral Keratoconus in a Male Child

    PubMed Central

    Dangra, Kavita Lohiya; Das, Manoranjan; Periasamy, Sundersan; Prajna, N. Venkatesh

    2016-01-01

    A 14-year-old male presented with decreased vision. Slit lamp examination indicated multiple anterior corneal stromal opacities with clear intervening spaces accompanied with superficial subepithelial lines arranged in a quasi-whorl-like fashion bilateral with greater prominence in the right eye. Corneal steepening associated with thinning was noted only in the right eye. Genetic analysis confirmed a mutation suggestive of granular corneal dystrophy. Here, we describe a rare case of an atypical granular dystrophy associated with unilateral keratoconus in a male child. PMID:27555713

  11. Bilateral Atypical Granular Corneal Dystrophy Associated with Unilateral Keratoconus in a Male Child.

    PubMed

    Dangra, Kavita Lohiya; Das, Manoranjan; Periasamy, Sundersan; Prajna, N Venkatesh

    2016-01-01

    A 14-year-old male presented with decreased vision. Slit lamp examination indicated multiple anterior corneal stromal opacities with clear intervening spaces accompanied with superficial subepithelial lines arranged in a quasi-whorl-like fashion bilateral with greater prominence in the right eye. Corneal steepening associated with thinning was noted only in the right eye. Genetic analysis confirmed a mutation suggestive of granular corneal dystrophy. Here, we describe a rare case of an atypical granular dystrophy associated with unilateral keratoconus in a male child. PMID:27555713

  12. Treatment of upper extremity reflex sympathetic dystrophy with joint stiffness using sympatholytic Bier blocks and manipulation.

    PubMed

    Duncan, K H; Lewis, R C; Racz, G; Nordyke, M D

    1988-06-01

    Twenty patients with reflex sympathetic dystrophy involving the upper extremity with associated joint stiffness were treated by manipulation under Bier blocks composed of lidocaine, methylprednisolone, and reserpine or guanethidine. Depending on the patients' response, repeat blocks were performed at 48- to 72-hour intervals. Range of motion in the affected joints (primarily the hand and wrist) improved from a pre-block mean of 46% to 81% of normal following the blocks. Patients also reported an 80% mean improvement in their pain. The treatment of advanced reflex sympathetic dystrophy using joint manipulation under sympatholytic Bier blocks appears to be a safe and effective method of treatment.

  13. Characterization of pulmonary function in Duchenne Muscular Dystrophy

    PubMed Central

    Finkel, R.S.; Rummey, C.; Benton, M.J.; Glanzman, A.M.; Flickinger, J.; Lindström, B.‐M.; Meier, T.

    2015-01-01

    Summary Decline in pulmonary function in Duchenne Muscular Dystrophy (DMD) contributes to significant morbidity and reduced longevity. Spirometry is a widely used and fairly easily performed technique to assess lung function, and in particular lung volume; however, the acceptability criteria from the American Thoracic Society (ATS) may be overly restrictive and inappropriate for patients with neuromuscular disease. We examined prospective spirometry data (Forced Vital Capacity [FVC] and peak expiratory flow [PEF]) from 60 DMD patients enrolled in a natural history cohort study (median age 10.3 years, range 5–24 years). Expiratory flow‐volume curves were examined by a pulmonologist and the data were evaluated for acceptability using ATS criteria modified based on the capabilities of patients with neuromuscular disease. Data were then analyzed for change with age, ambulation status, and glucocorticoid use. At least one acceptable study was obtained in 44 subjects (73%), and 81 of the 131 studies (62%) were acceptable. The FVC and PEF showed similar relative changes in absolute values with increasing age, i.e., an increase through 10 years, relative stabilization from 10–18 years, and then a decrease at an older age. The percent predicted, FVC and PEF showed a near linear decline of approximately 5% points/year from ages 5 to 24. Surprisingly, no difference was observed in FVC or PEF by ambulation or steroid treatment. Acceptable spirometry can be performed on DMD patients over a broad range of ages. Using modified ATS criteria, curated spirometry data, excluding technically unacceptable data, may provide a more reliable means of determining change in lung function over time. Pediatr Pulmonol. 2015; 50:487–494. © 2015 Wiley Periodicals, Inc. PMID:25755201

  14. Growth and psychomotor development of patients with Duchenne muscular dystrophy.

    PubMed

    Sarrazin, Elisabeth; von der Hagen, Maja; Schara, Ulrike; von Au, Katja; Kaindl, Angela M

    2014-01-01

    Duchenne muscular dystrophy (DMD) is one of the most common hereditary degenerative neuromuscular diseases and caused by mutations in the dystrophin gene. The objective of the retrospective study was to describe growth and psychomotor development of patients with DMD and to detect a possible genotype-phenotype correlation. Data from 263 patients with DMD (mean age 7.1 years) treated at the Departments of Pediatric Neurology in three German University Hospitals was assessed with respect to body measurements (length, weight, body mass index BMI, head circumference OFC), motor and cognitive development as well as genotype (site of mutation). Anthropometric measures and developmental data were compared to those of a reference population and deviations were analyzed for their frequency in the cohort as well as in relation to the genotypes. Corticosteroid therapy was implemented in 29 from 263 patients. Overall 30% of the patients exhibit a short statue (length < 3rd centile) with onset early in development at 2-5 years of age, and this is even more prevalent when steroid therapy is applied (45% of patients with steroid therapy). The BMI shows a rightwards shift (68% > 50th centile) and the OFC a leftwards shift (65% < 50th centile, 5% microcephaly). Gross motor development is delayed in a third of the patients (mean age at walking 18.3 months, 30% > 18 months, 8% > 24 months). Almost half of the patients show cognitive impairment (26% learning disability, 17% intellectual disability). Although there is no strict genotype-phenotype correlation, particularly mutations in the distal part of the dystrophin gene are frequently associated with short stature and a high rate of microcephaly as well as cognitive impairment.

  15. Gastrointestinal Dysfunction in Patients with Duchenne Muscular Dystrophy

    PubMed Central

    Latshang, Tsogyal D.; Bluemel, Sena; Frauenfelder, Thomas; Bloch, Konrad E.

    2016-01-01

    Background In adult patients with Duchenne muscular dystrophy (DMD) life-threatening constipation has been reported. Since gastrointestinal function in DMD has not been rigorously studied we investigated objective and subjective manifestations of gastrointestinal disturbances in DMD patients. Methods In 33 patients with DMD, age 12–41 years, eating behavior and gastrointestinal symptoms were evaluated by questionnaires. Gastric emptying half time (T1/2) and oro-cecal transit time (OCTT) were evaluated by analyzing 13CO2 exhalation curves after ingestion of 13C labeled test meals. Colonic transit time (CTT) was measured by abdominal radiography following ingestion of radiopaque markers. Results The median (quartiles) T1/2 was 187 (168, 220) minutes, the OCTT was 6.3 (5.0, 7.9) hours, both substantially longer than normal data (Goetze 2005, T1/2: 107±10; Geypens 1999, OCTT 4.3±0.1 hours). The median CTT was 60 (48, 82) hours despite extensive use of laxative measures (Meier 1995, upper limit of normal: 60 hours). T1/2 and OCTT did not correlate with symptoms evaluated by the Gastroparesis Cardinal Symptom Index (GCSI) (Spearman r = -0.3, p = 0.1; and r = -0.15, p = 0.4, respectively). CTT was not correlated with symptoms of constipation assessed by ROME III criteria (r = 0.12, p = 0.5). Conclusions DMD patients have a markedly disturbed gastrointestinal motor function. Since objective measures of impaired gastrointestinal transport are not correlated with symptoms of gastroparesis or constipation our findings suggest that measures assuring adequate intestinal transport should be taken independent of the patient’s perception in order to prevent potentially life threatening constipation, particularly in older DMD patients. PMID:27736891

