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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. Molecular genetics of facioscapulohumeral muscular dystrophy (FSHD).

    PubMed

    Fisher, J; Upadhyaya, M

    1997-01-01

    Facioscapulohumeral muscular dystrophy (FSHD; MIM 158900), is an autosomal dominant neuromuscular disorder. The disease is characterized by the weakness of the muscles of the face, upper-arm and shoulder girdle. The gene for FSHD has been mapped to 4q35 (FSHD1A) and is closely linked to D4F1O4S1, which detects two highly polymorphic loci (located at 4q35 and 10q26), with restriction enzyme EcoRI. The polymorphic EcoRI fragment detected with D4F1O4S1 is composed almost entirely of D4Z4 (3.3 kb) tandem repeats. In FSHD patients a deletion of the integral number of D4Z4 repeats generates a fragment which is usually smaller than 35 kb, whereas in normal controls, the size usually ranges from 50 to 300 kb. These 'small' EcoRI fragments segregate with FSHD in families but appear as de novo deletions in the majority of sporadic cases. Each 3.3 kb repeat contains two homeobox domains neither of which has yet been proven to encode a protein. D4Z4 is located adjacent to the 4q telomere and cross hybridizes to several different regions of the genome. Although D4Z4 probably does not encode a protein with any direct association to FSHD, a clear correlation has been shown between the deletion size at this locus and the age at onset of the disease in FSHD patients. In approximately 5-10% of FSHD families the disease locus is unlinked to 4q35 (locus designated FSHD1B), however, none of the non 4q35 loci for FSHD have yet been chromosomally located. Thus so far, only one gene, FRG1 (FSHD region gene 1) has been identified from the FSHD candidate region on 4q35. The apparent low level of expressed sequences from within this region, the integral deletions of D4Z4 repeats observed in FSHD patients and the close proximity of these repeats to the 4q telomere, all suggest that the disease may be the result of position effect variegation. To date, the molecular diagnosis of FSHD with D4F104S1 has been most secure in those families which are linked to other 4q35 markers. Recent studies

  4. 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

  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. 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.

  9. Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations.

    PubMed

    Hamanaka, Kohei; Goto, Kanako; Arai, Mami; Nagao, Koji; Obuse, Chikashi; Noguchi, Satoru; Hayashi, Yukiko K; Mitsuhashi, Satomi; Nishino, Ichizo

    2016-01-01

    Facioscapulohumeral muscular dystrophy 2 (FSHD2) is a genetic muscular disorder characterized by DNA hypomethylation on the 4q-subtelomeric macrosatellite repeat array, D4Z4. FSHD2 is caused by heterozygous mutations in the gene encoding structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1). Because there has been no study on FSHD2 in Asian populations, it is not known whether this disease mechanism is widely seen. To identify FSHD2 patients with SMCHD1 mutations in the Japanese population, bisulfite pyrosequencing was used to measure DNA methylation on the D4Z4 repeat array, and in patients with DNA hypomethylation, the SMCHD1 gene was sequenced by the Sanger method. Twenty patients with D4Z4 hypomethylation were identified. Of these, 13 patients from 11 unrelated families had ten novel and one reported SMCHD1 mutations: four splice-site, two nonsense, two in-frame deletion, two out-of-frame deletion, and one missense mutations. One of the splice-site mutations was homozygous in the single patient identified with this. In summary, we identified novel SMCHD1 mutations in a Japanese cohort of FSHD2 patients, confirming the presence of this disease in a wider population than previously known. PMID:27061275

  10. 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

  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. Facioscapulohumeral muscular dystrophy.

    PubMed

    Sacconi, Sabrina; Salviati, Leonardo; Desnuelle, Claude

    2015-04-01

    Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and asymmetric pattern of muscle involvement and disease progression. Two forms of FSHD, FSHD1 and FSHD2, have been identified displaying identical clinical phenotype but different genetic and epigenetic basis. Autosomal dominant FSHD1 (95% of patients) is characterized by chromatin relaxation induced by pathogenic contraction of a macrosatellite repeat called D4Z4 located on the 4q subtelomere (FSHD1 patients harbor 1 to 10 D4Z4 repeated units). Chromatin relaxation is associated with inappropriate expression of DUX4, a retrogene, which in muscles induces apoptosis and inflammation. Consistent with this hypothesis, individuals carrying zero repeat on chromosome 4 do not develop FSHD1. Not all D4Z4 contracted alleles cause FSHD. Distal to the last D4Z4 unit, a polymorphic site with two allelic variants has been identified: 4qA and 4qB. 4qA is in cis with a functional polyadenylation consensus site. Only contractions on 4qA alleles are pathogenic because the DUX4 transcript is polyadenylated and translated into stable protein. FSHD2 is instead a digenic disease. Chromatin relaxation of the D4Z4 locus is caused by heterozygous mutations in the SMCHD1 gene encoding a protein essential for chromatin condensation. These patients also harbor at least one 4qA allele in order to express stable DUX4 transcripts. FSHD1 and FSHD2 may have an additive effect: patients harboring D4Z4 contraction and SMCHD1 mutations display a more severe clinical phenotype than with either defect alone. Knowledge of the complex genetic and epigenetic defects causing these diseases is essential in view of designing novel therapeutic strategies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. PMID:24882751

  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. An integrated approach in a case of facioscapulohumeral dystrophy

    PubMed Central

    2014-01-01

    Background Muscle fatigue, weakness and atrophy are basilar clinical features that accompany facioscapulohumeral dystrophy (FSHD) the third most common muscular dystrophy. No therapy is available for FSHD. Case presentation We describe the effects of 6mo exercise therapy and nutritional supplementation in a 43-year-old woman severely affected by FSHD. Conclusion A mixed exercise program combined with nutritional supplementation can be safely used with beneficial effects in selected patients with FSHD. PMID:24886582

  16. A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): implications for therapeutic trials. The FSH-DY Group.

    PubMed

    1997-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder localized to 4q35. Neither the gene nor the gene product has been identified. There is presently no established treatment for FSHD. Prospective data on the natural history of this disorder are essential for the effective design of therapeutic trials. We systematically followed 81 well defined FSHD patients for up to 3 years using a standardized protocol that included manual muscle testing (MMT), maximum voluntary isometric contraction testing (MVICT), and functional testing. Muscle strength was strongly associated with measures of muscle mass, age at onset, and duration of disease. Decline in strength over time was slow but detectable with both MVICT and MMT. The magnitude of decline was not associated with either age, gender, age at onset, or duration of disease. This study establishes reliable and valid measures of disease state and progression for use as outcome variables in clinical trials in FSHD, and also provides guidelines for determining sample size and duration of follow-up. A two-armed clinical trial involving 160 patients per group and 1 year of follow-up would provide 80% power to detect complete arrest of the progression of the disease. Trials with fewer patients would thus have adequate power to detect only improvements in strength, unless follow-up duration were extended well beyond 1 year. PMID:9008491

  17. Refined localization of myd, a candidate animal model for facioscapulohumeral dystrophy (FSHD)

    SciTech Connect

    Mills, K.A.; Bailey, H.L.; Murray, J.C.

    1994-09-01

    The mouse mutant myd is a candidate model for FSHD on the basis of phenotypic description and the linkage homology we have established between distal human chromosome 4q and the midregion of mouse chromosome 8. The human disease is associated with a deletion in a subtelomeric repeat element at 4q35, but isolation of genes from this region has been difficult to date. The myd gene will be an excellent candidate gene for the human disease. Refined genetic localization of the mutant is a first step in the positional cloning of the gene for myd. We have mapped myd in 128 affected mice (65 confirmed with muscle histology) from an intersubspecific backcross of B6C3Fe-a/a-myd/+ X Mus musculus castaneus (CAST/Ei). Previous work with 38 animals found two recombinants that placed the gene in the 3-6 cM interval between D8Mit30 and D8Mit75, with complete linkage to D8Mit74. New markers and an enlarged panel of affected animals now indicate 2 recombinants with D8Mit74 and complete linkage to D8Mit101. Our results suggest the order of genes and Mit markers is (F11/Kal-3/Clcn-3) - 30 - 101 - 74 - 75 - Ucp. The interval of interest, between D8Mit30 and D8Mit74, is about 1 cM by the current mouse SSLP map generated at MIT. We are currently screening mouse YAC libraries for clones covering this region. There may be a position effect on the FSHD gene by the subtelomeric deletion in its vicinity. If a structurally normal gene is being so affected, it will be difficult to show that is is the FSHD gene. The mouse gene is likely to be affected by a different type of mutation, and could facilitate analysis of candidate human genes.

  18. 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

  19. 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

  20. 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

  1. Facioscapulohumeral muscular dystrophy

    MedlinePlus

    ... of cases, the parents do not carry the gene. Facioscapulohumeral muscular dystrophy affects about 5 out of 100,000 people. ... Treatment There is no ... worse. Physical therapy may help maintain muscle strength. Other possible treatments ...

  2. 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

  3. Upper Girdle Imaging in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Tasca, Giorgio; Monforte, Mauro; Iannaccone, Elisabetta; Laschena, Francesco; Ottaviani, Pierfrancesco; Leoncini, Emanuele; Boccia, Stefania; Galluzzi, Giuliana; Pelliccioni, Marco; Masciullo, Marcella; Frusciante, Roberto; Mercuri, Eugenio; Ricci, Enzo

    2014-01-01

    Background In Facioscapulohumeral muscular dystrophy (FSHD), the upper girdle is early involved and often difficult to assess only relying on physical examination. Our aim was to evaluate the pattern and degree of involvement of upper girdle muscles in FSHD compared with other muscle diseases with scapular girdle impairment. Methods We propose an MRI protocol evaluating neck and upper girdle muscles. One hundred-eight consecutive symptomatic FSHD patients and 45 patients affected by muscular dystrophies and myopathies with prominent upper girdle involvement underwent this protocol. Acquired scans were retrospectively analyzed. Results The trapezius (100% of the patients) and serratus anterior (85% of the patients) were the most and earliest affected muscles in FSHD, followed by the latissimus dorsi and pectoralis major, whilst spinati and subscapularis (involved in less than 4% of the patients) were consistently spared even in late disease stages. Asymmetry and hyperintensities on short-tau inversion recovery (STIR) sequences were common features, and STIR hyperintensities could also be found in muscles not showing signs of fatty replacement. The overall involvement appears to be disease-specific in FSHD as it significantly differed from that encountered in the other myopathies. Conclusions The detailed knowledge of single muscle involvement provides useful information for correctly evaluating patients' motor function and to set a baseline for natural history studies. Upper girdle imaging can also be used as an additional tool helpful in supporting the diagnosis of FSHD in unclear situations, and may contribute with hints on the currently largely unknown molecular pathogenesis of this disease. PMID:24932477

  4. 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

  5. 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

  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. Treatment of facioscapulohumeral muscular dystrophy with Denosumab

    PubMed Central

    Lefkowitz, Stanley S.; Lefkowitz, Doris L.; Kethley, Jeremy

    2012-01-01

    Summary Background: Facioscapulohumeral muscular dystrophy (FSHD) is the 3rd most common form of muscular dystrophy. Effective treatments for any of the muscular dystrophies have yet to be realized. This report describes such a treatment. Case Report: A 66 year old female was diagnosed with osteoporosis. She had been diagnosed with FSHD muscular dystrophy a number of years previously by both genetic and clinical studies. Following a 2 year course with Forteo for osteoporosis, she was given an injection of Denosumab (Prolia) to maintain her bone density. By 24 hours, she exhibited increased strength and a dramatic reduction of her dystrophic symptoms e.g. she could walk unassisted in high heels. She was able to accomplish other things that had not been possible for a number of years. After approximately 5 weeks she gradually lost the newfound strength with a complete loss by about 6 weeks. A second injection of Denosumab resulted in the same effect, i.e. reversal of symptoms and increased functionality. A number of measurements and videos were taken to establish the beneficial effects of Prolia for future studies. This was repeated with a 3rd and 4th injection in order to establish the unequivocal beneficial effects on muscular dystrophy. Conclusions: Further studies will be required to establish Denosumab as a major “front line” treatment for this disease and possibly other muscular dystrophies. PMID:23569491

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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

  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. Direct interplay between two candidate genes in FSHD muscular dystrophy

    PubMed Central

    Ferri, Giulia; Huichalaf, Claudia H.; Caccia, Roberta; Gabellini, Davide

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders. The major form of the disease (FSHD1) is linked to decrease in copy number of a 3.3-kb tandem repeated macrosatellite (D4Z4), located on chromosome 4q35. D4Z4 deletion alters chromatin structure of the locus leading to aberrant expression of nearby 4q35 genes. Given the high variability in disease onset and progression, multiple factors could contribute to the pathogenesis of FSHD. Among the FSHD candidate genes are double homeobox 4 (DUX4), encoded by the most telomeric D4Z4 unit, and FSHD region gene 1 (FRG1). DUX4 is a sequence-specific transcription factor. Here, we located putative DUX4 binding sites in the human FRG1 genomic area and we show specific DUX4 association to these regions. We found also that ectopically expressed DUX4 up-regulates the endogenous human FRG1 gene in healthy muscle cells, while DUX4 knockdown leads to a decrease in FRG1 expression in FSHD muscle cells. Moreover, DUX4 binds directly and specifically to its binding site located in the human FRG1 gene and transactivates constructs containing FRG1 genomic regions. Intriguingly, the mouse Frg1 genomic area lacks DUX4 binding sites and DUX4 is unable to activate the endogenous mouse Frg1 gene providing a possible explanation for the lack of muscle phenotype in DUX4 transgenic mice. Altogether, our results demonstrate that FRG1 is a direct DUX4 transcriptional target uncovering a novel regulatory circuit contributing to FSHD. PMID:25326393

