Chapter 216.1

#### Abstract

1. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies in adults. FSHD has an incidence of approximately 1 in 8,000 individuals, although there is geographic variability. The first symptoms typically arise in the second decade of age, although onset at early childhood has been reported.

2. FSHD is characterized by progressive and asymmetric muscle weakness in a specific subset of muscles. It sequentially affects the facial mimic and shoulder girdle muscles, followed by the foot extensors and the abdominal and hip-girdle muscles. Approximately 25% of patients require the use of a wheelchair. Extra-muscular manifestations including retinal vasculopathy, sensorineural hearing loss, cardiac involvement, and respiratory defects have been reported in FSHD, but these pathologies have high variability and are mostly described in severely affected patients.

3. At the histological level, no specific myopathic alterations are associated with FSHD. Muscle biopsies display variable myopathic changes that do not correlate with the general degree of muscle pathology. Increased variability in fiber size is detected as well as an increased number of centrally nucleated fibers. Necrosis and inflammatory infiltrate are commonly found in muscle biopsies.

4. FSHD1, which accounts for 95% of FSHD cases, is associated with a reduction in the number of D4Z4 macrosatellite repeats located in the subtelomeric region of chromosome 4 (4q35). In healthy subjects, the D4Z4 array contains from 11 to as many as 100 units, whereas FSHD1 patients carry only 1 to 10 repeats.

5. FSHD2 patients do not show a contraction of the D4Z4 array but are clinically identical to FSHD1 patients. A subset of FSHD2 patients harbors mutations at the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain-containing 1) gene, which encodes a protein involved in chromatin compaction and DNA methylation at CpG islands.

6. In FSHD patients, the 4q35 locus undergoes a deregulation of its epigenetic status. In healthy subjects, the D4Z4 array shows high levels of DNA methylation and enrichment for repressive histone modifications. In FSHD, the region is hypomethylated and displays a reduction in heterochromatic histone modifications. This epigenetic deregulation is associated with higher-order chromatin reorganization and the transcription of the activating chromatin-associated long non-coding RNA (lncRNA) DBE-T. DBE-T triggers the aberrant expression of several 4q35 protein-coding genes, including ANT1, FRG1, FRG2 and DUX4.

7. DUX4, FRG1, and FAT1 are believed to be the main candidate genes for FSHD. DUX4 is encoded by the last D4Z4 unit. It is a transcription factor that is normally expressed in the germ line but silenced in somatic tissues. DUX4 expression in somatic cells leads to the activation of germline and developmentally associated genes and to apoptosis. FRG1 is located 120 kb proximally to the D4Z4 array and encodes a highly evolutionarily conserved protein. FRG1 is ubiquitously expressed in somatic tissues, but its overexpression in skeletal muscle leads to muscle stem cell defects and muscular dystrophy.FAT1 encodes a protocadherin that is downregulated in FSHD. Fat1 hypomorphic mice display muscle and extra-muscular defects that are reminiscent of ...

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