  16. TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs

    PubMed Central

    Jagannathan, Vidhya; Wohlsein, Peter; Baumgärtner, Wolfgang; Seehusen, Frauke; Spitzbarth, Ingo; Grandon, Rodrigo; Drögemüller, Cord; Jäderlund, Karin Hultin

    2015-01-01

    Clinical, pathological and genetic examination revealed an as yet uncharacterized juvenile-onset neuroaxonal dystrophy (NAD) in Spanish water dogs. Affected dogs presented with various neurological deficits including gait abnormalities and behavioral deficits. Histopathology demonstrated spheroid formation accentuated in the grey matter of the cerebral hemispheres, the cerebellum, the brain stem and in the sensory pathways of the spinal cord. Iron accumulation was absent. Ultrastructurally spheroids contained predominantly closely packed vesicles with a double-layered membrane, which were characterized as autophagosomes using immunohistochemistry. The family history of the four affected dogs suggested an autosomal recessive inheritance. SNP genotyping showed a single genomic region of extended homozygosity of 4.5 Mb in the four cases on CFA 8. Linkage analysis revealed a maximal parametric LOD score of 2.5 at this region. By whole genome re-sequencing of one affected dog, a perfectly associated, single, non-synonymous coding variant in the canine tectonin beta-propeller repeat-containing protein 2 (TECPR2) gene affecting a highly conserved region was detected (c.4009C>T or p.R1337W). This canine NAD form displays etiologic parallels to an inherited TECPR2 associated type of human hereditary spastic paraparesis (HSP). In contrast to the canine NAD, the spinal cord lesions in most types of human HSP involve the sensory and the motor pathways. Furthermore, the canine NAD form reveals similarities to cases of human NAD defined by widespread spheroid formation without iron accumulation in the basal ganglia. Thus TECPR2 should also be considered as candidate gene for human NAD. Immunohistochemistry and the ultrastructural findings further support the assumption, that TECPR2 regulates autophagosome accumulation in the autophagic pathways. Consequently, this report provides the first genetic characterization of juvenile canine NAD, describes the histopathological features

  17. Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease.

    PubMed

    Brais, B

    2003-01-01

    Oculopharyngeal muscular dystrophy (OPMD) is a muscle disease of late onset associated with progressive ptosis of the eyelids, dysphagia, and unique tubulofilamentous intranuclear inclusions (INIs). OPMD is usually transmitted as an autosomal dominant trait (OMIM 164300). A rarer allelic autosomal recessive form has also been observed (OMIM 257950). Both forms are caused by short (GCG)8-13 expansions in the polyadenylate-binding protein nuclear 1 gene (PABPN1) located on chromosome 14q11.1. The mutations cause the lengthening of an N-terminal polyalanine domain. Both slippage and unequal recombination have been proposed as the mutation mechanisms. The size of the mutation has not yet been conclusively shown to inversely correlate with the severity of the phenotype. Mutated PABPN1 proteins have been shown to be constituents of the INIs. The INIs also contain ubiquitin, proteasome subunits, HSP 40, HSP 70, SKIP, and abundant poly(A)-mRNA. The exact mechanism responsible for polyalanine toxicity in OPMD is unknown. Various intranuclear inclusion dependent and independent mechanisms have been proposed based on the major known function of PABPN1 in polyadenylation of mRNA and its shuttling from the nucleus to the cytoplasm. OPMD is one of the few triplet-repeat diseases for which the function of the mutated gene is known. Because of the increasing number of diseases caused by polyalanine expansions and the pathological overlap with CAG/polyglutamine diseases, what pathological insight is gained by the study of OPMD could lead to a better understanding of a much larger group of developmental and degenerative diseases.

  18. Muscle wasting in myotonic dystrophies: a model of premature aging

    PubMed Central

    Mateos-Aierdi, Alba Judith; Goicoechea, Maria; Aiastui, Ana; Fernández-Torrón, Roberto; Garcia-Puga, Mikel; Matheu, Ander; López de Munain, Adolfo

    2015-01-01

    Myotonic dystrophy type 1 (DM1 or Steinert’s disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3′ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the

  19. Spectral Domain Optical Coherence Tomographic Findings of Bietti Crystalline Dystrophy

    PubMed Central

    Öner, Ferit Hakan

    2014-01-01

    We analyzed the OCT features of 24 eyes of 12 patients with Bietti crystalline dystrophy (BCD) with the Heidelberg HRA2-OCT. Seventeen of 24 eyes were in intermediate stage of the disease and seven in advanced stage of the disease at the time of latest OCT examination performed in 2014. Outer retinal tubulations and retinal hyperreflective dots were present in 20 of 24 eyes. The remaining four eyes had advanced disease with very thin retina. Appearance of bright plaque on top of RPE-Bruch membrane was present in all eyes. Choroidal hyperreflective spots were noted in 19 of 24 eyes. The remaining five eyes had advanced disease stage with very thin choroid. Mean central macular thickness was 163.08 μm ± 62.52 for all eyes (170.35 μm ± 56.46 in eyes with intermediate disease and 145.42 μm ± 77.2 in eyes with advanced disease). Mean subfoveal choroidal thickness was 95.37 μm ± 55.93 for the study eyes (116.47 ± 46.92 μm in eyes with intermediate disease and 44.14 μm ± 42.43 in eyes with advanced disease). Choroidal hyperreflective spots were noted in 21 of 24 eyes (87.5%). SD-OCT shows the disease progression in retinal and choroidal layers delicately in eyes with BCD and expands our knowledge about the ongoing disease process. PMID:25505979

  20. Patterns of late gadolinium enhancement in Duchenne muscular dystrophy carriers

    PubMed Central

    2014-01-01

    Background This study was designed to assess whether cardiovascular magnetic resonance imaging (CMR) in Duchenne muscular dystrophy carriers (DMDc) may index any cell milieu elements of LV dysfunction and whether this cardiac phenotype may be related to genotype. The null hypothesis was that myocardial fibrosis, assessed by late gadolinium enhancement (LGE), might be similarly accounted for in DMDc and gender and age-matched controls. Methods Thirty DMDc patients had CMR and genotyping with 37 gender and age-matched controls. Systolic and diastolic LV function was assessed by 2D-echocardiography. Results Absolute and percent LGE were higher in muscular symptomatic (sym) than asymptomatic (asy) DMDc (1.77 ± 0.27 vs 0.76 ± 0.17 ml; F = 19.6, p < 0.0001 and 1.86 ± 0.26% vs 0.68 ± 0.17%, F = 22.1, p < 0.0001, respectively). There was no correlation between LGE and age. LGE was seen most frequently in segments 5 and 6; segment 5 was involved in all asy-DMDc. Subepicardial LGE predominated, compared to the mid-myocardial one (11 out of 14 DMDc). LGE was absent in the subendocardium. No correlations were seen between genotyping (type of mutation, gene region and protein domain), confined to the exon’s study, and cardiac phenotype. Conclusions A typical myocardial LGE-pattern location (LV segments 5 and 6) was a common finding in DMDc. LGE was more frequently subepicardial plus midmyocardial in sym-DMDc, with normal LV systolic and diastolic function. No genotype-phenothype correlation was found. PMID:25008475

  1. Extremely varied phenotypes in granular corneal dystrophy type 2 heterozygotes

    PubMed Central

    Han, Kyung Eun; Choi, Seung-il; Chung, Woo Suk; Jung, Se Hwan; Katsanis, Nicholas; Kim, Tae-im

