Facioscapulohumeral Muscular Dystrophy

Abstract

Facioscapulohumeral Muscular Dystrophy is a common form of muscular dystrophy that presents clinically with progressive weakness of the facial, scapular, and humeral muscles, with later involvement of the trunk and lower extremities. While typically inherited as autosomal dominant, facioscapulohumeral muscular dystrophy (FSHD) has a complex genetic and epigenetic etiology that has only recently been well described. The most prevalent form of the disease, FSHD1, is associated with the contraction of the D4Z4 microsatellite repeat array located on a permissive 4qA chromosome. D4Z4 contraction allows epigenetic derepression of the array, and possibly the surrounding 4q35 region, allowing misexpression of the toxic DUX4 transcription factor encoded within the terminal D4Z4 repeat in skeletal muscles. The less common form of the disease, FSHD2, results from haploinsufficiency of the SMCHD1 gene in individuals carrying a permissive 4qA allele, also leading to the derepression of DUX4, further supporting a central role for DUX4. How DUX4 misexpression contributes to FSHD muscle pathology is a major focus of current investigation. Misexpression of other genes at the 4q35 locus, including FRG1 and FAT1, and unlinked genes, such as SMCHD1, has also been implicated as disease modifiers, leading to several competing disease models. In this review, we describe recent advances in understanding the pathophysiology of FSHD, including the application of MRI as a research and diagnostic tool, the genetic and epigenetic disruptions associated with the disease, and the molecular basis of FSHD. We discuss how these advances are leading to the emergence of new approaches to enable development of FSHD therapeutics. © 2017 American Physiological Society. Compr Physiol 7:1229-1279, 2017.

Digenic Inheritance of Shortened Repeat Units of the D4Z4 Region and a Loss-of-Function Variant in SMCHD1 in a Family With FSHD

“…Facioscapulohumeral muscular dystrophy (FSHD; OMIM #158900 and #158901) is one of the most common adult form of myopathy, with an overall incidence of 1 in 8,300 individuals. FSHD is described as a heterogeneous disorder characterized by progressive weakness of the shoulder girdle, facial, humeral, and, at later stages, of the trunk muscles ( 1 ). The onset of disease can occur at any age, from the infancy to the advanced age.…”

“…In some cases, anticipation of disease symptoms has also been described ( 2 ). Approximately 10% of cases display the first symptoms before age 20 (infantile or early onset forms, namely iFSHD), reporting a severe muscle symptomatology with concomitant hearing loss (often bilateral), eye problems (retinal telangiectasias), and seizures ( 1 , 3 ).…”

“…FSHD is generally transmitted by an autosomal dominant pattern, although reduced penetrance and sporadic cases caused by de novo mutations are often observed ( 1 , 4 ). FSHD is associated with a contraction of a repetitive element, located on a subtelomeric region of chromosome 4 (4q35).…”

“…In presence of FSHD, the D4Z4 repeats are found to be shortened up to 1–10 repeats (short-allele) causing thereby a significant hypomethylation of the distal D4Z4 repeats (which are normally hypermethylated). This condition results in a de-repression of DUX4 in cells and tissues, whose activation causes myofiber death, defects of myogenesis regeneration, and a higher sensitivity to oxidative stress ( 1 ). Furthermore, DUX4 is located in the proximity of a DNA regulatory region named pLAM sequence, that is crucial for the DUX4 protein expression and functioning.…”

“…In fact, a small fraction of FSHD cases (5%) do not carry the short allele in D4Z4 region, which can be present in healthy people as well. Such a variable penetrance is peculiar of FSHD and it is generally associated with different genetic, epigenetic, and environmental factors ( 1 , 6 – 8 ).…”