  16. Direct interplay between two candidate genes in FSHD muscular dystrophy.

    PubMed

    Ferri, Giulia; Huichalaf, Claudia H; Caccia, Roberta; Gabellini, Davide

    2015-03-01

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders. The major form of the disease (FSHD1) is linked to decrease in copy number of a 3.3-kb tandem repeated macrosatellite (D4Z4), located on chromosome 4q35. D4Z4 deletion alters chromatin structure of the locus leading to aberrant expression of nearby 4q35 genes. Given the high variability in disease onset and progression, multiple factors could contribute to the pathogenesis of FSHD. Among the FSHD candidate genes are double homeobox 4 (DUX4), encoded by the most telomeric D4Z4 unit, and FSHD region gene 1 (FRG1). DUX4 is a sequence-specific transcription factor. Here, we located putative DUX4 binding sites in the human FRG1 genomic area and we show specific DUX4 association to these regions. We found also that ectopically expressed DUX4 up-regulates the endogenous human FRG1 gene in healthy muscle cells, while DUX4 knockdown leads to a decrease in FRG1 expression in FSHD muscle cells. Moreover, DUX4 binds directly and specifically to its binding site located in the human FRG1 gene and transactivates constructs containing FRG1 genomic regions. Intriguingly, the mouse Frg1 genomic area lacks DUX4 binding sites and DUX4 is unable to activate the endogenous mouse Frg1 gene providing a possible explanation for the lack of muscle phenotype in DUX4 transgenic mice. Altogether, our results demonstrate that FRG1 is a direct DUX4 transcriptional target uncovering a novel regulatory circuit contributing to FSHD. PMID:25326393

  17. Facioscapulohumeral dystrophy: a distinct regional myopathy with a novel molecular pathogenesis. FSH Consortium.

    PubMed

    Tawil, R; Figlewicz, D A; Griggs, R C; Weiffenbach, B

    1998-03-01

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited diseases of muscle. Until recently, FSHD had received little attention because of its relatively benign course and the perception that it represented a syndrome rather than a distinct myopathy. Research interest into this disease was reignited with the demonstration of linkage of FSHD to chromosome 4q35 in 1990. Clinical and molecular genetic research in FSHD has since helped define it as a distinct clinical entity, outlined its natural history, and defined the primary molecular defect associated with the condition. FSHD is now known to be associated with large deletions of variable size on chromosome 4q35. These deletions, however, do not appear to disrupt a transcribed gene but are thought to interfere with the expression of a gene or genes located proximal to the deletions. These observations complicate the search for the FSHD gene but also imply the presence of a potentially novel molecular pathogenesis. PMID:9506542

  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. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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. PMID:25551153

  9. 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 ...

  10. 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

  11. Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy.

    PubMed

    Winston, Jincy; Duerden, Laura; Mort, Matthew; Frayling, Ian M; Rogers, Mark T; Upadhyaya, Meena

    2015-01-01

    Facioscapulohumeral muscular dystrophy 1 (FSHD1) is caused by a contraction in the number of D4Z4 repeats on chromosome 4, resulting in relaxation of D4Z4 chromatin causing inappropriate expression of DUX4 in skeletal muscle. Clinical severity is inversely related to the number of repeats. In contrast, FSHD2 patients also have inappropriate expression of DUX4 in skeletal muscle, but due to constitutional mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1), which cause global hypomethylation and hence general relaxation of chromatin. Thirty patients originally referred for FSHD testing were screened for SMCHD1 mutations. Twenty-nine had >11 D4Z4 repeats. SMCHD1 c.1040+1G>A, a pathogenic splice-site variant, was identified in a FSHD1 family with a borderline number of D4Z4 repeats (10) and a variable phenotype (in which a LMNA1 sequence variant was previously described), and SMCHD1 c.2606 G>T, a putative missense variant (p.Gly869Val) with strong in vitro indications of pathogenicity, was identified in a family with an unusual muscular dystrophy with some FSHD-like features. The two families described here emphasise the genetic complexity of muscular dystrophies. As SMCHD1 has a wider role in global genomic methylation, the possibility exists that it could be involved in other complex undiagnosed muscle disorders. Thus far, only 15 constitutional mutations have been identified in SMCHD1, and these two sequence variants add to the molecular and phenotypic spectrum associated with FSHD. PMID:24755953

  12. 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.

  13. 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

  14. 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

  15. 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

  16. 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

  17. DNA Methylation Analysis of the Macrosatellite Repeat Associated with FSHD Muscular Dystrophy at Single Nucleotide Level

    PubMed Central

    Huichalaf, Claudia; Micheloni, Stefano; Ferri, Giulia; Caccia, Roberta; Gabellini, Davide

    2014-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited diseases of the skeletal muscle. It is characterized by asymmetric muscle weakness and variable penetrance. FSHD is linked to a reduction in copy number of the D4Z4 3.3 kb macrosatellite repeat, located in 4q35. This causes the epigenetic de-repression of FSHD candidate genes leading to disease. Nevertheless, the molecular mechanism responsible for silencing of FSHD candidate genes in healthy subjects is not fully understood. While a role for DNA methylation has been suggested, so far there is limited information regarding the methylation status of the 325 CpGs contained in each D4Z4 unit. Using a human/rodent monochromosomal hybrid cell line containing a single human chromosome 4, we performed an in depth analysis of DNA methylation for the majority of the CpGs inside D4Z4 at single nucleotide level. We found that D4Z4 is not uniformly methylated and that the level of DNA methylation does not correlate with the density of CpG dinucleotides. Moreover, in several D4Z4 regions characterized by near complete methylation, we found specific unmethylated CpGs. These elements are enriched in transcription factor binding sites that could be involved in muscle-specific D4Z4 activity. Our approach also detected differential methylation among different D4Z4 units, suggesting that the D4Z4 array is a mosaic of euchromatic and heterochromatic domains. Finally, we found that DNA methylation and histone de-acetylation are required to maintain FSHD candidate genes repressed. Taken together, our data underscore new players involved in the epigenetic regulation of the FSHD locus that could be targeted for therapeutic purposes. PMID:25545674

  18. 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

  19. A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

    PubMed Central

    Homma, Sachiko; Chen, Jennifer CJ; Rahimov, Fedik; Beermann, Mary Lou; Hanger, Kendal; Bibat, Genila M; Wagner, Kathryn R; Kunkel, Louis M; Emerson, Charles P; Miller, Jeffrey Boone

    2012-01-01

    To explore possible mechanisms of pathology in facioscapulohumeral muscular dystrophy (FSHD), we generated a novel library of myogenic cells composed of paired cultures derived from FSHD subjects and unaffected first-degree relatives. We prepared cells from biopsies of both biceps and deltoid muscles obtained from each of 10 FSHD and 9 unaffected donors. We used this new collection to determine how family background and disease affected patterns of growth and differentiation, expression of a panel of candidate, and muscle-specific genes, and responses to exogenous stressors. We found that FSHD and unaffected cells had, on average, indistinguishable patterns of differentiation, gene expression, and dose-response curves to staurosporine, paraquat, hydrogen peroxide, and glutathione depletion. Differentiated FSHD and unaffected cultures were both more sensitive to glutathione depletion than proliferating cultures, but showed similar responses to paraquat, staurosporine, and peroxide. For stress responses, the sample size was sufficient to detect a 10% change in effect at the observed variability with a power of >99%. In contrast, for each of these properties, we found significant differences among cells from different cohorts, and these differences were independent of disease status, gender, or muscle biopsied. Thus, though none of the properties we examined could be used to reliably distinguish between FSHD and unaffected cells, family of origin was an important contributor to gene-expression patterns and stressor responses in cultures of both FSHD and unaffected myogenic cells. PMID:22108603

  20. A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy.

    PubMed

    Feng, Qing; Snider, Lauren; Jagannathan, Sujatha; Tawil, Rabi; van der Maarel, Silvère M; Tapscott, Stephen J; Bradley, Robert K

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy caused by inefficient epigenetic repression of the D4Z4 macrosatellite array and somatic expression of the DUX4 retrogene. DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when misexpressed in skeletal muscle. The mechanism(s) of DUX4 toxicity in muscle is incompletely understood. We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates. DUX4 mRNA is itself degraded by NMD, such that inhibition of NMD by DUX4 protein stabilizes DUX4 mRNA through a double-negative feedback loop in FSHD muscle cells. This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with 'bursts' of DUX4 expression in FSHD muscle, and has implications for FSHD pathogenesis. PMID:25564732

  1. 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

  2. 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.

  3. 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

  4. A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy

    PubMed Central

    Cabianca, Daphne S.; Casa, Valentina; Bodega, Beatrice; Xynos, Alexandros; Ginelli, Enrico; Tanaka, Yujiro; Gabellini, Davide

    2012-01-01

    Summary Repetitive sequences account for more than 50% of the human genome. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease associated with reduction in the copy number of the D4Z4 repeat mapping to 4q35. By an unknown mechanism, D4Z4 deletion causes an epigenetic switch leading to de-repression of 4q35 genes. Here we show that the Polycomb group of epigenetic repressors targets D4Z4 in healthy subjects and that D4Z4 deletion is associated with reduced Polycomb silencing in FSHD patients. We identify DBE-T, a chromatin-associated noncoding RNA produced selectively in FSHD patients that coordinates de-repression of 4q35 genes. DBE-T recruits the Trithorax group protein Ash1L to the FSHD locus, driving histone H3 lysine 36 dimethylation, chromatin remodeling, and 4q35 gene transcription. This study provides insights into the biological function of repetitive sequences in regulating gene expression and shows how mutations of such elements can influence the progression of a human genetic disease. PMID:22541069

  5. [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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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

  13. 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

  14. The D4Z4 Macrosatellite Repeat Acts as a CTCF and A-Type Lamins-Dependent Insulator in Facio-Scapulo-Humeral Dystrophy

    PubMed Central

    Boussouar, Amina; Foerster, Andrea M.; Rondier, Delphine; Sacconi, Sabrina; Desnuelle, Claude; Gilson, Eric; Magdinier, Frédérique

    2009-01-01

    Both genetic and epigenetic alterations contribute to Facio-Scapulo-Humeral Dystrophy (FSHD), which is linked to the shortening of the array of D4Z4 repeats at the 4q35 locus. The consequence of this rearrangement remains enigmatic, but deletion of this 3.3-kb macrosatellite element might affect the expression of the FSHD-associated gene(s) through position effect mechanisms. We investigated this hypothesis by creating a large collection of constructs carrying 1 to >11 D4Z4 repeats integrated into the human genome, either at random sites or proximal to a telomere, mimicking thereby the organization of the 4q35 locus. We show that D4Z4 acts as an insulator that interferes with enhancer–promoter communication and protects transgenes from position effect. This last property depends on both CTCF and A-type Lamins. We further demonstrate that both anti-silencing activity of D4Z4 and CTCF binding are lost upon multimerization of the repeat in cells from FSHD patients compared to control myoblasts from healthy individuals, suggesting that FSHD corresponds to a gain-of-function of CTCF at the residual D4Z4 repeats. We propose that contraction of the D4Z4 array contributes to FSHD physio-pathology by acting as a CTCF-dependent insulator in patients. PMID:19247430

  15. Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy.

    PubMed

    van den Boogaard, Marlinde L; Lemmers, Richard J L F; Balog, Judit; Wohlgemuth, Mariëlle; Auranen, Mari; Mitsuhashi, Satomi; van der Vliet, Patrick J; Straasheijm, Kirsten R; van den Akker, Rob F P; Kriek, Marjolein; Laurense-Bik, Marlies E Y; Raz, Vered; van Ostaijen-Ten Dam, Monique M; Hansson, Kerstin B M; van der Kooi, Elly L; Kiuru-Enari, Sari; Udd, Bjarne; van Tol, Maarten J D; Nishino, Ichizo; Tawil, Rabi; Tapscott, Stephen J; van Engelen, Baziel G M; van der Maarel, Silvère M

    2016-05-01

    Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families. PMID:27153398

  16. 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

  17. 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.

  18. 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.

  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. 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

  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. 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

  3. Emerging preclinical animal models for FSHD

    PubMed Central

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

    2015-01-01

    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. Due 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 are limited to emphasize only specific aspects of the disease, thus highlighting the need for more collaborative research and novel paradigms to advance the translational research space of FSHD. PMID:25801126

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1.