    2012-01-01

    Purpose To investigate the phenotypic variability of patients bearing the heterozygous R124H mutation in the TGFBI (transforming growth factor-beta-induced) gene that causes granular corneal dystrophy type 2 (GCD2). Methods We describe the phenotypic range of GCD2 heterozygotes for the common R124H mutation in TGFBI; seven with an extremely mild phenotype and six with an extremely severe phenotype. Detailed slit-lamp photographs of these patients were generated. All patients had no history of ocular surgery and were diagnosed as being heterozygous for GCD2 by DNA analysis from peripheral blood. Expression levels of transforming growth factor-beta-induced protein (TGFBIp) were compared among cultured corneal fibroblasts from ten normal donors. Results We report profound differences in the severity of the phenotype across our case series. Two patients with a mild phenotype were diagnosed as unaffected at presentation; however follow-up examinations revealed granular deposits. Importantly, we also observed familial clustering of phenotypic variance; five patients from two families with a mild phenotype showed a similarly mild phenotype within family members. Similarly, six patients from two families with severe phenotypes showed corneal deposits with similar patterns and severity within each distinct family, but distinct patterns between families. TGFBIp expressions from different donor derived cultured corneal fibroblasts were different between one another. Conclusions GCD2 heterozygotes have extremely varied phenotypes between individual patients. However phenotypes were broadly consistent within families, suggesting that the observed variable expressivity might be regulated by other genetic factors that could influence the abundance of TGFBIp or the function of the pathway. From a clinical perspective, our data also highlighted that genetic analysis and meticulous slit-lamp examination in both eyes at multiple time intervals is necessary. PMID:22815629

  2. Dysphagia in Duchenne muscular dystrophy assessed objectively by surface electromyography.

    PubMed

    Archer, Sally K; Garrod, Rachel; Hart, Nicholas; Miller, Simon

    2013-06-01

    Objective swallowing assessment is indicated in the management of patients with Duchenne muscular dystrophy (DMD). Surface electromyography (sEMG) provides a non-invasive, objective method of quantifying muscle activity. It was hypothesised that the measurement of sEMG activity during swallowing would distinguish between preserved and disordered swallow function in DMD. This comparative study investigated the peak, duration, and relative timing of muscle activity during swallowing of four muscle groups: orbicularis oris, masseter, submental, and infrahyoid. The study included three groups of participants: Nine DMD patients with dysphagia (mean age = 21.7 ± 4.2 years), six DMD patients with preserved swallow function (21.0 ± 3.0 years), and 12 healthy controls (24.8 ± 3.1 years). Dysphagic DMD participants produced significantly higher normalised peak amplitude measurements than the healthy control group for masseter (61.77 vs. 5.07; p ≤ 0.01) and orbicularis oris muscles (71.87 vs. 26.22; p ≤ 0.05). Intrasubject variability for masseter peak amplitude was significantly greater for dysphagic DMD participants than the other groups (16.01 vs. 5.86 vs. 2.18; p ≤ 0.05). There were no differences in timing measurements between groups. Different characteristic sEMG waveforms were observed for the three groups. sEMG provides useful physiological information for the evaluation of swallowing in DMD patients, justifying further study.

  3. Sarcopenia and Sarcopenic Obesity in Patients with Muscular Dystrophy

    PubMed Central

    Merlini, Luciano; Vagheggini, Alessandro; Cocchi, Daniela

    2014-01-01

    Aging sarcopenia and muscular dystrophy (MD) are two conditions characterized by lower skeletal muscle quantity, lower muscle strength, and lower physical performance. Aging is associated with a peculiar alteration in body composition called “sarcopenic obesity” characterized by a decrease in lean body mass and increase in fat mass. To evaluate the presence of sarcopenia and obesity in a cohort of adult patients with MD, we have used the measurement techniques considered golden standard for sarcopenia that is for muscle mass dual-energy X-ray absorptiometry (DXA), for muscle strength hand-held dynamometry (HHD), and for physical performance gait speed. The study involved 14 adult patients with different types of MD. We were able to demonstrate that all patients were sarcopenic obese. We showed, in fact, that all were sarcopenic based on appendicular lean, fat and bone free, mass index (ALMI). In addition, all resulted obese according to the percentage of body fat determined by DXA in contrast to their body mass index ranging from underweight to obese. Skeletal muscle mass determined by DXA was markedly reduced in all patients and correlated with residual muscle strength determined by HHD, and physical performances determined by gait speed and respiratory function. Finally, we showed that ALMI was the best linear explicator of muscle strength and physical function. Altogether, our study suggests the relevance of a proper evaluation of body composition in MD and we propose to use, both in research and practice, the measurement techniques that has already been demonstrated effective in aging sarcopenia. PMID:25339901

  4. Red-Green Color Vision Impairment in Duchenne Muscular Dystrophy

    PubMed Central

    Costa, Marcelo Fernandes ; Oliveira, Andre Gustavo Fernandes ; Feitosa-Santana, Claudia ; Zatz, Mayana ; Ventura, Dora Fix 

    2007-01-01

    The present study evaluated the color vision of 44 patients with Duchenne muscular dystrophy (DMD) (mean age 14.8 years; SD 4.9) who were submitted to a battery of four different color tests: Cambridge Colour Test (CCT), Neitz Anomaloscope, Ishihara, and American Optical Hardy-Rand-Rittler (AO H-R-R). Patients were divided into two groups according to the region of deletion in the dystrophin gene: upstream of exon 30 (n=12) and downstream of exon 30 (n=32). The control group was composed of 70 age-matched healthy male subjects with no ophthalmological complaints. Of the patients with DMD, 47% (21/44) had a red-green color vision defect in the CCT, confirmed by the Neitz Anomaloscope with statistical agreement (P<.001). The Ishihara and the AO H-R-R had a lower capacity to detect color defects—5% and 7%, respectively, with no statistical similarity between the results of these two tests nor between CCT and Anomaloscope results (P>.05). Of the patients with deletion downstream of exon 30, 66% had a red-green color defect. No color defect was found in the patients with deletion upstream of exon 30. A negative correlation between the color thresholds and age was found for the controls and patients with DMD, suggesting a nonprogressive color defect. The percentage (66%) of patients with a red-green defect was significantly higher than the expected <10% for the normal male population (P<.001). In contrast, patients with DMD with deletion upstream of exon 30 had normal color vision. This color defect might be partially explained by a retina impairment related to dystrophin isoform Dp260. PMID:17503325

  5. 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.

  6. Computer task performance by subjects with Duchenne muscular dystrophy

    PubMed Central

    Malheiros, Silvia Regina Pinheiro; da Silva, Talita Dias; Favero, Francis Meire; de Abreu, Luiz Carlos; Fregni, Felipe; Ribeiro, Denise Cardoso; de Mello Monteiro, Carlos Bandeira

    2016-01-01

    Aims Two specific objectives were established to quantify computer task performance among people with Duchenne muscular dystrophy (DMD). First, we compared simple computational task performance between subjects with DMD and age-matched typically developing (TD) subjects. Second, we examined correlations between the ability of subjects with DMD to learn the computational task and their motor functionality, age, and initial task performance. Method The study included 84 individuals (42 with DMD, mean age of 18±5.5 years, and 42 age-matched controls). They executed a computer maze task; all participants performed the acquisition (20 attempts) and retention (five attempts) phases, repeating the same maze. A different maze was used to verify transfer performance (five attempts). The Motor Function Measure Scale was applied, and the results were compared with maze task performance. Results In the acquisition phase, a significant decrease was found in movement time (MT) between the first and last acquisition block, but only for the DMD group. For the DMD group, MT during transfer was shorter than during the first acquisition block, indicating improvement from the first acquisition block to transfer. In addition, the TD group showed shorter MT than the DMD group across the study. Conclusion DMD participants improved their performance after practicing a computational task; however, the difference in MT was present in all attempts among DMD and control subjects. Computational task improvement was positively influenced by the initial performance of individuals with DMD. In turn, the initial performance was influenced by their distal functionality but not their age or overall functionality. PMID:26766911

  7. Corneal Hydration Control in Fuchs' Endothelial Corneal Dystrophy

    PubMed Central

    Wacker, Katrin; McLaren, Jay W.; Kane, Katrina M.; Baratz, Keith H.; Patel, Sanjay V.

