Facioscapulohumeral muscular dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is caused by a cascade of epigenetic events following contraction of the polymorphic macrosatellite repeat D4Z4 in the subtelomere of chromosome 4q. Currently, the central issue is whether immediate downstream effects are local (i.e. at chromosome 4q) or global (genome-wide) and there is evidence for both scenarios. Currently, there is no therapy for FSHD, mostly because of our lack of understanding of the primary pathogenic process in FSHD muscle. Clinical trials based on suppression of inflammatory reactions or increasing muscle mass by drugs or training have been disappointing. A recent, probably the first evidence-based pilot trial to revert epigenetic changes did also not provide grounds for a larger clinical study. Clearly, better disease models need to be developed to identify and test novel intervention strategies to eventually improve the quality of life for patients with FSHD. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT Clinical featuresPatients usually present with symptoms related to weakness of the scapula-fixators; rarely do they report onset of the disease in the facial, foot-extensor or pelvic girdle muscles. Shoulder Contractures are rare with exception of ankle contractures. A subclinical high tone hearing loss and a subclinical retinal vasculopathy have been described as part of the disease [7,8]. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTRarely, and almost exclusively in early onset disease, they become symptomatic.Early, i.e. infantile, onset has in the past been thought of as an independent entity but has turned out to be the more severe end of the clinical spectrum with usually small residual D4Z4 repeat sizes (see genetic defect), while the other end of the spectrum reveals often minimally to mildly affected patients with probably more frequently non-penetrant gene carriers in these families.The characteristics of FSHD often lie in subtle signs when a physician is confronted with a patient with a facio-scapulo-humeral syndrome. But the rarity of the disorders in the differential diagnosis make that FSHD should be considered first [2]. Genetic diagnostics is recommended as the first step and, only when FSHD has been ruled out, family examination, EMG and muscle biopsy are indicated. become apparent that there are many complications to this relative straightforward diagnosis of FSHD, which we will briefly discuss below. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTFirst, it was shown that an almost identical and equally polymorphic repeat resides in the subtelomere of chromosome 10q as a result of an ancient duplication [19,20]. Repeat contractions on chromosome 10q are non-pathogenic [21,22]. Second, apparent unconstrained exchanges between repeat units on both chromosomes can be encountered in the population and although generally the precise allele constitution for all chromosomes 4 and 10 can be precisely defined, even for the most complicated repeat exchanges, it needs sophisticated In addition t...

Dnmt1 regulates the myogenic lineage specification of muscle stem cells

“…Mutations in DNMT3B have been linked to human ICF syndrome3637, and abnormalities in genomic methylation patterns of DNMT3L has been linked to infertility38. Mutations in DNMT1 have also recently been implicated in neurodegenerative diseases39, while hypomethylation of the A161 allele is associated with the pathogenesis of facioscapulohumeral muscular dystrophy4041. We have shown here that Dnmt1 plays a functional role in myogenesis, and that the Acta1-cre + : Dnmt1 fl/fl mice display a runted, dystrophic-like phenotype.…”

Respiratory pattern in an adult population of dystrophic patients

“…All subjects were at least 18 years old and had a confirmed clinical and molecular diagnosis of LGMD, BMD and FSHD, according to international criteria [10,[20][21][22][23].…”

Large family cohorts of lymphoblastoid cells provide a new cellular model for investigating facioscapulohumeral muscular dystrophy

“…All forms of FSHD are genetically and epigenetically linked to the chromosome 4q35 D4Z4 macrosatellite array, with the interplay between these factors accounting for much of the high variability in disease penetrance and severity characteristic of the disease [1, 6–15]. The predominant form of the disease, FSHD1 (OMIM 158900), represents >95% of reported cases and results from large DNA deletions within the 4q35 D4Z4 repeat array [16, 17].…”