    PubMed

    Larsen, Mirjam; Rost, Simone; El Hajj, Nady; Ferbert, Andreas; Deschauer, Marcus; Walter, Maggie C; Schoser, Benedikt; Tacik, Pawel; Kress, Wolfram; Müller, Clemens R

    2015-06-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disorder with a wide clinical variability. Contractions of the D4Z4 macrosatellite repeat on chromosome 4q35 are the molecular basis of the pathophysiology. Recently, in a subset of patients without D4Z4 repeat contractions, variants in the SMCHD1 gene have been identified that lead to hypomethylation of D4Z4 and thus DUX4 transcription, which causes FSHD type 2. In this study, we have screened 55 FSHD1-negative and 40 FSHD1-positive patients from unrelated families for potentially pathogenic variants in SMCHD1 by next-generation sequencing (NGS). We identified variants in SMCHD1 in 11 index patients, including missense, splice site and non-sense mutations. We developed a pyrosequencing assay to determine the methylation status of the D4Z4 repeat array and found significantly lower methylation levels for FSHD2 patients than for healthy controls and FSHD1 patients. Two out of eleven SMCHD1 mutation carriers had moderately contracted D4Z4 alleles thus these patients are suffering from FSHD1 and 2. Comparing the phenotype of patients, all FSHD2 patients were relatively mildly affected while patients with FSHD1+2 were much more severely affected than expected from their D4Z4 copy number. Our findings confirm the role of SMCHD1 mutations in FSHD2 and as a modifier of disease severity. With SMCHD1 variants found in 16.4% of phenotypic FSHD patients without D4Z4 repeat contractions, the incidence of FSHD2 is rather high and hence we suggest including sequencing of SMCHD1, haplotyping and methylation analysis in the workflow of molecular FSHD diagnostics. PMID:25370034

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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).

  16. Facioscapulohumeral muscular dystrophy region gene 1 (FRG1) is a dynamic RNA-associated and actin bundling protein

    PubMed Central

    Jessica Sun, Chia-Yun; van Koningsbruggen, Silvana; Long, Steven W.; Straasheijm, Kirsten; Klooster, Rinse; Jones, Takako I.; Bellini, Michel; Levesque, Lyne; Brieher, William M.; van der Maarel, Silvère M.; Jones, Peter L.

    2011-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a dynamic nuclear and cytoplasmic protein that, in skeletal muscle, shows an additional localization to the sarcomere. Maintaining appropriate levels of FRG1 protein is critical for the muscle and vascular development in the vertebrate, however its precise molecular function is unknown. This study investigates the molecular functions of human FRG1 along with mouse and Xenopus frg1 using molecular, biochemical and cell-biological approach to provide further insight into its roles in vertebrate development. The nuclear fraction of the endogenous FRG1 is localized in nucleoli, Cajal bodies, and actively transcribed chromatin; however, contrary to overexpressed FRG1, the endogenous FRG1 is not associated with nuclear speckles. We characterize the nuclear and nucleolar import of FRG1, the potential role for phosphorylation, and its interaction with the importin karyophernα2 (KPNA2). Consistent with a role in RNA biogenesis, human FRG1 is associated with mRNA in vivo and in vitro and interacts directly with TAP, the major mRNA export receptor, and is a dynamic nuclear-cytoplasmic shuttling protein supporting a function for FRG1 in mRNA transport. Biochemically, we characterize FRG1 actin binding activity and show that the cytoplasmic pool of FRG1 is dependent on an intact actin cytoskeleton for its localization. These data provide the first biochemical activities - actin binding and RNA binding - for human FRG1 and the characterizations of the endogenous human FRG1, together indicating FRG1 is involved in multiple aspects of RNA biogenesis including mRNA transport and potentially cytoplasmic mRNA localization. PMID:21699900

  17. 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

  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. FSHD Myotubes with Different Phenotypes Exhibit Distinct Proteomes

    PubMed Central

    Laoudj-Chenivesse, Dalila; Wauters, Armelle; Vanderplanck, Céline; Le Bihan, Marie-Catherine; Coppée, Frédérique; Wattiez, Ruddy; Belayew, Alexandra

    2012-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disorder linked to a contraction of the D4Z4 repeat array in the 4q35 subtelomeric region. This deletion induces epigenetic modifications that affect the expression of several genes located in the vicinity. In each D4Z4 element, we identified the double homeobox 4 (DUX4) gene. DUX4 expresses a transcription factor that plays a major role in the development of FSHD through the initiation of a large gene dysregulation cascade that causes myogenic differentiation defects, atrophy and reduced response to oxidative stress. Because miRNAs variably affect mRNA expression, proteomic approaches are required to define the dysregulated pathways in FSHD. In this study, we optimized a differential isotope protein labeling (ICPL) method combined with shotgun proteomic analysis using a gel-free system (2DLC-MS/MS) to study FSHD myotubes. Primary CD56+ FSHD myoblasts were found to fuse into myotubes presenting various proportions of an atrophic or a disorganized phenotype. To better understand the FSHD myogenic defect, our improved proteomic procedure was used to compare predominantly atrophic or disorganized myotubes to the same matching healthy control. FSHD atrophic myotubes presented decreased structural and contractile muscle components. This phenotype suggests the occurrence of atrophy-associated proteolysis that likely results from the DUX4-mediated gene dysregulation cascade. The skeletal muscle myosin isoforms were decreased while non-muscle myosin complexes were more abundant. In FSHD disorganized myotubes, myosin isoforms were not reduced, and increased proteins were mostly involved in microtubule network organization and myofibrillar remodeling. A common feature of both FSHD myotube phenotypes was the disturbance of several caveolar proteins, such as PTRF and MURC. Taken together, our data suggest changes in trafficking and in the membrane microdomains of FSHD myotubes. Finally, the adjustment of a

  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. Myoblasts from affected and non-affected FSHD muscles exhibit morphological differentiation defects

    PubMed Central

    Barro, Marietta; Carnac, Gilles; Flavier, Sébastien; Mercier, Jacques; Vassetzky, Yegor; Laoudj-Chenivesse, Dalila

    2010-01-01

    Abstract Facioscapulohumeral dystrophy (FSHD) is a muscular hereditary disease with a prevalence of 1 in 20,000 caused by a partial deletion of a subtelomeric repeat array on chromosome 4q. However, very little is known about the pathogenesis as well as the molecular and biochemical changes linked to the progressive muscle degeneration observed in these patients. Several studies have investigated possible pathophysiological pathways in FSHD myoblasts and mature muscle cells but some of these reports were apparently in contradiction. The discrepancy between these studies may be explained by differences between the sources of myoblasts. Therefore, we decided to thoroughly analyze affected and unaffected muscles from patients with FSHD in terms of vulnerability to oxidative stress, differentiation capacity and morphological abnormalities. We have established a panel of primary myoblast cell cultures from patients affected with FSHD and matched healthy individuals. Our results show that primary myoblasts are more susceptible to an induced oxidative stress than control myoblasts. Moreover, we demonstrate that both types of FSHD primary myoblasts differentiate into multi-nucleated myotubes, which present morphological abnormalities. Whereas control myoblasts fuse to form branched myotubes with aligned nuclei, FSHD myoblasts fuse to form either thin and branched myotubes with aligned nuclei or large myotubes with random nuclei distribution. In conclusion, we postulate that these abnormalities could be responsible for muscle weakness in patients with FSHD and provide an important marker for FSHD myoblasts. PMID:18505476

  2. RNA interference inhibits DUX4-induced muscle toxicity in vivo: implications for a targeted FSHD therapy.

    PubMed

    Wallace, Lindsay M; Liu, Jian; Domire, Jacqueline S; Garwick-Coppens, Sara E; Guckes, Susan M; Mendell, Jerry R; Flanigan, Kevin M; Harper, Scott Q

    2012-07-01

    No treatment exists for facioscapulohumeral muscular dystrophy (FSHD), one of the most common inherited muscle diseases. Although FSHD can be debilitating, little effort has been made to develop targeted therapies. This lack of focus on targeted FSHD therapy perpetuated because the genes and pathways involved in the disorder were not understood. Now, more than 2 decades after efforts to decipher the root cause of FSHD began, this barrier to translation is finally lowering. Specifically, several recent studies support an FSHD pathogenesis model involving overexpression of the myopathic DUX4 gene. DUX4 inhibition has therefore emerged as a promising therapeutic strategy for FSHD. In this study, we tested a preclinical RNA interference (RNAi)-based DUX4 gene silencing approach as a prospective treatment for FSHD. We found that adeno-associated viral (AAV) vector-delivered therapeutic microRNAs corrected DUX4-associated myopathy in mouse muscle. These results provide proof-of-principle for RNAi therapy of FSHD through DUX4 inhibition. PMID:22508491

  3. Gene expression during normal and FSHD myogenesis

    PubMed Central

    2011-01-01

    Background Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contraction of an array of tandem 3.3-kb repeats (D4Z4) at 4q35. Within each repeat unit is a gene, DUX4, that can encode a protein containing two homeodomains. A DUX4 transcript derived from the last repeat unit in a contracted array is associated with pathogenesis but it is unclear how. Methods Using exon-based microarrays, the expression profiles of myogenic precursor cells were determined. Both undifferentiated myoblasts and myoblasts differentiated to myotubes derived from FSHD patients and controls were studied after immunocytochemical verification of the quality of the cultures. To further our understanding of FSHD and normal myogenesis, the expression profiles obtained were compared to those of 19 non-muscle cell types analyzed by identical methods. Results Many of the ~17,000 examined genes were differentially expressed (> 2-fold, p < 0.01) in control myoblasts or myotubes vs. non-muscle cells (2185 and 3006, respectively) or in FSHD vs. control myoblasts or myotubes (295 and 797, respectively). Surprisingly, despite the morphologically normal differentiation of FSHD myoblasts to myotubes, most of the disease-related dysregulation was seen as dampening of normal myogenesis-specific expression changes, including in genes for muscle structure, mitochondrial function, stress responses, and signal transduction. Other classes of genes, including those encoding extracellular matrix or pro-inflammatory proteins, were upregulated in FSHD myogenic cells independent of an inverse myogenesis association. Importantly, the disease-linked DUX4 RNA isoform was detected by RT-PCR in FSHD myoblast and myotube preparations only at extremely low levels. Unique insights into myogenesis-specific gene expression were also obtained. For example, all four Argonaute genes involved in RNA-silencing were significantly upregulated during normal (but not FSHD) myogenesis relative to non

  4. 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

  5. Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2

    PubMed Central

    Lemmers, Richard J.L.F.; Goeman, Jelle J.; van der Vliet, Patrick J.; van Nieuwenhuizen, Merlijn P.; Balog, Judit; Vos-Versteeg, Marianne; Camano, Pilar; Ramos Arroyo, Maria Antonia; Jerico, Ivonne; Rogers, Mark T.; Miller, Daniel G.; Upadhyaya, Meena; Verschuuren, Jan J.G.M.; Lopez de Munain Arregui, Adolfo; van Engelen, Baziel G.M.; Padberg, George W.; Sacconi, Sabrina; Tawil, Rabi; Tapscott, Stephen J.; Bakker, Bert; van der Maarel, Silvère M.

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD: MIM#158900) is a common myopathy with marked but largely unexplained clinical inter- and intra-familial variability. It is caused by contractions of the D4Z4 repeat array on chromosome 4 to 1–10 units (FSHD1), or by mutations in the D4Z4-binding chromatin modifier SMCHD1 (FSHD2). Both situations lead to a partial opening of the D4Z4 chromatin structure and transcription of D4Z4-encoded polyadenylated DUX4 mRNA in muscle. We measured D4Z4 CpG methylation in control, FSHD1 and FSHD2 individuals and found a significant correlation with the D4Z4 repeat array size. After correction for repeat array size, we show that the variability in clinical severity in FSHD1 and FSHD2 individuals is dependent on individual differences in susceptibility to D4Z4 hypomethylation. In FSHD1, for individuals with D4Z4 repeat arrays of 1–6 units, the clinical severity mainly depends on the size of the D4Z4 repeat. However, in individuals with arrays of 7–10 units, the clinical severity also depends on other factors that regulate D4Z4 methylation because affected individuals, but not non-penetrant mutation carriers, have a greater reduction of D4Z4 CpG methylation than can be expected based on the size of the pathogenic D4Z4 repeat array. In FSHD2, this epigenetic susceptibility depends on the nature of the SMCHD1 mutation in combination with D4Z4 repeat array size with dominant negative mutations being more deleterious than haploinsufficiency mutations. Our study thus identifies an epigenetic basis for the striking variability in onset and disease progression that is considered a clinical hallmark of FSHD. PMID:25256356

  6. Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2.