    2016-01-01

    Purpose To assess corneal hydration control across a range of severity of Fuchs' endothelial corneal dystrophy (FECD) by measuring the percent recovery per hour (PRPH) of central corneal thickness after swelling the cornea and to determine its association with corneal morphologic parameters. Methods Twenty-three corneas of 23 phakic FECD patients and 8 corneas of 8 healthy control participants devoid of guttae were graded (modified Krachmer scale). Effective endothelial cell density (ECDe) was determined from the area of guttae and local cell density in confocal microscopy images. Steady-state corneal thickness (CTss) and standardized central corneal backscatter were derived from Scheimpflug images. Corneal swelling was induced by wearing a low-oxygen transmissible contact lens for 2 hours in the morning. De-swelling was measured over 5 hours after lens removal or until corneal thickness returned to CTss. Percent recovery per hour was 100 × (1 – e−k), where k was determined from CT(t) = (de−kt) + CTss, and where d was the initial change from CTss. Results After contact lens wear, corneas swelled by 9% (95% CI 9–10). Percent recovery per hour was 49%/h (95% CI 41–57) in controls and 37%/h in advanced FECD (95% CI 29–43, P = 0.028). Low PRPH was associated with disease severity, low ECDe, and increased anterior and posterior corneal backscatter. Anterior backscatter was associated with PRPH in a multivariable model (R2 = 0.44). Conclusions Corneal hydration control is impaired in advanced FECD and is inversely related to anterior corneal backscatter. Anterior corneal backscatter might serve as an indicator of impaired endothelium in FECD. PMID:27661858

  8. Oculopharyngeal muscular dystrophy as a paradigm for muscle aging.

    PubMed

    Raz, Yotam; Raz, Vered

    2014-01-01

    Symptoms in late-onset neuromuscular disorders initiate only from midlife onward and progress with age. These disorders are primarily determined by identified hereditable mutations, but their late-onset symptom manifestation is not fully understood. Here, we review recent research developments on the late-onset autosomal dominant oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by an expansion mutation in the gene encoding for poly-adenylate RNA binding protein1 (PABPN1). The molecular pathogenesis for the disease is still poorly understood. Despite a ubiquitous expression of PABPN1, symptoms in OPMD are limited to skeletal muscles. We discuss recent studies showing that PABPN1 levels in skeletal muscles are lower compared with other tissues, and specifically in skeletal muscles, PABPN1 expression declines from midlife onward. In OPMD, aggregation of expanded PABPN1 causes an additional decline in the level of the functional protein, which is associated with severe muscle weakness in OPMD. Reduced PABNPN1 expression in muscle cell culture causes myogenic defects, suggesting that PABPN1 loss-of-function causes muscle weakness in OPMD and in the elderly. Molecular signatures of OPMD muscles are similar to those of normal muscle aging, although expression trends progress faster in OPMD. We discuss a working hypothesis that aging-associated factors trigger late-onset symptoms in OPMD, and contribute to accelerated muscle weakness in OPMD. We focus on the pharyngeal and eyelid muscles, which are often affected in OPMD patients. We suggest that muscle weakness in OPMD is a paradigm for muscle aging.

  9. Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy.

    PubMed

    Saito, K; Osawa, M; Wang, Z P; Ikeya, K; Fukuyama, Y; Kondo-Iida, E; Toda, T; Ohashi, H; Kurosawa, K; Wakai, S; Kaneko, K

    2000-05-29

    In typical Fukuyama congenital muscular dystrophy (FCMD), peak motor function is usually only unassisted sitting or sliding on the buttocks, though a few patients are able to walk at some point. However, a few patients have a severe phenotype and never acquire head control. In addition, it is clinically difficult to differentiate this severe FCMD from Walker-Warburg syndrome (WWS) or from muscle-eye-brain disease (MEBD). In order to establish a genotype-phenotype correlation, we performed haplotype analysis using microsatellite markers closest to the FCMD gene (FCMD) in 56 Japanese FCMD families, including 35 families whose children were diagnosed as FCMD with the typical phenotype, 12 families with a mild phenotype, and 9 families with a severe phenotype. Of the 12 propositi with the mild phenotype, 8 could walk and the other 4 could stand with support; 10 cases were homozygous for the ancestral founder (A-F) haplotype whereas the other 2 were heterozygous for the haplotype. In the 9 severe cases, who had never acquired head control or the ability to sit without support, 3 had progressive hydrocephalus, 2 required a shunt operation, and 7 had ophthalmological abnormalities. Haplotype analysis showed that 8 of the 9 cases of the severe phenotype are heterozygous for the A-F haplotype, and the other one homozygous for the haplotype. We confirmed that at least one chromosome in each of the 56 FCMD patients has the A-F haplotype. The rate of heterozygosity for the A-F haplotypes was significantly higher in severe cases than in typical or mild cases (P < 0.005). Severe FCMD patients appeared to be compound heterozygotes for the founder mutation and another mutation. Thus, the present study yielded molecular genetic evidence of a broad clinical spectrum in FCMD.

  10. Phototherapeutic keratectomy for recurrent granular dystrophy in postpenetrating keratoplasty eyes

    PubMed Central

    Rathi, Varsha M; Taneja, Mukesh; Murthy, Somasheila I; Bagga, Bhupesh; Vaddavalli, Pravin Krishna; Sangwan, Virender S

    2016-01-01

    Purpose: The purpose is to assess the clinical and visual outcome after phototherapeutic keratectomy (PTK) procedure in eyes with prior penetrating keratoplasty (PKP) for granular corneal dystrophy (GCD) and the time of performance of repeat PTK for recurrence. Methods: PTK was performed for visually significant recurrence: A reduction in best-corrected visual acuity (BCVA) by >2 lines over BCVA before recurrence was considered as visually significant recurrence. Three eyes had amniotic membrane patch performed with PTK. The main outcome measures were a recurrence of GCD, clinical course, and visual outcome. Intervals between repeat PTK procedures were noted. Results: Six patients (n = 10 eyes; males: 4, mean age 39 ± 13.97 years) underwent PTK. The mean pachymetry before first PTK was 527.1 ± 34 microns. The mean duration between PKP and first PTK was 85.1 months (range: 37–108 months). Two and three PTK procedures were done for seven and five eyes, respectively. Mean duration between first and second and second and third PTK was 62.12 ± 34.41 and 42.8 ± 13.54 months respectively. The average cut depth was 43.66 ± 19.57, 75 ± 43.30 and 39 ± 19.79 microns after the first, second and third PTK procedures, respectively. All eyes had a corneal haze. Prefirst PTK mean BCVA was 20/200 and improved significantly after the first two PTK procedures to 20/40 and after the third PTK procedure to 20/32 (P < 0.001). Five eyes had hyperopia. One acute graft rejection was managed successfully at 5 months with medical therapy. Conclusion: Multiple PTK procedures can be performed safely with improved visual acuity in grafts without compromising graft survival. PMID:27050350

  11. Muscle-Derived Proteins as Serum Biomarkers for Monitoring Disease Progression in Three Forms of Muscular Dystrophy

    PubMed Central

    Goldstein, Richard; Bennett, Donald; Guglieri, Michela; Straub, Volker; Bushby, Kate; Lochmüller, Hanns; Morris, Carl

