Population-based incidence and prevalence of facioscapulohumeral dystrophy

Deenen, J.C.W.; Arnts, Hisse; Maarel, Silvère M. van der; Padberg, George W.; Verschuuren, Jan J.; Bakker, Egbert; Weinreich, S.; Verbeek, A.L.M.; Engelen, B.G.M. van

doi:10.1212/wnl.0000000000000797

Cited by 299 publications

(244 citation statements)

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“…Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders (Padberg et al 1995;Mostacciuolo et al 2009;Deenen et al 2014), yet the molecular mechanisms causing FSHD are unclear. FSHD is an autosomal dominant myopathy associated with a variable age of onset (Padberg et al 1995;Pastorello et al 2012).…”

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confidence: 99%

“…FSHD symptoms appear during adolescence, with 95% of the individuals carrying the genetic defect affected by the age of 20 (Pastorello et al 2012;Deenen et al 2014). Although the underlying genetic alteration is present at birth, additional factors or epigenetic changes may trigger disease onset and participate in disease variability and penetrance.…”

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confidence: 99%

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SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

et al. 2015

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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.

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confidence: 99%

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

et al. 2015

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“…Facioscapulohumeral muscular dystrophy (FSHD, OMIM #158900) is one of the most common hereditary muscular disorders, with a reported prevalence of 3.2-4.6 per 100,000 [1][2][3]. It is commonly defined as an asymmetric, descending and progressive disorder, initially affecting the face, shoulder, and arm muscles followed by the distal lower extremities and pelvic girdle [4].…”

Section: Introductionmentioning

confidence: 99%

Long-term follow-up of MRI changes in thigh muscles of patients with facioscapulohumeral dystrophy: a quantitative study

Salort‐Campana

Fatehi

Troter

et al. 2017

Neuromuscular Disorders

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Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary muscular disorders. Currently FSHD has no known effective treatment and detailed data on the natural history are lacking. Determination of the efficacy of a given therapeutic approach might be difficult in FSHD given the slow and highly variable disease progression. Magnetic resonance imaging (MRI) has been widely used to qualitatively and quantitatively evaluate in vivo the muscle alterations in various neuromuscular disorders. The main aim of the present study was to investigate longitudinally the time-dependent changes occurring in thigh muscles of FSHD patients using quantitative MRI and to assess the potential relationships with the clinical findings. Thirty-five FSHD1 patients (17 females) were enrolled. Clinical assessment tools including manual muscle testing using medical research council score (MRC), and motor function measure (MFM) were recorded each year for a period ranging from 1 to 2 years. For the MRI measurements, we used a new quantitative index, i.e., the mean pixel intensity (MPI) calculated from the pixel-intensity distribution in T1 weighted images. The corresponding MPI scores were calculated for each thigh, for each compartment and for both thighs totally (MPI total ). The total mean pixel intensity (MPI total ) refers to the sum of each pixel signal intensity divided by the corresponding number of pixels. An increased MPI total indicates both a raised fat infiltration together with a reduced muscle volume thereby illustrating disease progression. Clinical scores did not change significantly over time whereas MPI total increased significantly from an initial averaged value of 39.6 to 41.1 with a corresponding rate of 0.62/year. While clinical scores and MPI total measured at the start of the study were significantly related, no correlation was found between the rate of MPI total and MRC sum score changes, MFM total and MFM subscores. MPI total change was 2.3% (0.5-4.3)/year and was significantly higher than the corresponding rates measured for MRCS 0% (0-1.7) /year and MFM total 0% (0-2.0) /year (p = 0.000).On the basis of these results, we suggested that muscle MRI and more particularly the MPI total index could be used as a reliable biomarker and outcome measure of disease progression. In slowly progressive myopathies such as FSHD, the MPI total index might reveal subclinical changes, which could not be evidenced using clinical scales over a short period of time.

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“…While there are a dozen forms of muscular dystrophy, FSHD is the third most common muscular dystrophy after Duchenne muscular dystrophy (DMD) and myotonic dystrophy, affecting approximately 1 in 8,000 -20,000 individuals (2,3). However, since an individual can remain asymptomatic or exhibit mild symptoms, the frequency of FSHD occurrence could be underestimated.…”

Section: Introductionmentioning

confidence: 99%