    PubMed

    Lemmers, Richard J L F; Goeman, Jelle J; van der Vliet, Patrick J; van Nieuwenhuizen, Merlijn P; Balog, Judit; Vos-Versteeg, Marianne; Camano, Pilar; Ramos Arroyo, Maria Antonia; Jerico, Ivonne; Rogers, Mark T; Miller, Daniel G; Upadhyaya, Meena; Verschuuren, Jan J G M; Lopez de Munain Arregui, Adolfo; van Engelen, Baziel G M; Padberg, George W; Sacconi, Sabrina; Tawil, Rabi; Tapscott, Stephen J; Bakker, Bert; van der Maarel, Silvère M

    2015-02-01

    Facioscapulohumeral muscular dystrophy (FSHD: MIM#158900) is a common myopathy with marked but largely unexplained clinical inter- and intra-familial variability. It is caused by contractions of the D4Z4 repeat array on chromosome 4 to 1-10 units (FSHD1), or by mutations in the D4Z4-binding chromatin modifier SMCHD1 (FSHD2). Both situations lead to a partial opening of the D4Z4 chromatin structure and transcription of D4Z4-encoded polyadenylated DUX4 mRNA in muscle. We measured D4Z4 CpG methylation in control, FSHD1 and FSHD2 individuals and found a significant correlation with the D4Z4 repeat array size. After correction for repeat array size, we show that the variability in clinical severity in FSHD1 and FSHD2 individuals is dependent on individual differences in susceptibility to D4Z4 hypomethylation. In FSHD1, for individuals with D4Z4 repeat arrays of 1-6 units, the clinical severity mainly depends on the size of the D4Z4 repeat. However, in individuals with arrays of 7-10 units, the clinical severity also depends on other factors that regulate D4Z4 methylation because affected individuals, but not non-penetrant mutation carriers, have a greater reduction of D4Z4 CpG methylation than can be expected based on the size of the pathogenic D4Z4 repeat array. In FSHD2, this epigenetic susceptibility depends on the nature of the SMCHD1 mutation in combination with D4Z4 repeat array size with dominant negative mutations being more deleterious than haploinsufficiency mutations. Our study thus identifies an epigenetic basis for the striking variability in onset and disease progression that is considered a clinical hallmark of FSHD. PMID:25256356

  7. 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

  8. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle.

    PubMed

    Gabellini, Davide; Green, Michael R; Tupler, Rossella

    2002-08-01

    Facioscapulohumeral muscular dystrophy (FSHD), a common myopathy, is an autosomal dominant disease of unknown molecular mechanism. Almost all FSHD patients carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Here, we find that in FSHD muscle, 4q35 genes located upstream of D4Z4 are inappropriately overexpressed. We show that an element within D4Z4 specifically binds a multiprotein complex consisting of YY1, a known transcriptional repressor, HMGB2, an architectural protein, and nucleolin. We demonstrate that this multiprotein complex binds D4Z4 in vitro and in vivo and mediates transcriptional repression of 4q35 genes. Based upon these results, we propose that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes resulting in disease. PMID:12176321

  9. The FSHD Atrophic Myotube Phenotype Is Caused by DUX4 Expression

    PubMed Central

    Vanderplanck, Céline; Ansseau, Eugénie; Charron, Sébastien; Stricwant, Nadia; Tassin, Alexandra; Laoudj-Chenivesse, Dalila; Wilton, Steve D.

    2011-01-01

    Background Facioscapulohumeral muscular dystrophy (FSHD) is linked to deletions in 4q35 within the D4Z4 repeat array in which we identified the double homeobox 4 (DUX4) gene. We found stable DUX4 mRNAs only derived from the most distal D4Z4 unit and unexpectedly extended to the flanking pLAM region that provided an intron and a polyadenylation signal. DUX4 encodes a transcription factor expressed in FSHD but not control primary myoblasts or muscle biopsies. The DUX4 protein initiates a large transcription deregulation cascade leading to muscle atrophy and oxidative stress, which are FSHD key features. Methodology/Principal Findings We now show that transfection of myoblasts with a DUX4 expression vector leads to atrophic myotube formation associated with the induction of E3 ubiquitin ligases (MuRF1 and Atrogin1/MAFbx) typical of muscle atrophy. DUX4 induces expression of downstream targets deregulated in FSHD such as mu-crystallin and TP53. We developed specific siRNAs and antisense oligonucleotides (AOs) targeting the DUX4 mRNA. Addition of these antisense agents to primary FSHD myoblast cultures suppressed DUX4 protein expression and affected expression of the above-mentioned markers. Conclusions/Significance These results constitute a proof of concept for the development of therapeutic approaches for FSHD targeting DUX4 expression. PMID:22053214

  10. 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.

  11. 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.

  12. 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

  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. 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

  15. 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

  16. The genes encoding for D4Z4 binding proteins HMGB2, YY1, NCL, and MYOD1 are excluded as candidate genes for FSHD1B.

    PubMed

    Bastress, K L; Stajich, J M; Speer, M C; Gilbert, J R

    2005-04-01

    Facioscapulohumeral muscular dystrophy is a disease of skeletal muscle, with symptoms including both facial and shoulder girdle weakness and progression to involve the pelvic girdle and extremities in the majority of cases. For most cases of FSHD, the molecular basis of the disease can be identified as a partial deletion of the D4Z4 repeat array on the end of the long arm of chromosome 4. However, in up to 5% of FSHD families there is no linkage to 4q35. These cases are designated as FSHD1B. Proteins have been identified that bind to the D4Z4 repeats of chromosome 4q35. The genes encoding D4Z4 binding proteins YY1, HMGB2, NCL, and MYOD1 were investigated as candidate genes for FSHD1B. Coding sequences and promoter region were analyzed for HMBG2 and no sequence variations were detected. For YY1, all five exons were analyzed and a polymorphism was detected in both the unaffected and affected populations. In nucleolin (NCL), several SNPs were identified, including a SNP causing the non-synonymous change P515H; however, all polymorphisms either occurred in control samples or were previously reported. A novel polymorphism was also detected in MYOD1, but did not represent a disease-specific variation. These results suggest that HMBG2, YY1, NCL, and MYOD1 are unlikely to represent the genes responsible for FSHD in these families. PMID:15792872

  17. 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

  18. 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

  19. 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

  20. Facioscapulohumeral muscular dystrophy

    MedlinePlus

    ... make the muscle disease worse. Physical therapy may help maintain muscle strength. Other possible treatments include: Oral albuterol to increase muscle mass (but not strength) Speech therapy Surgery to fix a winged scapula Walking aids ...

  1. 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.

  2. RNA Interference Improves Myopathic Phenotypes in Mice Over-expressing FSHD Region Gene 1 (FRG1)

    PubMed Central

    Wallace, Lindsay M; Garwick-Coppens, Sara E; Tupler, Rossella; Harper, Scott Q

    2011-01-01

    Muscular dystrophies, and other diseases of muscle, arise from recessive and dominant gene mutations. Gene replacement strategies may be beneficial for the former, while gene silencing approaches may provide treatment for the latter. In the last two decades, muscle-directed gene therapies were primarily focused on treating recessive disorders. This disparity at least partly arose because feasible mechanisms to silence dominant disease genes lagged behind gene replacement strategies. With the discovery of RNA interference (RNAi) and its subsequent development as a promising new gene silencing tool, the landscape has changed. In this study, our objective was to demonstrate proof-of-principle for RNAi therapy of a dominant myopathy in vivo. We tested the potential of adeno-associated viral (AAV)-delivered therapeutic microRNAs, targeting the human Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1), to correct myopathic features in mice expressing toxic levels of human FRG1 (FRG1−high mice). We found that FRG1 gene silencing improved muscle mass, strength, and histopathological abnormalities associated with muscular dystrophy in FRG1−high mice, thereby demonstrating therapeutic promise for treatment of dominantly inherited myopathies using RNAi. This approach potentially applies to as many as 29 different gene mutations responsible for myopathies inherited as dominant disorders. PMID:21730972

  3. RNA interference improves myopathic phenotypes in mice over-expressing FSHD region gene 1 (FRG1).

    PubMed

    Wallace, Lindsay M; Garwick-Coppens, Sara E; Tupler, Rossella; Harper, Scott Q

    2011-11-01

    Muscular dystrophies, and other diseases of muscle, arise from recessive and dominant gene mutations. Gene replacement strategies may be beneficial for the former, while gene silencing approaches may provide treatment for the latter. In the last two decades, muscle-directed gene therapies were primarily focused on treating recessive disorders. This disparity at least partly arose because feasible mechanisms to silence dominant disease genes lagged behind gene replacement strategies. With the discovery of RNA interference (RNAi) and its subsequent development as a promising new gene silencing tool, the landscape has changed. In this study, our objective was to demonstrate proof-of-principle for RNAi therapy of a dominant myopathy in vivo. We tested the potential of adeno-associated viral (AAV)-delivered therapeutic microRNAs, targeting the human Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1), to correct myopathic features in mice expressing toxic levels of human FRG1 (FRG1(-high) mice). We found that FRG1 gene silencing improved muscle mass, strength, and histopathological abnormalities associated with muscular dystrophy in FRG1(-high) mice, thereby demonstrating therapeutic promise for treatment of dominantly inherited myopathies using RNAi. This approach potentially applies to as many as 29 different gene mutations responsible for myopathies inherited as dominant disorders. PMID:21730972

  4. 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

  5. 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

  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. 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

  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. 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

  10. 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

  11. 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

  12. 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

  13. A case of fascioscapulohumeral muscular dystrophy misdiagnosed as Becker's muscular dystrophy for 20 years.

    PubMed

    Ramos, Vesper Fe Marie Llaneza; Thaisetthawatkul, Pariwat

    2012-03-01

    A 60-year-old man diagnosed clinically with Becker's muscular dystrophy 20 years ago by another physician presented with gradually progressive proximal muscle weakness since teenage years. Family history revealed a strong paternal familial inheritance pattern of similar distribution of weakness-face, forearm flexion, knee extension and foot dorsiflexion. Work-ups revealed B12 deficiency and allele 1 deletion in fascioscapulohumeral muscular dystrophy (FSHD) DNA testing. FSHD is the third most common muscular dystrophy. Clinical diagnosis is made from the distinctive pattern of weakness, autosomal-dominant inheritance, and confirmed by genetic testing. This case strongly demonstrates the importance of a thorough and careful clinical evaluation even in a case with a long standing diagnosis. PMID:21795275

  14. 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 ...

  15. 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 ...

  16. 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 ...

  17. 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.

  18. Chronic spinal muscular atrophy of facioscapulohumeral type.

    PubMed Central

    Furukawa, T; Toyokura, Y

    1976-01-01

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

  19. 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

  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. Myotonic Dystrophy Family Registry

    ClinicalTrials.gov

    2016-03-28

    Myotonic Dystrophy; Congenital Myotonic Dystrophy; Myotonic Dystrophy 1; Myotonic Dystrophy 2; Dystrophia Myotonica; Dystrophia Myotonica 1; Dystrophia Myotonica 2; Myotonia Dystrophica; Myotonic Dystrophy, Congenital; Myotonic Myopathy, Proximal; PROMM (Proximal Myotonic Myopathy); Proximal Myotonic Myopathy; Steinert Disease; Steinert Myotonic Dystrophy; Steinert's Disease; Myotonia Atrophica

  3. Myotonic dystrophy.

    PubMed

    Jozefowicz, R F; Griggs, R C

    1988-08-01

    Myotonic dystrophy is an autosomal dominant disorder that results in skeletal muscle weakness and wasting, myotonia, and numerous nonmuscular manifestations including frontal balding, cataracts, gonadal dysfunction, cardiac conduction abnormalities, respiratory insufficiency, and hypersomnolence. Although the gene defect in myotonic dystrophy has been mapped to chromosome 19, the exact metabolic abnormalities responsible for this disorder are unknown. Skeletal muscle has been found to be relatively insulin-resistant in myotonic dystrophy, and a decrease in the anabolic action of insulin on skeletal muscle may be related to muscle wasting in this disorder. Laboratory studies, including electromyography, electrocardiography, and muscle biopsy, are helpful in evaluating patients for this disorder, but the clinical aspects and a careful family history remain the mainstays of diagnosis. A number of management strategies preserve function and prevent complications in myotonic dystrophy. PMID:3065594

  4. 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 ...

  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. 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. ...

  7. 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 ...

  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. Serum Enzyme Profiles Differentiate Five Types of Muscular Dystrophy

    PubMed Central

    Zhu, Yuling; Zhang, Huili; Sun, Yiming; Li, Yaqin; Deng, Langhui; Wen, Xingxuan; Wang, Huaqiao; Zhang, Cheng

    2015-01-01

    Background. Differentiation among types of muscular dystrophy (MD) has remained challenging. In this retrospective study, we sought to develop a methodology for differentiation of MD types using analysis of serum enzyme profiles. Methods. The serum levels of enzymes from 232 patients, including 120 with DMD, 36 with BMD, 36 with FSHD, 46 with LGMD, and 11 with EDMD, were evaluated. Results. The characteristic profiles of serum enzymes facilitated differentiation of these five types of MD. DMD was characterized by simultaneous elevation of ALT, AST, LDH, and ALP; BMD and LGMD were characterized by elevation of ALT, AST, and LDH; and FSHD and EDMD were characterized by a lack of abnormal serum enzyme levels. We further developed discriminant functions to distinguish BMD and LGMD. For LGMD, LGMD2B patients had significantly higher ALP levels than non-LGMD2B patients (98 ± 59 U/L versus 45 ± 9 U/L, resp., p < 0.05). Conclusions. Our approach enabled the determination of MD subtypes using serum enzyme profiles prior to genetic testing, which will increase the chance a mutation will be found in the first gene analyzed. PMID:26063958

  12. Depression in Myotonic Dystrophy type 1: clinical and neuronal correlates

    PubMed Central

    2010-01-01

    Background This study was designed to investigate the prevalence and correlates of depression in Myotonic dystrophy type 1 (DM1). Methods Thirty-one patients with DM1 and 47 subjects in a clinical contrast group, consisting of other neuromuscular disorders, including Spinal muscular atrophy, Limb girdle muscle atrophy and Facioscapulohumeral dystrophy, completed Beck Depression Inventory (BDI). We aimed to establish whether different factors associated with DM1 correlated with ratings in the BDI. Results Signs of a clinical depression were prevalent in 32% of the patients with DM1, which was comparable with ratings in the clinical contrast group. The depressive condition was mild to moderate in both groups. In DM1, a longer duration of clinical symptoms was associated with lower scores on the BDI and higher educational levels were correlated with higher scores on depression. We also found a negative association with brain white matter lesions. Conclusions Findings indicate significantly more DM1 patients than normative collectives showing signs of a clinical depression. The depressive condition is however mild to moderate and data indicate that the need for intervention is at hand preferentially early during the disease process. PMID:20482818

  13. 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)

  14. Becker muscular dystrophy

    MedlinePlus

    ... and wheelchairs may improve movement and self-care. Genetic counseling may be recommended. Daughters of a man with ... Genetic counseling may be advised if there is a family history of Becker muscular dystrophy.