    2016-01-01

    Background Identifying translatable, non-invasive biomarkers of muscular dystrophy that better reflect the disease pathology than those currently available would aid the development of new therapies, the monitoring of disease progression and the response to therapy. Objective The goal of this study was to evaluate a panel of serum protein biomarkers with the potential to specifically detect skeletal muscle injury. Method Serum concentrations of skeletal troponin I (sTnI), myosin light chain 3 (Myl3), fatty acid binding protein 3 (FABP3) and muscle-type creatine kinase (CKM) proteins were measured in 74 Duchenne muscular dystrophy (DMD), 38 Becker muscular dystrophy (BMD) and 49 Limb-girdle muscular dystrophy type 2B (LGMD2B) patients and 32 healthy controls. Results All four proteins were significantly elevated in the serum of these three muscular dystrophy patient populations when compared to healthy controls, but, interestingly, displayed different profiles depending on the type of muscular dystrophy. Additionally, the effects of patient age, ambulatory status, cardiac function and treatment status on the serum concentrations of the proteins were investigated. Statistical analysis revealed correlations between the serum concentrations and certain clinical endpoints including forced vital capacity in DMD patients and the time to walk ten meters in LGMD2B patients. Serum concentrations of these proteins were also elevated in two preclinical models of muscular dystrophy, the mdx mouse and the golden-retriever muscular dystrophy dog. Conclusions These proteins, therefore, are potential muscular dystrophy biomarkers for monitoring disease progression and therapeutic response in both preclinical and clinical studies. PMID:26870665

  12. Uncovering the profile of mutations of transforming growth factor beta-induced gene in Chinese corneal dystrophy patients

    PubMed Central

    Hao, Xiao-Dan; Zhang, Yang-Yang; Chen, Peng; Li, Su-Xia; Wang, Ye

    2016-01-01

    AIM To uncover the mutations profile of transforming growth factor beta-induced (TGFBI) gene in Chinese corneal dystrophy patients and further investigate the characteristics of genotype-phenotype correlations. METHODS Forty-two subjects (6 unrelated families including 15 patients and 8 unaffected members, and 19 sporadic patients) of Chinese origin were subjected to phenotypic and genotypic characterization. The corneal phenotypes of patients were documented by slit lamp photography. Mutation screening of the coding regions of TGFBI was performed by direct sequencing. RESULTS We detected four corneal dystrophy types. The most frequent phenotypes were granular corneal dystrophy (GCD) (including 3 families and 8 sporadic patients) and lattice corneal dystrophy (LCD) (including 2 families and 9 sporadic patients). The next phenotypes were corneal dystrophy of Bowman layer (CDB) (1 family and 1 sporadic patient) and epithelial basement membrane dystrophy (EBMD) (1 sporadic patient). Six distinct mutations responsible for TGFBI corneal dystrophies were identified in 30 individuals with corneal dystrophies. Those were, p.R124H mutation in 1 family and 2 sporadic patients with GCD, p.R555W mutation in 2 families and 3 sporadic patients with GCD, p.R124C mutation in 2 families and 7 sporadic patients with LCD, p.A620D mutation in 1 sporadic patient with LCD, p.H626R mutation in 1 sporadic patient with LCD, and p.R555Q in 1 family and 1 sporadic patient with CDB. No mutation was detected in the remaining 3 atypical GCD patients and 1 EBMD patient. CONCLUSION GCD and LCD are the most frequent phenotypes in Chinese population. R555W was the most common mutation for GCD; R124C was the most common mutation for LCD. Our findings extend the mutational spectrum of TFGBI, and this is the extensively delineated TGFBI mutation profile associated with the various corneal dystrophies in the Chinese population. PMID:26949635

  13. Pathogenesis of axonal dystrophy and demyelination in αA-crystallin-expressing transgenic mice

    PubMed Central

    Van Rijk, AF; Sweers, MAM; Merkx, GFM; Lammens, M; Bloemendal, H

    2003-01-01

    We recently described a transgenic mouse strain overexpressing hamster αA-crystallin, a small heat shock protein, under direction of the hamster vimentin promoter. As a result myelin was degraded and axonal dystrophy in both central nervous system (especially spinal cord) and peripheral nervous system occurred. Homozygous transgenic mice developed hind limb paralysis after 8 weeks of age and displayed progressive loss of myelin and axonal dystrophy in both the central and peripheral nervous system with ongoing age. Pathologically the phenotype resembled, to a certain extent, neuroaxonal dystrophy. The biochemical findings presented in this paper (activity of the enzymes superoxide dismutase, catalase and transglutamase, myelin protein zero expression levels and blood sugar levels) confirm this pathology and exclude other putative pathologies like Amyothrophic Lateral Sclerosis and Hereditary Motor and Sensory Neuropathy. Consequently, an excessive cytoplasmic accumulation of the transgenic protein or a disturbance of the normal metabolism are considered to cause the observed neuropathology. Therefore, extra-ocular αA-crystallin-expressing transgenic mice may serve as a useful animal model to study neuroaxonal dystrophy. PMID:12801283

  14. Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the diet...

  15. Zebrafish models flex their muscles to shed light on muscular dystrophies.

    PubMed

    Berger, Joachim; Currie, Peter D

    2012-11-01

    Muscular dystrophies are a group of genetic disorders that specifically affect skeletal muscle and are characterized by progressive muscle degeneration and weakening. To develop therapies and treatments for these diseases, a better understanding of the molecular basis of muscular dystrophies is required. Thus, identification of causative genes mutated in specific disorders and the study of relevant animal models are imperative. Zebrafish genetic models of human muscle disorders often closely resemble disease pathogenesis, and the optical clarity of zebrafish embryos and larvae enables visualization of dynamic molecular processes in vivo. As an adjunct tool, morpholino studies provide insight into the molecular function of genes and allow rapid assessment of candidate genes for human muscular dystrophies. This unique set of attributes makes the zebrafish model system particularly valuable for the study of muscle diseases. This review discusses how recent research using zebrafish has shed light on the pathological basis of muscular dystrophies, with particular focus on the muscle cell membrane and the linkage between the myofibre cytoskeleton and the extracellular matrix.

  16. Na+ Dysregulation Coupled with Ca2+ Entry through NCX1 Promotes Muscular Dystrophy in Mice

    PubMed Central

    Burr, Adam R.; Millay, Douglas P.; Goonasekera, Sanjeewa A.; Park, Ki Ho; Sargent, Michelle A.; Collins, James; Altamirano, Francisco; Philipson, Kenneth D.; Allen, Paul D.; Ma, Jianjie; López, José Rafael

    2014-01-01

    Unregulated Ca2+ entry is thought to underlie muscular dystrophy. Here, we generated skeletal-muscle-specific transgenic (TG) mice expressing the Na+-Ca2+ exchanger 1 (NCX1) to model its identified augmentation during muscular dystrophy. The NCX1 transgene induced dystrophy-like disease in all hind-limb musculature, as well as exacerbated the muscle disease phenotypes in δ-sarcoglycan (Sgcd−/−), Dysf−/−, and mdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of the Slc8a1 (NCX1) gene diminished hind-limb pathology in Sgcd−/− mice. Measured increases in baseline Na+ and Ca2+ in dystrophic muscle fibers of the hind-limb musculature predicts a net Ca2+ influx state due to reverse-mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm, where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward-mode NCX1 operation that reduces Ca2+ levels. Indeed, Atp1a2+/− (encoding Na+-K+ ATPase α2) mice, which have reduced Na+ clearance rates that would favor NCX1 reverse-mode operation, showed exacerbated disease in the hind limbs of NCX1 TG mice, similar to treatment with the Na+-K+ ATPase inhibitor digoxin. Treatment of Sgcd−/− mice with ranolazine, a broadly acting Na+ channel inhibitor that should increase NCX1 forward-mode operation, reduced muscular pathology. PMID:24662047

  17. Calcium influx is sufficient to induce muscular dystrophy through a TRPC-dependent mechanism

    PubMed Central

    Millay, Douglas P.; Goonasekera, Sanjeewa A.; Sargent, Michelle A.; Maillet, Marjorie; Aronow, Bruce J.; Molkentin, Jeffery D.