  15. 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 ...

  16. 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 ...

  17. 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

  18. 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

  19. 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

  20. Duchenne muscular dystrophy.

    PubMed

    Yiu, Eppie M; Kornberg, Andrew J

    2015-08-01

    Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies. PMID:25752877

  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. 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.

  3. Engraftment of embryonic stem cell-derived myogenic progenitors in a dominant model of muscular dystrophy

    PubMed Central

    Darabi, Radbod; Baik, June; Clee, Mark; Kyba, Michael; Tupler, Rossella; Perlingeiro, Rita C.R.

    2009-01-01

    Muscular dystrophies (MD) consist of a genetically heterogeneous group of disorders, recessive or dominant, characterized by progressive skeletal muscle weakening. To date, no effective treatment is available. Experimental strategies pursuing muscle regeneration through the transplantation of stem cell preparations have brought hope to patients affected by this disorder. Efficacy has been demonstrated in recessive MD models through contribution of wild-type nuclei to the muscle fiber heterokaryon, however to date, there has been no study investigating the efficacy of a cell therapy in a dominant model of MD. We have recently demonstrated that Pax3-induced embryonic stem (ES) cell- derived myogenic progenitors are able to engraft and improve muscle function in mdx mice, a recessive mouse model for Duchenne MD. To assess whether this therapeutic effect can be extended to a dominant type of muscle disorder, here we transplanted these cells into FRG1 transgenic mice, a dominant model that has been associated with Facioscapulohumeral muscular dystrophy. Our results show that Pax3-induced ES-derived myogenic progenitors are capable of significant engraftment after intramuscular or systemic transplantation into Frg1 mice. Analyses of contractile parameters revealed functional improvement in treated muscles of male mice, but not females, which are less severely affected. This study is the first to use Frg1 transgenic mice to assess muscle regeneration as well as to support the use of a cell-based therapy for autosomal dominant types of MD. PMID:19682990

  4. 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.

  5. Paternal transmission of congenital myotonic dystrophy.

    PubMed Central

    Bergoffen, J; Kant, J; Sladky, J; McDonald-McGinn, D; Zackai, E H; Fischbeck, K H

    1994-01-01

    The congenital form of myotonic dystrophy is reported to be almost exclusively, if not exclusively, maternally transmitted. We present a case of congenital myotonic dystrophy which was inherited from a mildly affected father. This family illustrates that the congenital form of myotonic dystrophy can occur without intrauterine or other maternal factors related to the disease. The possibility of paternal transmission of the congenital form of myotonic dystrophy could be considered when counselling myotonic dystrophy patients and their families. Images PMID:7966187

  6. Progressive cone dystrophies.

    PubMed

    François, J; De Rouck, A; De Laey, J J

    1976-01-01

    Patients with progressive generalized cone dystrophy often present nystagmus (or strabism) and complain of photophobia, decrease in visual acuity or disturbances in colour perception. The most classic fundus abnormality is the bull's eye maculopathy or a pallor of the optic disc. Minimal macular changes are sometimes seen, which may progress to a bull's eye type of macular degeneration. The photopic ERG is always very affected, whereas at first the scotopic ERG seems normal. Progressive deterioration of the visual functions is accompanied by increasing fundus lesions and rod involvement, as suggested by the modifications of the dark adaptation curve and the scotopic ERG. However, the progression of typical generalized cone dysfunction is very slow. On the contrary, in some cases of so-called Stargardt's disease with peripheral participation, a very rapid progression has been observed. In such cases a normal ERG does not necessarily mean that the disease will remain localized to the macular area. No definite prognosis can be made on one single ERG. In 3 cases with sector pigmentary retinopathy the photopic ERG was more affected than the scotopic ERG. However, these cases are probably primary cone-rod dystrophies. Although there is no electrophysiological control, our clinical impression is that the evolution, if possible, is very slow. PMID:1066593

  7. Wasting Mechanisms in Muscular Dystrophy

    PubMed Central

    Shin, Jonghyun; Tajrishi, Marjan M.; Ogura, Yuji; Kumar, Ashok

    2013-01-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. PMID:23669245

  8. Clinical Trials in Retinal Dystrophies

    PubMed Central

    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

  9. 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

  10. 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 ...

  11. [Reflex sympathetic dystrophy].

    PubMed

    Oliveira, Marta; Manuela, Manuela; Cantinho, Guilhermina

    2011-01-01

    Reflex Sympathetic Dystrophy is rare in pediatrics. It is a complex regional pain syndrome, of unknown etiology, usually post-traumatic, characterized by dysfunctions of the musculoskeletal, vascular and skin systems: severe persistent pain of a limb, sensory and vascular alterations, associated disability and psychosocial dysfunction. The diagnosis is based in high clinical suspection. In children and adolescents there are aspects that are different from the adult ones. Excessive tests may result in worsening of the clinical symptoms. Bone scintigraphy can help. Pain treatment is difficult, not specific. Physical therapies and relaxation technics give some relief. Depression must be treated. This syndrome includes fibromyalgia and complex regional pain syndrome type I. We present a clinical report of an adolescent girl, referred for pain, cold temperature, pallor and functional disability of an inferior limb, all signals disclosed by a minor trauma. She had been diagnosed depression the year before. The bone scintigraphy was a decisive test. The treatment with gabapentin, C vitamin, physiotherapy and pshycotherapy has been effective. PMID:22713207

  12. 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

  13. 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. PMID:23669245

  14. Modifying muscular dystrophy through TGFβ

    PubMed Central

    Ceco, Ermelinda; McNally, Elizabeth M.

    2013-01-01

    Muscular dystrophy arises from ongoing muscle degeneration and insufficient regeneration. This imbalance leads to loss of muscle with replacement by scar or fibrosis resulting in muscle weakness and, eventually, loss of muscle function. Human muscular dystrophy is characterized by a wide range of disease severity, even when the same genetic mutation is present. This variability implies that other factors, both genetic and environmental, modify the disease outcome. There has been an ongoing effort to define the genetic and molecular bases that influence muscular dystrophy onset and progression. Modifier genes for muscle disease have been identified through candidate gene approaches as well as genomewide surveys. Multiple lines of experimental evidence have now converged on the TGFβ pathway as a modifier for muscular dystrophy. TGFβ signaling is upregulated in dystrophic muscle as a result of a destabilized plasma membrane and/or altered extracellular matrix. Given the important biological role of the TGFβ pathway, and its role beyond muscle homeostasis, we review modifier genes that alter the TGFβ pathway and approaches to modulate TGFβ activity to ameliorate muscle disease. PMID:23551962

  15. 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...

  16. 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 ...

  17. 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 ...

  18. 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.

  19. Zebrafish orthologs of human muscular dystrophy genes

    PubMed Central

    Steffen, Leta S; Guyon, Jeffrey R; Vogel, Emily D; Beltre, Rosanna; Pusack, Timothy J; Zhou, Yi; Zon, Leonard I; Kunkel, Louis M

    2007-01-01

    Background Human muscular dystrophies are a heterogeneous group of genetic disorders which cause decreased muscle strength and often result in premature death. There is no known cure for muscular dystrophy, nor have all causative genes been identified. Recent work in the small vertebrate zebrafish Danio rerio suggests that mutation or misregulation of zebrafish dystrophy orthologs can also cause muscular degeneration phenotypes in fish. To aid in the identification of new causative genes, this study identifies and maps zebrafish orthologs for all known human muscular dystrophy genes. Results Zebrafish sequence databases were queried for transcripts orthologous to human dystrophy-causing genes, identifying transcripts for 28 out of 29 genes of interest. In addition, the genomic locations of all 29 genes have been found, allowing rapid candidate gene discovery during genetic mapping of zebrafish dystrophy mutants. 19 genes show conservation of syntenic relationships with humans and at least two genes appear to be duplicated in zebrafish. Significant sequence coverage on one or more BAC clone(s) was also identified for 24 of the genes to provide better local sequence information and easy updating of genomic locations as the zebrafish genome assembly continues to evolve. Conclusion This resource supports zebrafish as a dystrophy model, suggesting maintenance of all known dystrophy-associated genes in the zebrafish genome. Coupled with the ability to conduct genetic screens and small molecule screens, zebrafish are thus an attractive model organism for isolating new dystrophy-causing genes/pathways and for use in high-throughput therapeutic discovery. PMID:17374169

  20. 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

  1. 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

  2. Morpholino Treatment Improves Muscle Function and Pathology of Pitx1 Transgenic Mice

    PubMed Central

    Pandey, Sachchida Nand; Lee, Yi-Chien; Yokota, Toshifumi; Chen, Yi-Wen

    2014-01-01

    Paired-like homeodomain transcription factor 1 (PITX1) was proposed to be part of the disease mechanisms of facioscapulohumeral muscular dystrophy (FSHD). We generated a tet-repressible muscle-specific Pitx1 transgenic mouse model which develops phenotypes of muscular dystrophy after the PITX1 expression is induced. In this study, we attempted to block the translation of PITX1 protein using morpholinos. Three groups of the transgenic mice received intravenous injections of phosphorodiamidate morpholino oligomers (PMO) (100 mg/kg), octaguanidinium dendrimer-conjugated morpholino (vivo-morpholino) (10 mg/kg), or phosphate-buffered saline (PBS) after the PITX1 expression was induced. Immunoblotting data showed that PITX1 expression in the triceps and quadriceps was significantly reduced 70% and 63% by the vivo-morpholino treatment, respectively. Muscle pathology of the mice treated with the vivo-morpholino was improved by showing 44% fewer angular-shaped atrophic myofibers. Muscle function determined by grip strength was significantly improved by the vivo-morpholino treatment. The study showed that systemic delivery of the vivo-morpholino reduced the PITX1 expression and improved the muscle phenotypes. Aberrant expression of DUX4 from the last unit of the D4Z4 array has been proposed to be the cause of FSHD. The findings of this study suggest that the same principle may be applied to suppress the aberrantly expressed DUX4 in FSHD. PMID:24232919

  3. Morpholino treatment improves muscle function and pathology of Pitx1 transgenic mice.

    PubMed

    Pandey, Sachchida Nand; Lee, Yi-Chien; Yokota, Toshifumi; Chen, Yi-Wen

    2014-02-01

    Paired-like homeodomain transcription factor 1 (PITX1) was proposed to be part of the disease mechanisms of facioscapulohumeral muscular dystrophy (FSHD). We generated a tet-repressible muscle-specific Pitx1 transgenic mouse model which develops phenotypes of muscular dystrophy after the PITX1 expression is induced. In this study, we attempted to block the translation of PITX1 protein using morpholinos. Three groups of the transgenic mice received intravenous injections of phosphorodiamidate morpholino oligomers (PMO) (100 mg/kg), octaguanidinium dendrimer-conjugated morpholino (vivo-morpholino) (10 mg/kg), or phosphate-buffered saline (PBS) after the PITX1 expression was induced. Immunoblotting data showed that PITX1 expression in the triceps and quadriceps was significantly reduced 70% and 63% by the vivo-morpholino treatment, respectively. Muscle pathology of the mice treated with the vivo-morpholino was improved by showing 44% fewer angular-shaped atrophic myofibers. Muscle function determined by grip strength was significantly improved by the vivo-morpholino treatment. The study showed that systemic delivery of the vivo-morpholino reduced the PITX1 expression and improved the muscle phenotypes. Aberrant expression of DUX4 from the last unit of the D4Z4 array has been proposed to be the cause of FSHD. The findings of this study suggest that the same principle may be applied to suppress the aberrantly expressed DUX4 in FSHD. PMID:24232919

  4. [Duodenal dystrophy: An interdisciplinary problem].