    2009-01-01

    Muscular dystrophy is a general term encompassing muscle disorders that cause weakness and wasting, typically leading to premature death. Membrane instability, as a result of a genetic disruption within the dystrophin-glycoprotein complex (DGC), is thought to induce myofiber degeneration, although the downstream mechanism whereby membrane fragility leads to disease remains controversial. One potential mechanism that has yet to be definitively proven in vivo is that unregulated calcium influx initiates disease in dystrophic myofibers. Here we demonstrate that calcium itself is sufficient to cause a dystrophic phenotype in skeletal muscle independent of membrane fragility. For example, overexpression of transient receptor potential canonical 3 (TRPC3) and the associated increase in calcium influx resulted in a phenotype of muscular dystrophy nearly identical to that observed in DGC-lacking dystrophic disease models, including a highly similar molecular signature of gene expression changes. Furthermore, transgene-mediated inhibition of TRPC channels in mice dramatically reduced calcium influx and dystrophic disease manifestations associated with the mdx mutation (dystrophin gene) and deletion of the δ-sarcoglycan (Scgd) gene. These results demonstrate that calcium itself is sufficient to induce muscular dystrophy in vivo, and that TRPC channels are key disease initiators downstream of the unstable membrane that characterizes many types of muscular dystrophy. PMID:19864620

  18. Two cases of myotonic dystrophy manifesting various ophthalmic findings with genetic evaluation.

    PubMed

    Kang, Min Ji; Yim, Hye Bin; Hwang, Hyung Bin

    2016-07-01

    We report two cases of myotonic dystrophy in one family; both diagnosed from genetic analysis following ophthalmic indications, but before the manifestation of systemic symptoms. A 39-year-old female visited our clinic for routine examination. Mild ptosis, sluggish pupillary response, and bilateral snowflake cataracts were found. Fundus examination revealed an increased cup-to-disc ratio (CDR) in both eyes and a defect in the retinal nerve fiber layer in the right eye. Intraocular pressure was low, but within the normal range in both eyes. Because cataracts are characteristic of myotonic dystrophy, we suggested that her 14-year-old daughter, who did not have any systemic complaints, undergo ophthalmic examination. She also had mild ptosis and snowflake cataracts. Both patients underwent genetic evaluation and were diagnosed with myotonic dystrophy caused by unstable expansion of cytosine-thymine-guanine trinucleotide repeats in the dystrophia myotonica-protein kinase gene. Ophthalmologists can diagnose myotonic dystrophy based on clinical and genetic findings, before the manifestation of systemic abnormalities. PMID:27609169

  19. Reflex sympathetic dystrophy syndrome associated with burns of the upper extremity

    PubMed Central

    Balakrishnan, Chenicheri; Bradt, Lisa M; Rankin, David; Pane, Thomas A

    2004-01-01

    Reflex sympathetic dystrophy syndrome is an ill-defined symptom complex with clinical manifestations of excessive pain, joint stiffness and soft tissue changes. It rarely manifests following burns. Diagnosis is usually made from clinical symptoms and ganglion block. Early diagnosis and institution of conservative management is required to control symptoms and disability. PMID:24115872

  20. Na+ dysregulation coupled with Ca2+ entry through NCX1 promotes muscular dystrophy in mice.

    PubMed

    Burr, Adam R; Millay, Douglas P; Goonasekera, Sanjeewa A; Park, Ki Ho; Sargent, Michelle A; Collins, James; Altamirano, Francisco; Philipson, Kenneth D; Allen, Paul D; Ma, Jianjie; López, José Rafael; Molkentin, Jeffery D

    2014-06-01

    Unregulated Ca(2+) entry is thought to underlie muscular dystrophy. Here, we generated skeletal-muscle-specific transgenic (TG) mice expressing the Na(+)-Ca(2+) exchanger 1 (NCX1) to model its identified augmentation during muscular dystrophy. The NCX1 transgene induced dystrophy-like disease in all hind-limb musculature, as well as exacerbated the muscle disease phenotypes in δ-sarcoglycan (Sgcd(-/-)), Dysf(-/-), and mdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of the Slc8a1 (NCX1) gene diminished hind-limb pathology in Sgcd(-/-) mice. Measured increases in baseline Na(+) and Ca(2+) in dystrophic muscle fibers of the hind-limb musculature predicts a net Ca(2+) influx state due to reverse-mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm, where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward-mode NCX1 operation that reduces Ca(2+) levels. Indeed, Atp1a2(+/-) (encoding Na(+)-K(+) ATPase α2) mice, which have reduced Na(+) clearance rates that would favor NCX1 reverse-mode operation, showed exacerbated disease in the hind limbs of NCX1 TG mice, similar to treatment with the Na(+)-K(+) ATPase inhibitor digoxin. Treatment of Sgcd(-/-) mice with ranolazine, a broadly acting Na(+) channel inhibitor that should increase NCX1 forward-mode operation, reduced muscular pathology. PMID:24662047

  1. Two cases of myotonic dystrophy manifesting various ophthalmic findings with genetic evaluation

    PubMed Central

    Kang, Min Ji; Yim, Hye Bin; Hwang, Hyung Bin

    2016-01-01

    We report two cases of myotonic dystrophy in one family; both diagnosed from genetic analysis following ophthalmic indications, but before the manifestation of systemic symptoms. A 39-year-old female visited our clinic for routine examination. Mild ptosis, sluggish pupillary response, and bilateral snowflake cataracts were found. Fundus examination revealed an increased cup-to-disc ratio (CDR) in both eyes and a defect in the retinal nerve fiber layer in the right eye. Intraocular pressure was low, but within the normal range in both eyes. Because cataracts are characteristic of myotonic dystrophy, we suggested that her 14-year-old daughter, who did not have any systemic complaints, undergo ophthalmic examination. She also had mild ptosis and snowflake cataracts. Both patients underwent genetic evaluation and were diagnosed with myotonic dystrophy caused by unstable expansion of cytosine-thymine-guanine trinucleotide repeats in the dystrophia myotonica-protein kinase gene. Ophthalmologists can diagnose myotonic dystrophy based on clinical and genetic findings, before the manifestation of systemic abnormalities. PMID:27609169

  2. Infrared imaging enhances retinal crystals in Bietti’s crystalline dystrophy

    PubMed Central

    Brar, Vikram S; Benson, William H

    2015-01-01

    Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti’s crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time. PMID:25931805

  3. [Development of an ultrasound-mediated nucleic acid delivery system for treating muscular dystrophies].

    PubMed

    Negishi, Yoichi; Hamano, Nobuhito; Shiono, Hitomi; Akiyama, Saki; Endo-Takahashi, Yoko; Suzuki, Ryo; Maruyama, Kazuo; Aramaki, Yukihiko

    2012-01-01

    Muscular dystrophies are a group of heterogeneous diseases that are characterized by progressive muscle weakness, wasting and degeneration. These muscular deficiencies are often caused by the loss of the protein dystrophin, a crucial element of the dystrophin-glycoprotein complex of muscle fibers. Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscular disease that occurs in 1 out of every 3500 males. Therefore, feasible strategies for replacing or repairing the defective gene are required; however, to date, no effective therapeutic strategies for muscular dystrophies have been established. In this review, we first introduce gene therapies mediated by adeno-associated viruses (AAVs) including a functional dystrophin cDNA or antisense oligonucleotide (AO)-induced exon-skipping therapies, which are designed to exclude the mutated or additional exon(s) in the defective gene and thereby correct the translational reading frame. Recently, we developed "Bubble liposomes" (BLs), which are polyethylene glycol (PEG)-modified liposomes entrapping echo-contrast gas that is known as ultrasound (US) imaging gas. BL application combined with US exposure can function as a novel gene delivery tool, and we demonstrate that the US-mediated eruption of BLs is a feasible and efficient technique to deliver plasmid DNA or AOs for the treatment of muscular dystrophies.

  4. SIRT1: A Novel Target for the Treatment of Muscular Dystrophies

    PubMed Central

    Kuno, Atsushi; Horio, Yoshiyuki

    2016-01-01

    Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy and is caused by mutations in the gene that encodes the cytoskeletal protein dystrophin. The treatment for DMD is limited to glucocorticoids, which are associated with multiple side effects. Thus, the identification of novel therapeutic targets is urgently needed. SIRT1 is an NAD+-dependent histone/protein deacetylase that plays roles in diverse cellular processes, including stress resistance and cell survival. Studies have shown that SIRT1 activation provides beneficial effects in the dystrophin-deficient mdx mouse, a model of DMD. SIRT1 activation leads to the attenuation of oxidative stress and inflammation, a shift from the fast to slow myofiber phenotype, and the suppression of tissue fibrosis. Although further research is needed to clarify the molecular mechanisms underlying the protective role of SIRT1 in mdx mice, we propose SIRT1 as a novel therapeutic target for patients with muscular dystrophies. PMID:27073590

  5. Dystrophin insufficiency causes a Becker muscular dystrophy-like phenotype in swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Duchenne muscular dystrophy (DMD) is caused by a dystrophin deficiency while Becker MD is caused by a dystrophin insufficiency or expression of a partially functional dystrophin protein. Deficiencies in existing mouse and dog models necessitate the development of a novel large animal model. Our pu...

  6. Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice.

    PubMed

    Tjondrokoesoemo, Andoria; Schips, Tobias G; Sargent, Michelle A; Vanhoutte, Davy; Kanisicak, Onur; Prasad, Vikram; Lin, Suh-Chin J; Maillet, Marjorie; Molkentin, Jeffery D

    2016-05-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin protein compromises the stability of the sarcolemma membrane surrounding each muscle cell fiber, leading to membrane ruptures and leakiness that induces myofiber necrosis, a subsequent inflammatory response, and progressive tissue fibrosis with loss of functional capacity. Cathepsin S (Ctss) is a cysteine protease that is actively secreted in areas of tissue injury and ongoing inflammation, where it participates in extracellular matrix remodeling and healing. Here we show significant induction of Ctss expression and proteolytic activity following acute muscle injury or in muscle from mdx mice, a model of DMD. To examine the functional ramifications associated with greater Ctss expression, the Ctss gene was deleted in the mdx genetic background, resulting in protection from muscular dystrophy pathogenesis that included reduced myofiber turnover and histopathology, reduced fibrosis, and improved running capacity. Mechanistically, deletion of the Ctss gene in the mdx background significantly increased myofiber sarcolemmal membrane stability with greater expression and membrane localization of utrophin, integrins, and β-dystroglycan, which anchor the membrane to the basal lamina and underlying cytoskeletal proteins. Consistent with these results, skeletal muscle-specific transgenic mice overexpressing Ctss showed increased myofiber necrosis, muscle histopathology, and a functional deficit reminiscent of muscular dystrophy. Hence, Ctss induction during muscular dystrophy is a pathologic event that partially underlies disease pathogenesis, and its inhibition might serve as a new therapeutic strategy in DMD.

  7. Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity

    PubMed Central

    Saksens, Nicole T.M.; Krebs, Mark P.; Schoenmaker-Koller, Frederieke E.; Hicks, Wanda; Yu, Minzhong; Shi, Lanying; Rowe, Lucy; Collin, Gayle B.; Charette, Jeremy R.; Letteboer, Stef J.; Neveling, Kornelia; van Moorsel, Tamara W.; Abu-Ltaif, Sleiman; De Baere, Elfride; Walraedt, Sophie; Banfi, Sandro; Simonelli, Francesca; Cremers, Frans P.M.; Boon, Camiel J.F.; Roepman, Ronald; Leroy, Bart P.; Peachey, Neal S.; Hoyng, Carel B.; Nishina, Patsy M.; den Hollander, Anneke I.

    2015-01-01

    Butterfly-shaped pigment dystrophy is an eye disease characterized by lesions in the macula that can resemble the wings of a butterfly. Here, we report the identification of heterozygous missense mutations in the α-catenin 1 (CTNNA1) gene in three families with butterfly-shaped pigment dystrophy. In addition, we identified a Ctnna1 missense mutation in a chemically induced mouse mutant, tvrm5. Parallel clinical phenotypes were observed in the retinal pigment epithelium (RPE) of individuals with butterfly-shaped pigment dystrophy and in tvrm5 mice, including pigmentary abnormalities, focal thickening and elevated lesions, and decreased light-activated responses. Morphological studies in tvrm5 mice revealed increased cell shedding and large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis. This study identifies CTNNA1 gene variants as a cause of macular dystrophy, suggests that CTNNA1 is involved in maintaining RPE integrity, and suggests that other components that participate in intercellular adhesion may be implicated in macular disease. PMID:26691986

  8. Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Hinton, V. J.; De Vivo, D. C.; Fee, R.; Goldstein, E.; Stern, Y.

    2004-01-01

    Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the absence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within the…

  9. Improving the Reading Skills of Young People with Duchenne Muscular Dystrophy in Preparation for Adulthood

    ERIC Educational Resources Information Center

    Hoskin, Janet; Fawcett, Angela

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a progressive genetic condition that affects both muscle and brain. Children with DMD are at risk of psycho-social difficulties such as poor academic achievement and behavioural and socio-emotional problems. This article by Janet Hoskin and Angela Fawcett, both from the University of Swansea, describes how 34…

  10. Mild and severe muscular dystrophy caused by a single {gamma}-sarcoglycan mutation

    SciTech Connect

    McNally, E.M.; Boennemann, C.G.; Lidov, H.G.W.

    1996-11-01

    Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein {gamma}-sarcoglycan. The previous mutation analysis of {gamma}-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the {gamma}-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding {gamma}-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the {gamma}-sarcoglycan gene. These patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of {alpha}-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the {gamma}-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from {gamma}-sarcoglycan gene mutations. 19 refs., 5 figs., 3 tabs.

  11. Stem Cell Differentiation Toward the Myogenic Lineage for Muscle Tissue Regeneration: A Focus on Muscular Dystrophy.

    PubMed

    Ostrovidov, Serge; Shi, Xuetao; Sadeghian, Ramin Banan; Salehi, Sahar; Fujie, Toshinori; Bae, Hojae; Ramalingam, Murugan; Khademhosseini, Ali

    2015-12-01

    Skeletal muscle tissue engineering is one of the important ways for regenerating functionally defective muscles. Among the myopathies, the Duchenne muscular dystrophy (DMD) is a progressive disease due to mutations of the dystrophin gene leading to progressive myofiber degeneration with severe symptoms. Although current therapies in muscular dystrophy are still very challenging, important progress has been made in materials science and in cellular technologies with the use of stem cells. It is therefore useful to review these advances and the results obtained in a clinical point of view. This article focuses on the differentiation of stem cells into myoblasts, and their application in muscular dystrophy. After an overview of the different stem cells that can be induced to differentiate into the myogenic lineage, we introduce scaffolding materials used for muscular tissue engineering. We then described some widely used methods to differentiate different types of stem cell into myoblasts. We highlight recent insights obtained in therapies for muscular dystrophy. Finally, we conclude with a discussion on stem cell technology. We discussed in parallel the benefits brought by the evolution of the materials and by the expansion of cell sources which can differentiate into myoblasts. We also discussed on future challenges for clinical applications and how to accelerate the translation from the research to the clinic in the frame of DMD.