    PubMed

    Vinokurova, L V; Khatkov, I E; Izrailov, R E; Bordin, D S; Dubtsova, E A; Nikolskaya, K A; Agafonov, M A; Andrianov, A V

    2016-01-01

    Duodenal dystrophy (DD) is the pathological change in the wall of the duodenum, which is caused by chronic inflammation in its ectopic pancreatic tissue. The most common complications of DD are acute or chronic pancreatitis and impaired duodenal patency, which along with severe pain are an indication for surgical treatment. Pancreaticoduodenal resection is recognized as the operation of choice. The paper describes a clinical case demonstrating the efficiency and safety of minimally invasive (laparoscopic) surgical technologies in this category of patients. Resectional interventions of this volume are also shown to be accompanied by the development of pancreatic insufficiency that necessitates continuous enzyme replacement therapy. PMID:27030187

  5. Arrhythmias in the muscular dystrophies.

    PubMed

    Rajdev, Archana; Groh, William J

    2015-06-01

    In patients with muscular dystrophies, cardiac involvement leading to cardiomyopathy and arrhythmias occurs with variable prevalence, mirroring the phenotypic variability seen among and within the various hereditary myopathies. Knowledge of the incidence of arrhythmias and predictors of sudden death in the various hereditary myopathies can help guide screening and appropriate management of these patients, thereby improving survival. The noncardiac manifestations can lead to delayed recognition of symptoms, affect the decision to implant a prophylactic device, and once a decision is made to proceed with device implant, increase peri-procedural respiratory and anesthesia-related complications. PMID:26002394

  6. Segregation distortion in myotonic dystrophy.

    PubMed Central

    Magee, A C; Hughes, A E

    1998-01-01

    Myotonic dystrophy (DM) is an autosomal dominant disease which, in the typical pedigree, shows a three generation anticipation cascade. This results in infertility and congenital myotonic dystrophy (CDM) with the disappearance of DM in that pedigree. The concept of segregation distortion, where there is preferential transmission of the larger allele at the DM locus, has been put forward to explain partially the maintenance of DM in the population. In a survey of DM in Northern Ireland, 59 pedigrees were ascertained. Sibships where the status of all the members had been identified were examined to determine the transmission of the DM expansion from affected parents to their offspring. Where the transmitting parent was male, 58.3% of the offspring were affected, and in the case of a female transmitting parent, 68.7% were affected. Studies on meiotic drive in DM have shown increased transmission of the larger allele at the DM locus in non-DM heterozygotes for CTGn. This study provides further evidence that the DM expansion tends to be transmitted preferentially. PMID:9863607

  7. 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

  8. 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 ...

  9. [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. PMID:27011029

  10. 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 ...

  11. 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

  12. 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 ...

  13. Non-Coding RNAs in Muscle Dystrophies

    PubMed Central

    Erriquez, Daniela; Perini, Giovanni; Ferlini, Alessandra

    2013-01-01

    ncRNAs are the most recently identified class of regulatory RNAs with vital functions in gene expression regulation and cell development. Among the variety of roles they play, their involvement in human diseases has opened new avenues of research towards the discovery and development of novel therapeutic approaches. Important data come from the field of hereditary muscle dystrophies, like Duchenne muscle dystrophy and Myotonic dystrophies, rare diseases affecting 1 in 7000–15,000 newborns and is characterized by severe to mild muscle weakness associated with cardiac involvement. Novel therapeutic approaches are now ongoing for these diseases, also based on splicing modulation. In this review we provide an overview about ncRNAs and their behavior in muscular dystrophy and explore their links with diagnosis, prognosis and treatments, highlighting the role of regulatory RNAs in these pathologies. PMID:24084719

  14. Flicker fusion thresholds in Best macular dystrophy.

    PubMed

    Massof, R W; Fleischman, J A; Fine, S L; Yoder, F

    1977-06-01

    Flicker fusion threshold intensities were measured as a function of flicker frequency for patients with Best macular dystrophy having normal or near-normal Snellen visual acuity. These data were found to differ from normal in ways that may be interpreted to be an abnormal elevation of the foveal cone threshold, a loss of cone temporal resolution, or both. The results led to the conclusion that Best macular dystrophy affects the neurosensory retina even when Snellen visual acuity is normal. PMID:869758

  15. 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

  16. Arrhythmias in the Muscular Dystrophies

    PubMed Central

    Rajdev, Archana; Groh, William J.

    2015-01-01

    Synopsis In patients with muscular dystrophies, cardiac involvement leading to cardiomyopathy and arrhythmias occur with variable prevalence mirroring the phenotypic variability seen among and within the various hereditary myopathies. These patients are at risk for development for bradyarrhythmias and tachyarrhythmias including sudden cardiac death. Knowledge of the incidence of arrhythmias and predictors of sudden death in the various hereditary myopathies can help guide screening and appropriate management of these patients, thereby improving survival. The non-cardiac manifestations can lead to delayed recognition of symptoms (limited mobility and respiratory weakness masking cardiac manifestations), affect decision to implant prophylactic device (quantity vs. quality of life) and once a decision is made to proceed with device implant, increase peri-procedural respiratory and anesthesia-related complications. PMID:26002394

  17. Animal Models of Muscular Dystrophy

    PubMed Central

    Ng, Rainer; Banks, Glen B.; Hall, John K.; Muir, Lindsey A.; Ramos, Julian N.; Wicki, Jacqueline; Odom, Guy L.; Konieczny, Patryk; Seto, Jane; Chamberlain, Joel R.; Chamberlain, Jeffrey S.

    2016-01-01

    The muscular dystrophies (MDs) represent a diverse collection of inherited human disorders, which affect to varying degrees skeletal, cardiac, and sometimes smooth muscle (Emery, 20021). To date, more than 50 different genes have been implicated as causing one or more types of MD (Bansal et al., 20032). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (Arnett et al., 20093). The large number of genes that are associated with MD and the tremendous number of animal models that have been developed preclude a complete discussion of each in the context of this review. However, we summarize here a number of the more commonly used models together with a mixture of different types of gene and MD, which serves to give a general overview of the value of animal models of MD for research and therapeutic development. PMID:22137430

  18. Cardiac involvement in myotonic dystrophy

    PubMed Central

    Khalighi, Koroush; Kodali, Archana; Thapamagar, Suman B.; Walker, Stanley R.

    2015-01-01

    Background Myotonic dystrophy (DM) is an inherited progressive muscle disorder caused by defects in muscle proteins. As the incidence of this condition is low, not many are familiar with the multisystem involvement. At times, cardiac disease may even be the predominant manifestation in the form of arrhythmias, conduction defects, and cardiomyopathies. The progression of the disease can lead to sudden, unpredictable death. Thus, it is important to identify this subgroup and treat accordingly. Objective To identify patients with DM and assess their risk for sudden cardiac death. Methods Nine patients previously diagnosed with muscular dystrophy were evaluated by cardiologists for various reasons, from a general follow-up to cardiac arrest. All of them had electrocardiograms (EKG) and 2-D echocardiograms, and seven of them had further electrophysiological (EP) studies. Results Of the nine patients with DM, eight had EKG evidence of conduction abnormalities ranging from first-degree heart block to complete heart block. Of the seven who had EP studies, five had inducible ventricular tachycardia requiring immediate cardioversion and implantable cardioverter defibrillator (ICD) implant. Two of them underwent permanent pacemaker placement due to complete heart block and infra-Hissian block. The remaining two patients opted for a conservative approach with yearly EKG monitoring. Conclusion Because one-third of the cardiac deaths in patients with DM are sudden, there is a strong need to identify these patients and intervene in those at high risk. Prophylactic pacemaker placement is recommended even in those with minimal conduction system abnormality. However, the common practice is to identify patients at high risk of conduction abnormalities by EP studies and then provide them with prophylactic invasive strategies. PMID:25656662

  19. 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

  20. 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

  1. 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

  2. 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

  3. [The heartache of muscular dystrophy].

    PubMed

    Hoogerwaard, E M; Ginjaar, H B; Wilde, A A; Leschot, N J; de Voogt, W G; de Visser, M

    2000-11-11

    Duchenne and Becker muscular dystrophy are caused by a mutation in the dystrophin gene, located on the short arm of the X chromosome. Three so called dystrophinopathy patients, a women aged 54 and two men aged 23 and 21 years, suffered from a severe dilated cardiomyopathy. Such a cardiomyopathy can develop in both carriers and patients. In addition, it is often more important for prognosis than muscle weakness. For these two reasons it is important to screen both groups for (early) cardiological abnormalities. If these are present, regular follow-up is necessary to start timely therapy. When cardiological investigations yield normal results, it is advised to screen carriers with a five-year interval. Dystrophinopathy patients should be checked every year, because the cardiomyopathy sometimes develops and deteriorates over a short period of time. Patients with dilated cardiomyopathy and with a positive family history for dilated cardiomyopathy, muscle weakness or high serum creatine kinase activity should be screened for a mutation in the dystrophin gene. PMID:11103252

  4. Myoglobin in Primary Muscular Disease: I. Duchenne Muscular Dystrophy: and: II. Muscular Dystrophy of Distal Type

    PubMed Central

    Romero-Herrera, A. E.; Lehmann, H.; Tomlinson, B. E.; Walton, J. N.

    1973-01-01

    Skeletal myoglobin from two cases of muscular dystrophy, one of Duchenne muscular dystrophy, and one of muscular dystrophy of distal type, have been examined and no differences from normal human myoglobin were found. The opportunity has been taken to discuss the nature of minor fractions of myoglobin-like material which are found when human skeletal myoglobin is isolated. Those which have been observed in the present study have been artefacts and it was possible to demonstrate that they were due to deamidation of certain glutamine and asparagine residues. Images PMID:4590363

  5. Median Nail Dystrophy Involving the Thumb Nail

    PubMed Central

    Kota, Rahulkrishna; Pilani, Abhishek; Nair, Pragya Ashok

    2016-01-01

    Median canaliform dystrophy of Heller is a rare entity characterized by a midline or a paramedian ridge or split and canal formation in nail plate of one or both the thumb nails. It is an acquired condition resulting from a temporary defect in the matrix that interferes with nail formation. Habitual picking of the nail base may be responsible for some cases. Histopathology classically shows parakeratosis, accumulation of melanin within and between the nail bed keratinocytes. Treatment of median nail dystrophy includes injectable triamcinalone acetonide, topical 0.1% tacrolimus, and tazarotene 0.05%, which is many a times challenging for a dermatologist. Psychiatric opinion should be taken when associated with the depressive, obsessive-compulsive, or impulse-control disorder. We report a case of 19-year-old male diagnosed as median nail dystrophy. PMID:26955129

  6. Other limb-girdle muscular dystrophies.

    PubMed

    Amato, Anthony A

    2011-01-01

    The secondary α-dystroglycanopathies usually present in infancy as congenital muscular dystrophies but may manifest later in childhood or adult life (limb-girdle muscular dystrophy (LGMD) 2I, LGMD2K, LGMD2M, LGMD2N, and LGMD2O). Patients with telethoninopathy (LGMD2B) may present with mainly proximal or distal lower extremity weakness, and notably the muscle biopsies may demonstrate rimmed vacuoles. LGMD2L is caused by newly described mutations in ANO5 and can sometimes present with distal weakness resembling Miyoshi myopathy. PMID:21496628

  7. 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

  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. Cellular and molecular mechanisms underlying muscular dystrophy

    PubMed Central

    2013-01-01

    The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes. PMID:23671309

  10. Prevalence of congenital muscular dystrophy in Italy

    PubMed Central

    Graziano, Alessandra; Bianco, Flaviana; D'Amico, Adele; Moroni, Isabella; Messina, Sonia; Bruno, Claudio; Pegoraro, Elena; Mora, Marina; Astrea, Guja; Magri, Francesca; Comi, Giacomo P.; Berardinelli, Angela; Moggio, Maurizio; Morandi, Lucia; Pini, Antonella; Petillo, Roberta; Tasca, Giorgio; Monforte, Mauro; Minetti, Carlo; Mongini, Tiziana; Ricci, Enzo; Gorni, Ksenija; Battini, Roberta; Villanova, Marcello; Politano, Luisa; Gualandi, Francesca; Ferlini, Alessandra; Muntoni, Francesco; Santorelli, Filippo Maria; Bertini, Enrico; Pane, Marika

    2015-01-01

    Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy. Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results: The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions: Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries. PMID:25653289

  11. Cardiomyopathy in becker muscular dystrophy: Overview.

    PubMed

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

    2016-06-26

    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

  12. 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

  13. 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…

  14. Exon Snipping in Duchenne Muscular Dystrophy.

    PubMed

    Kemaladewi, Dwi U; Cohn, Ronald D

    2016-03-01

    Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder caused by mutations in the DMD gene encoding dystrophin. We discuss very recent studies that used CRISPR/Cas9 technology to 'snip out' mutated exons in DMD, restoring the reading frame of the gene. We also present cautionary aspects of translating this exciting technology into clinical practice. PMID:26856237

  15. Nutrition Considerations in Duchenne Muscular Dystrophy.

    PubMed

    Davis, Jillian; Samuels, Emily; Mullins, Lucille

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a serious degenerative muscular disease affecting males. Diagnosis usually occurs in childhood and is confirmed through genetic testing and/or muscle biopsy. Accompanying the disease are several nutrition-related concerns: growth, body composition, energy and protein requirements, constipation, swallowing difficulties, bone health, and complementary medicine. This review article addresses the nutrition aspects of DMD. PMID:25977513