  12. Some Dynamics of Personality Development in Boys Suffering from Muscular Dystrophy

    ERIC Educational Resources Information Center

    Mearig, Judith S.

    1973-01-01

    Discussed are personality aspects of Duchenne or pseudohypertrophic muscular dystrophy, a progressive wasting of muscular tissue, which afflicts only boys, and usually has its noticeable onset before the age of 6 years; and described is the development of three male dystrophic siblings. (DB)

  13. Parents' Perspectives on Coping with Duchenne Muscular Dystrophy and Concomitant Specific Learning Disabilities

    ERIC Educational Resources Information Center

    Webb, Carol L.

    2005-01-01

    This study addresses parental perspectives and coping strategies related to Duchenne muscular dystrophy and specific learning disabilities. Data were collected through individual semi-structured in-depth interviews with fifteen sets of parents. Participants were selected based on variables such as age of children, number of children with both…

  14. Evaluation of Narrative Abilities in Patients Suffering from Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Marini, A.; Lorusso, M. L.; D'Angelo, M. G.; Civati, F.; Turconi, A. C.; Fabbro, F.; Bresolin, N.

    2007-01-01

    The present work investigated cognitive, linguistic and narrative abilities in a group of children suffering from Duchenne Muscular Dystrophy, an allelic X-linked recessive disorder caused by mutations in the gene encoding dystrophin. The patients showed mildly reduced IQ with lower Verbal than Performance Intelligence Quotient and were mildly…

  15. Muscular dystrophy in a family of Labrador Retrievers with no muscle dystrophin and a mild phenotype.

    PubMed

    Vieira, Natassia M; Guo, Ling T; Estrela, Elicia; Kunkel, Louis M; Zatz, Mayana; Shelton, G Diane

    2015-05-01

    Animal models of dystrophin deficient muscular dystrophy, most notably canine X-linked muscular dystrophy, play an important role in developing new therapies for human Duchenne muscular dystrophy. Although the canine disease is a model of the human disease, the variable severity of clinical presentations in the canine may be problematic for pre-clinical trials, but also informative. Here we describe a family of Labrador Retrievers with three generations of male dogs having markedly increased serum creatine kinase activity, absence of membrane dystrophin, but with undetectable clinical signs of muscle weakness. Clinically normal young male Labrador Retriever puppies were evaluated prior to surgical neuter by screening laboratory blood work, including serum creatine kinase activity. Serum creatine kinase activities were markedly increased in the absence of clinical signs of muscle weakness. Evaluation of muscle biopsies confirmed a dystrophic phenotype with both degeneration and regeneration. Further evaluations by immunofluorescence and western blot analysis confirmed the absence of muscle dystrophin. Although dystrophin was not identified in the muscles, we did not find any detectable deletions or duplications in the dystrophin gene. Sequencing is now ongoing to search for point mutations. Our findings in this family of Labrador Retriever dogs lend support to the hypothesis that, in exceptional situations, muscle with no dystrophin may be functional. Unlocking the secrets that protect these dogs from a severe clinical myopathy is a great challenge which may have important implications for future treatment of human muscular dystrophies.

  16. Bietti's tapetoretinal degeneration with marginal corneal dystrophy (crystalline retinopathy): case report.

    PubMed Central

    Harrison, R J; Acheson, R R; Dean-Hart, J C

    1987-01-01

    A patient with Bietti's tapetoretinal degeneration and marginal corneal dystrophy is reported on. Refractile deposits found in both the retina and cornea are the most striking feature of this condition. Apart from a slight reduction in left visual acuity there were no visual symptoms. The dark adapted electroretinogram was abnormal. No metabolic disturbance was detected. Images PMID:3493804

  17. Congenital muscular dystrophy with glycosylation defects of alpha-dystroglycan in Japan.

    PubMed

    Matsumoto, Hiroshi; Hayashi, Yukiko K; Kim, Dae-Son; Ogawa, Megumu; Murakami, Terumi; Noguchi, Satoru; Nonaka, Ikuya; Nakazawa, Tomoyuki; Matsuo, Takiko; Futagami, Satoshi; Campbell, Kevin P; Nishino, Ichizo

    2005-05-01

    Glycosylation defects of alpha-dystroglycan (alpha-DG) cause various muscular dystrophies. We performed clinical, pathological and genetic analyses of 62 Japanese patients with congenital muscular dystrophy, whose skeletal muscle showed deficiency of glycosylated form of alpha-DG. We found, the first Japanese patient with congenital muscular dystrophy 1C with a novel compound heterozygous mutation in the fukutin-related protein gene. Fukuyama-type congenital muscular dystrophy was genetically confirmed in 54 of 62 patients. Two patients with muscle-eye-brain disease and one Walker-Warburg syndrome were also genetically confirmed. Four patients had no mutation in any known genes associated with glycosylation of alpha-DG. Interestingly, the molecular mass of alpha-DG in the skeletal muscle was similar and was reduced to approximately 90 kDa among these patients, even though the causative gene and the clinico-pathological severity were different. This result suggests that other factors can modify clinical features of the patients with glycosylation defects of alpha-DG. PMID:15833426

  18. Mild and severe muscular dystrophy caused by a single gamma-sarcoglycan mutation.

    PubMed

    McNally, E M; Passos-Bueno, M R; Bönnemann, C G; Vainzof, M; de Sá Moreira, E; Lidov, H G; Othmane, K B; Denton, P H; Vance, J M; Zatz, M; Kunkel, L M

    1996-11-01

    Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein gamma-sarcoglycan. The previous mutation analysis of gamma-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the gamma-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding gamma-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the gamma-sarcoglycan gene. These patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of alpha-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the gamma-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from gamma-sarcoglycan gene mutations. PMID:8900232

  19. DNA Damage, Somatic Aneuploidy, and Malignant Sarcoma Susceptibility in Muscular Dystrophies

    PubMed Central

    Schmidt, Wolfgang M.; Uddin, Mohammed H.; Dysek, Sandra; Moser-Thier, Karin; Pirker, Christine; Höger, Harald; Ambros, Inge M.; Ambros, Peter F.; Berger, Walter; Bittner, Reginald E.

    2011-01-01

    Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD–pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD–gene defects and strain background strongly influence sarcoma incidence, latency, localization, and gender prevalence. Combined loss of dystrophin and dysferlin, as well as dystrophin and calpain-3, leads to accelerated tumor formation. Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1), amplification of oncogenes (Met, Jun), recurrent duplications of whole chromosomes 8 and 15, and DNA damage. Remarkably, these sarcoma-specific genetic lesions are already regularly present in skeletal muscles in aged MD mice even prior to sarcoma development. Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies. These novel aspects of molecular pathologies common to muscular dystrophies and tumor biology will potentially influence the strategies to combat these diseases. PMID:21533183

  20. Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour.

    PubMed

    Hernández-Hernández, Oscar; Guiraud-Dogan, Céline; Sicot, Géraldine; Huguet, Aline; Luilier, Sabrina; Steidl, Esther; Saenger, Stefanie; Marciniak, Elodie; Obriot, Hélène; Chevarin, Caroline; Nicole, Annie; Revillod, Lucile; Charizanis, Konstantinos; Lee, Kuang-Yung; Suzuki, Yasuhiro; Kimura, Takashi; Matsuura, Tohru; Cisneros, Bulmaro; Swanson, Maurice S; Trovero, Fabrice; Buisson, Bruno; Bizot, Jean-Charles; Hamon, Michel; Humez, Sandrine; Bassez, Guillaume; Metzger, Friedrich; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève; Gomes-Pereira, Mário

    2013-03-01

    Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.