  16. Zebrafish models for human FKRP muscular dystrophies.

    PubMed

    Kawahara, Genri; Guyon, Jeffrey R; Nakamura, Yukio; Kunkel, Louis M

    2010-02-15

    Various muscular dystrophies are associated with the defective glycosylation of alpha-dystroglycan and are known to result from mutations in genes encoding glycosyltransferases. Fukutin-related protein (FKRP) was identified as a homolog of fukutin, the defective protein in Fukuyama-type congenital muscular dystrophy (FCMD), that is thought to function as a glycosyltransferase. Mutations in FKRP have been linked to a variety of phenotypes including Walker-Warburg syndrome (WWS), limb girdle muscular dystrophy (LGMD) 2I and congenital muscular dystrophy 1C (MDC1C). Zebrafish are a useful animal model to reveal the mechanism of these diseases caused by mutations in FKRP gene. Downregulating FKRP expression in zebrafish by two different morpholinos resulted in embryos which had developmental defects similar to those observed in human muscular dystrophies associated with mutations in FKRP. The FKRP morphants showed phenotypes involving alterations in somitic structure and muscle fiber organization, as well as defects in developing eye morphology. Additionally, they were found to have a reduction in alpha-dystroglycan glycosylation and a shortened myofiber length. Moreover, co-injection of fish or human FKRP mRNA along with the morpholino restored normal development, alpha-dystroglycan glycosylation and laminin binding activity of alpha-dystroglycan in the morphants. Co-injection of the human FKRP mRNA containing causative mutations found in human patients of WWS, MDC1C and LGMD2I could not restore their phenotypes significantly. Interestingly, these morphant fish having human FKRP mutations showed a wide phenotypic range similar to that seen in humans. PMID:19955119

  17. Zebrafish models for human FKRP muscular dystrophies

    PubMed Central

    Kawahara, Genri; Guyon, Jeffrey R.; Nakamura, Yukio; Kunkel, Louis M.

    2010-01-01

    Various muscular dystrophies are associated with the defective glycosylation of α-dystroglycan and are known to result from mutations in genes encoding glycosyltransferases. Fukutin-related protein (FKRP) was identified as a homolog of fukutin, the defective protein in Fukuyama-type congenital muscular dystrophy (FCMD), that is thought to function as a glycosyltransferase. Mutations in FKRP have been linked to a variety of phenotypes including Walker–Warburg syndrome (WWS), limb girdle muscular dystrophy (LGMD) 2I and congenital muscular dystrophy 1C (MDC1C). Zebrafish are a useful animal model to reveal the mechanism of these diseases caused by mutations in FKRP gene. Downregulating FKRP expression in zebrafish by two different morpholinos resulted in embryos which had developmental defects similar to those observed in human muscular dystrophies associated with mutations in FKRP. The FKRP morphants showed phenotypes involving alterations in somitic structure and muscle fiber organization, as well as defects in developing eye morphology. Additionally, they were found to have a reduction in α-dystroglycan glycosylation and a shortened myofiber length. Moreover, co-injection of fish or human FKRP mRNA along with the morpholino restored normal development, α-dystroglycan glycosylation and laminin binding activity of α-dystroglycan in the morphants. Co-injection of the human FKRP mRNA containing causative mutations found in human patients of WWS, MDC1C and LGMD2I could not restore their phenotypes significantly. Interestingly, these morphant fish having human FKRP mutations showed a wide phenotypic range similar to that seen in humans. PMID:19955119

  18. Muscular dystrophies due to glycosylation defects.

    PubMed

    Muntoni, Francesco; Torelli, Silvia; Brockington, Martin

    2008-10-01

    In the last few years, muscular dystrophies due to reduced glycosylation of alpha-dystroglycan (ADG) have emerged as a common group of conditions, now referred to as dystroglycanopathies. Mutations in six genes (POMT1, POMT2, POMGnT1, Fukutin, FKRP and LARGE) have so far been identified in patients with a dystroglycanopathy. Allelic mutations in each of these genes can result in a wide spectrum of clinical conditions, ranging from severe congenital onset with associated structural brain malformations (Walker Warburg syndrome; muscle-eye-brain disease; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D) to a relatively milder congenital variant with no brain involvement (congenital muscular dystrophy type 1C), and to limb-girdle muscular dystrophy (LGMD) type 2 variants with onset in childhood or adult life (LGMD2I, LGMD2L, and LGMD2N). ADG is a peripheral membrane protein that undergoes multiple and complex glycosylation steps to regulate its ability to effectively interact with extracellular matrix proteins, such as laminin, agrin, and perlecan. Although the precise composition of the glycans present on ADG are not known, it has been demonstrated that the forced overexpression of LARGE, or its paralog LARGE2, is capable of increasing the glycosylation of ADG in normal cells. In addition, its overexpression is capable of restoring dystroglycan glycosylation and laminin binding properties in primary cell cultures of patients affected by different genetically defined dystroglycanopathy variants. These observations suggest that there could be a role for therapeutic strategies to overcome the glycosylation defect in these conditions via the overexpression of LARGE. PMID:19019316

  19. 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

  20. Caveolae and caveolin-3 in muscular dystrophy.

    PubMed

    Galbiati, F; Razani, B; Lisanti, M P

    2001-10-01

    Caveolae are vesicular invaginations of the plasma membrane, and function as 'message centers' for regulating signal transduction events. Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolar membrane domains in skeletal muscle and in the heart. Several mutations within the coding sequence of the human caveolin-3 gene (located at 3p25) have been identified. Mutations that lead to a loss of approximately 95% of caveolin-3 protein expression are responsible for a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans. By contrast, upregulation of the caveolin-3 protein is associated with Duchenne muscular dystrophy (DMD). Thus, tight regulation of caveolin-3 appears essential for maintaining normal muscle health and homeostasis. PMID:11597517

  1. 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

  2. Fuchs endothelial corneal dystrophy: current perspectives

    PubMed Central

    Vedana, Gustavo; Villarreal, Guadalupe; Jun, Albert S

    2016-01-01

    Fuchs endothelial corneal dystrophy (FECD) is the most common corneal dystrophy and frequently results in vision loss. Hallmarks of the disease include loss of corneal endothelial cells and formation of excrescences of Descemet’s membrane. Later stages involve all layers of the cornea. Impairment of endothelial barrier and pump function and cell death from oxidative and unfolded protein stress contribute to disease progression. The genetic basis of FECD includes numerous genes and chromosomal loci, although alterations in the transcription factor 4 gene are associated with the majority of cases. Definitive treatment of FECD is corneal transplantation. In this paper, we highlight advances that have been made in understanding FECD’s clinical features, pathophysiology, and genetics. We also discuss recent advances in endothelial keratoplasty and potential future treatments. PMID:26937169

  3. 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

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

    PubMed

    Kanitkar, Shubhangi A; 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

  5. Myotonic dystrophy protein kinase (DMPK) and its role in the pathogenesis of myotonic dystrophy 1.

    PubMed

    Kaliman, Perla; Llagostera, Esther

    2008-11-01

    Myotonic dystrophy 1 (DM1) is an autosomal, dominant inherited, neuromuscular disorder. The DM1 mutation consists in the expansion of an unstable CTG-repeat in the 3'-untranslated region of a gene encoding DMPK (myotonic dystrophy protein kinase). Clinical expression of DM1 is variable, presenting a progressive muscular dystrophy that affects distal muscles more than proximal and is associated with the inability to relax muscles appropriately (myotonia), cataracts, cardiac arrhythmia, testicular atrophy and insulin resistance. DMPK is a Ser/Thr protein kinase homologous to the p21-activated kinases MRCK and ROCK/rho-kinase/ROK. The most abundant isoform of DMPK is an 80 kDa protein mainly expressed in smooth, skeletal and cardiac muscles. Decreased DMPK protein levels may contribute to the pathology of DM1, as revealed by gene target studies. Here we review current understanding of the structural, functional and pathophysiological characteristics of DMPK. PMID:18583094

  6. 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

  7. 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

  8. Mutational spectrum of Korean patients with corneal dystrophy.

    PubMed

    Chae, H; Kim, M; Kim, Y; Kim, J; Kwon, A; Choi, H; Park, J; Jang, W; Lee, Y S; Park, S H; Kim, M S

    2016-06-01

    Corneal dystrophy typically refers to a group of rare hereditary disorders with a heterogeneous genetic background. A comprehensive molecular genetic analysis was performed to characterize the genetic spectrum of corneal dystrophies in Korean patients. Patients with various corneal dystrophies underwent thorough ophthalmic examination, histopathologic examination, and Sanger sequencing. A total of 120 probands were included, with a mean age of 50 years (SD = 18 years) and 70% were female. A total of 26 mutations in five genes (14 clearly pathogenic and 12 likely pathogenic) were identified in 49 probands (41%). Epithelial-stromal TGFBI dystrophies, macular corneal dystrophy and Schnyder corneal dystrophy (SCD) showed 100% mutation detection rates, while endothelial corneal dystrophies showed lower detection rates of 3%. Twenty six non-duplicate mutations including eight novel mutations were identified and mutations associated with SCD were identified genetically for the first time in this population. This study provides a comprehensive characterization of the genetic aberrations in Korean patients and also highlights the diagnostic value of molecular genetic analysis in corneal dystrophies. PMID:26748743

  9. Consensus statement on standard of care for congenital muscular dystrophies.

    PubMed

    Wang, Ching H; Bonnemann, Carsten G; Rutkowski, Anne; Sejersen, Thomas; Bellini, Jonathan; Battista, Vanessa; Florence, Julaine M; Schara, Ulrike; Schuler, Pamela M; Wahbi, Karim; Aloysius, Annie; Bash, Robert O; Béroud, Christophe; Bertini, Enrico; Bushby, Kate; Cohn, Ronald D; Connolly, Anne M; Deconinck, Nicolas; Desguerre, Isabelle; Eagle, Michelle; Estournet-Mathiaud, Brigitte; Ferreiro, Ana; Fujak, Albert; Goemans, Nathalie; Iannaccone, Susan T; Jouinot, Patricia; Main, Marion; Melacini, Paola; Mueller-Felber, Wolfgang; Muntoni, Francesco; Nelson, Leslie L; Rahbek, Jes; Quijano-Roy, Susana; Sewry, Caroline; Storhaug, Kari; Simonds, Anita; Tseng, Brian; Vajsar, Jiri; Vianello, Andrea; Zeller, Reinhard

    2010-12-01

    Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. Advances in many areas of medical technology have not been adopted in clinical practice. The International Standard of Care Committee for Congenital Muscular Dystrophy was established to identify current care issues, review literature for evidence-based practice, and achieve consensus on care recommendations in 7 areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/ nutrition/speech/oral care, cardiology, and palliative care. To achieve consensus on the care recommendations, 2 separate online surveys were conducted to poll opinions from experts in the field and from congenital muscular dystrophy families. The final consensus was achieved in a 3-day workshop conducted in Brussels, Belgium, in November 2009. This consensus statement describes the care recommendations from this committee. PMID:21078917

  10. Journey into muscular dystrophies caused by abnormal glycosylation.

    PubMed

    Muntoni, Francesco

    2004-09-01

    An increasing number of genes encoding for putative or demonstrated glycosyltransferases are being associated with muscular dystrophies of variable severity, ranging from severe congenital onset and associated structural eye and brain changes, to relatively mild forms with onset into adulthood. Five of these genes (POMT1; POMGnT1; FXRP; Fukutin; LARGE) encode for proteins involved in the glycosylation of alpha-dystroglycan and, indeed, abnormal glycosylation of this molecule is a common finding in all the respective conditions (Walker Warburg syndrome; Muscle-Eye-Brain disease; congenital muscular dystrophy type 1C and Limb girdle muscular dystrophy type 21; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D). A 6th gene, GNE, responsible for the hereditary form of inclusion body myositis, encodes for a glycosyltransferase the substrate(s) of which is, however, still unclear. This article provides an overview of the clinical, biochemical and genetic features of this group of disorders. PMID:15605948

  11. First Identification of a Triple Corneal Dystrophy Association: Keratoconus, Epithelial Basement Membrane Corneal Dystrophy and Fuchs’ Endothelial Corneal Dystrophy

    PubMed Central

    Mazzotta, Cosimo; Traversi, Claudio; Raiskup, Frederik; Rizzo, Caterina Lo; Renieri, Alessandra

    2014-01-01

    Purpose To report the observation of a triple corneal dystrophy association consisting of keratoconus (KC), epithelial basement membrane corneal dystrophy (EBMCD) and Fuchs’ endothelial corneal dystrophy (FECD). Methods A 55-year-old male patient was referred to our cornea service for blurred vision and recurrent foreign body sensation. He reported bilateral recurrent corneal erosions with diurnal visual fluctuations. He underwent corneal biomicroscopy, Scheimpflug tomography, in vivo HRT confocal laser scanning microscopy and genetic testing for TGFBI and ZEB1 mutations using direct DNA sequencing. Results Biomicroscopic examination revealed the presence of subepithelial central and paracentral corneal opacities. The endothelium showed a bilateral flecked appearance, and the posterior corneal curvature suggested a possible concomitant ectatic disorder. Corneal tomography confirmed the presence of a stage II KC in both eyes. In vivo confocal laser scanning microscopy revealed a concomitant bilateral EBMCD with hyperreflective deposits in basal epithelial cells, subbasal Bowman's layer microfolds and ridges with truncated subbasal nerves as pseudodendritic elements. Stromal analysis revealed honeycomb edematous areas, and the endothelium showed a strawberry surface configuration typical of FECD. The genetic analysis resulted negative for TGFBI mutations and positive for a heterozygous mutation in exon 7 of the gene ZEB1. Conclusion This is the first case reported in the literature in which KC, EBMCD and FECD are present in the same patient and associated with ZEB1 gene mutation. The triple association was previously established by means of morphological analysis of the cornea using corneal Scheimpflug tomography and in vivo HRT II confocal laser scanning microscopy. PMID:25408666

  12. Exon skipping therapy for Duchenne muscular dystrophy.

    PubMed

    Kole, Ryszard; Krieg, Arthur M

    2015-06-29

    Duchenne muscular dystrophy (DMD) is caused mostly by internal deletions in the gene for dystrophin, a protein essential for maintaining muscle cell membrane integrity. These deletions abrogate the reading frame and the lack of dystrophin results in progressive muscle deterioration. DMD patients experience progressive loss of ambulation, followed by a need for assisted ventilation, and eventual death in mid-twenties. By the method of exon skipping in dystrophin pre-mRNA the reading frame is restored and the internally deleted but functional dystrophin is produced. Two oligonucleotide drugs that induce desired exon skipping are currently in advanced clinical trials. PMID:25980936

  13. Dynamic thoracoplasty for asphyxiating thoracic dystrophy.

    PubMed

    Kaddoura, I L; Obeid, M Y; Mroueh, S M; Nasser, A A

    2001-11-01

    The life-saving procedures to expand the chests of infants born with Jeune asphyxiating thoracic dystrophy provide a static solution incapable of responding to the growth demands of thriving patients. We describe an instrument that provided a dynamic solution for an infant, where an initial methyl methacrylate midsternotomy spacer placed at 4 months of age was followed at 11 months with recurrence of his difficulties. At 8 months after the second operation the patient was stable and thriving with no recurrence of symptoms. The instrument modifications, limitations, and possible complications are described. PMID:11722089

  14. [Treatment progress of Duchenne Muscular Dystrophy (DMD)].

    PubMed

    Smogorzewska, Elzbieta Monika; Weinberg, Kenneth I

    2004-01-01

    Duchenne muscular dystrophy (DMD) is a common lethal disease for which no effective treatment is currently available. There exists a mouse model of the disease in which the usefulness of gene therapy was established. However, no progress towards human application was made due to the lack of a proper method for gene delivery. During the past several years, researchers acquired data which led them to believe that bone marrow stem cells are capable of generating not only blood cells, but also liver, heart, skin, muscle, and other tissue. Although the term "stem cell plasticity" became very popular, other studies have suggested that bone marrow might contain different types of stem cells that can produce non-hematopoietic cells. For example, mesenchymal stem cell (MSC) in bone marrow give rise to osteocytes, chondrocytes, adipocytes, and skeletal muscle. Recently, researchers have been able to show that transplanted bone marrow cells can contribute to muscle cells in a human patient who was diagnosed with two genetic diseases: severe combined immunodeficiency (SCID) and Duchenne muscular dystrophy. The odds of this happening is estimated at one in seven million. The results of studying this patient's medical history were reported by collaborating researchers at Children's Hospital, Los Angeles and Children's Hospital, Boston in an article titled "Long-term persistence of donor nuclei in a Duchenne muscular dystrophy (DMD) patient receiving bone marrow transplantation" published in the September 2002 issue of the Journal of Clinical Investigation. This patient was transplanted 15 years ago at Children's Hospital Los Angeles with paternal HLA-haploidentical T cell-depleted bone marrow. He engrafted and became a hematopoietic chimera having T and NK lymphocytes of donor origin. Studies performed on the muscle biopsy from the patient 13 years after transplantation demonstrated that the muscle showed evidence of donor derived nuclei. In addition, analysis of his bone marrow

  15. 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

  16. [Fukuyama congenital muscular dystrophy and related alpha-dystroglycanopathies].

    PubMed

    Murakami, Terumi; Nishino, Ichizo

    2008-10-01

    Alpha-dystroglycan (alpha-DG) is a glycoprotein that binds to laminin in the basal lamina and helps provide mechanical support. A group of muscular dystrophies are caused by glycosylation defects of alpha-DG and are hence collectively called alpha-dystroglycanopathy (alpha-DGP). Alpha-DGP is clinically characterized by a combination of muscular dystrophies, structural brain anomalies, and ocular involvement. So far, 6 causative genes have been identified: LARGE, POMGNT1, POMT1, POMT2, FKRP, and FKTN. Initially, alpha-DGP was classified under congenital muscular dystrophies; however, the clinical phenotype is now expanded to include a markedly wide spectrum ranging from the most severe, lethal congenital muscular dystrophy with severe brain deformity to the mildest limb girdle muscular dystrophy with minimal muscle weakness. This is exemplified by Fukuyama congenital muscular dystrophy (FCMD), which is the most prevalent alpha-DGP in Japan, and is caused by mutations in FKTN. FCMD is clinically characterized by a triad of mental retardation, brain deformities, and congenital muscular dystrophy, and a majority of FCMD patients have a homozygous 3-kb retrotransposal insertion in the 3'non-coding region. Typically, they are able to sit but never attain independent ambulation in their lives. Recently, a patient from Turkey harboring homozygous 1-bp insertion reportedly showed a severe brain deformity with hydrocephalus and died 10 days after birth. In contrast, the mildest FKTN phenotype, LGMD2L, was identified in 6 cases from 4 families in Japan. These patients harbored compound heterozygous mutation with 3-kb retrotransposal insertion in the 3'non-coding region and a novel missense mutation in the coding region. Clinically, these patients presented with minimal muscle weakness and dilated cardiomyopathy and had normal intelligence. These data clearly indicate that FKTN mutations can cause a broad spectrum of muscular dystrophies. Therefore, clinicians should always

  17. Myotonic Dystrophy Type 1 or Steinert's disease.

    PubMed

    Romeo, Vincenzo

    2012-01-01

    Myotonic Dystrophy Type 1 (DM1) is the most common worldwide autosomal dominant muscular dystrophy due to polynucleotide [CTG]( n ) triplet expansion located on the 3'UTR of chromosome 19q13.3. A toxic gain-of-function of abnormally stored RNA in the nuclei of affected cells is assumed to be responsible for several clinical features of the disease. It plays a basic role in deregulating RNA binding protein levels and in several mRNA splicing processes of several genes, thus leading to the multisystemic features typical of DM1. In DM1, the musculoskeletal apparatus, heart, brain, eye, endocrine, respiratory and gastroenteric systems are involved with variable levels of severity. DM1 onset can be congenital, juvenile, adult or late. DM1 can be diagnosed on the grounds of clinical presentation (distal muscular atrophy and weakness, grip and percussion myotonia, ptosis, hatchet face, slurred speech, rhinolalia), EMG myotonic pattern, EKG (such as AV-blocks) or routine blood test abnormalities (such as increased CK values or hypogamma-globulinemia) and history of cataract. Its confirmation can come by DNA analysis. At present, only symptomatic therapy is possible and is addressed at correcting hormonal and glycemic balance, removing cataract, preventing respiratory failure and, above all, major cardiac disturbances. Efficacious therapies targeted at the pathogenic mechanism of DM1 are not yet available, while studies that seek to block toxic RNA intranuclear storage with specific molecules are still ongoing. PMID:22411247

  18. 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

  19. Cardiac findings in congenital muscular dystrophies.

    PubMed

    Finsterer, Josef; Ramaciotti, Claudio; Wang, Ching H; Wahbi, Karim; Rosenthal, David; Duboc, Denis; Melacini, Paola

    2010-09-01

    Cardiac involvement (CI) in congenital muscular dystrophies (CMDs) has been only rarely investigated so far. By means of a systematic literature search we reviewed the literature about CI in CMD and found that CI is apparently absent in Ullrich CMD or CMD with integrin deficiency and only mild in Bethlem CMD. CI in merosin deficiency includes dilated cardiomyopathy and systolic dysfunction. CI in dystroglycanopathies seems most prevalent among all CMDs and includes dilated cardiomyopathy, systolic dysfunction, and myocardial fibrosis in Fukuyama CMD. Among the nonspecified dystroglycanopathies, CI manifests as dilated cardiomyopathy, hypertrophic cardiomyopathy (CMP) or systolic dysfunction. With CMD type 1C, as well as with limb-girdle muscular dystrophy 2I, up to half of the patients develop dilated cardiomyopathy. In rigid-spine syndrome, predominantly the right heart is affected secondary to thoracic deformity. In patients who carry LMNA mutations, CI may manifest as dilated cardiomyopathy, hypertrophic cardiomyopathy, or fatal ventricular arrhythmias. Overall, CI in patients with CMD varies considerably between the different CMD types from absent or mild CI to severe cardiac disease, particularly in merosin deficiency, dystroglycanopathies, and laminopathies. Patients with CMD with CI require regular cardiologic surveillance so that severe, treatable cardiac disease is not overlooked. PMID:20679303

  20. [Gene therapy for inherited retinal dystrophies].

    PubMed

    Côco, Monique; Han, Sang Won; Sallum, Juliana Maria Ferraz

    2009-01-01

    The inherited retinal dystrophies comprise a large number of disorders characterized by a slow and progressive retinal degeneration. They are the result of mutations in genes that express in either the photoreceptor cells or the retinal pigment epithelium. The mode of inheritance can be autosomal dominant, autosomal recessive, X linked recessive, digenic or mitochondrial DNA inherited. At the moment, there is no treatment for these conditions and the patients can expect a progressive loss of vision. Accurate genetic counseling and support for rehabilitation are indicated. Research into the molecular and genetic basis of disease is continually expanding and improving the prospects for rational treatments. In this way, gene therapy, defined as the introduction of exogenous genetic material into human cells for therapeutic purposes, may ultimately offer the greatest treatment for the inherited retinal dystrophies. The eye is an attractive target for gene therapy because of its accessibility, immune privilege and translucent media. A number of retinal diseases affecting the eye have known gene defects. Besides, there is a well characterized animal model for many of these conditions. Proposals for clinical trials of gene therapy for inherited retinal degenerations owing to defects in the gene RPE65, have recently received ethical approval and the obtained preliminary results brought large prospects in the improvement on patient's quality of life. PMID:19820803

  1. 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

  2. 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

  3. 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. PMID:26427454

  4. Developments in gene therapy for muscular dystrophy.

    PubMed

    Hartigan-O'Connor, D; Chamberlain, J S

    Gene therapy for muscular dystrophy (MD) presents significant challenges, including the large amount of muscle tissue in the body, the large size of many genes defective in different muscular dystrophies, and the possibility of a host immune response against the therapeutic gene. Overcoming these challenges requires the development and delivery of suitable gene transfer vectors. Encouraging progress has been made in modifying adenovirus (Ad) vectors to reduce immune response and increase capacity. Recently developed gutted Ad vectors can deliver full-length dystrophin cDNA expression vectors to muscle tissue. Using muscle-specific promoters to drive dystrophin expression, a strong immune response has not been observed in mdx mice. Adeno-associated virus (AAV) vectors can deliver small genes to muscle without provocation of a significant immune response, which should allow long-term expression of several MD genes. AAV vectors have also been used to deliver sarcoglycan genes to entire muscle groups. These advances and others reviewed here suggest that barriers to gene therapy for MD are surmountable. PMID:10679969

  5. 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

  6. Bilateral cloudy cornea: is the usual suspect congenital hereditary endothelial dystrophy or stromal dystrophy?

    PubMed

    Acar, Banu Torun; Bozkurt, Kansu Tahir; Duman, Erkan; Acar, Suphi

    2016-01-01

    We provide the diagnosis, treatment and follow-up period of a patient with cloudy cornea in both eyes from birth. A 4-year-old girl presented with blurring in both eyes. Penetrating keratoplasty (PK) was performed with the preliminary diagnosis of congenital hereditary endothelial dystrophy in June 2012. According to the pathology report for extracted host tissue, the Descemet's membrane (DM) and endothelium were healthy and diagnosis was reported to be congenital hereditary stromal dystrophy. Deep anterior lamellar keratoplasty was performed on the left eye. The DM was transparent at follow-up. Cornea transplantation is the only choice to provide visual rehabilitation in children with congenital cloudy cornea. However, it is known that the prognosis of traditional PK in the paediatric age group is not good. Therefore, when using alternative keratoplasty (deep anterior lamellar keratoplasty, Descemet's stripping automated endothelial keratoplasty) options, pathological examination of the host tissue should be made. PMID:27107055

  7. 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

  8. 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

  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