Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Abstract

A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of DUX4, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. DUX4 derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in SMCHD1, a gene involved in chromatin methylation (FSHD2). The resulting expression of DUX4, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting DUX4 expression or blocking 1 or more of several downstream effects of DUX4. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed.

DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

“…Weakness in the orbicularis oris often presents as a mild dimpling in the areas lateral to the angles of the mouth, an inability to whistle, difficulty drinking through a straw, difficulty in puckering of the lips, or everted lips in severe cases. Facial weakness can be absent or mild early in the course of disease and can remain mild for many years later [29,31].…”

Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review

“…FSHD1 is a dominantly inherited disease caused by a genetic defect located in the chromosome 4q35 region, where variable deletions occur on a 3.3 kb tandem repeat (D4Z4) array, which can be visualized by Eco RI/B ln 1 digested DNA fragment on the Southern blotting gel. In general, healthy individuals have 11 to more than 100 copies ( Eco RI 50–300 kb) of D4Z4 repeats, whereas patients with FSHD1 have only ten or fewer D4Z4 repeats (<39 kb) on each copy of 4q35 [ 5 , 8 , 12 ]. Disruption of CpG methylation (hypomethylation), related to contraction of D4Z4 repeats, leads to chromatin relaxation of the 4q35 region, which initiates DUX4 production ( Figure 1 ).…”

“…Interestingly, the inheritance of infantile FSHD is often sporadic, and de novo mutations were more frequent in patients with infantile FSHD than classical FSHD [ 10 , 20 ]. Although positive family history is rare, patients with infantile FSHD obtaining a de novo mutation usually have unaffected carrier parents who carry somatic mosaicism of the mutation [ 12 , 13 ]. FSHD with somatic mosaicism of D4Z4 array lengths is more penetrant in males than in females [ 32 ].…”

The Changed Transcriptome of Muscular Dystrophy and Inflammatory Myopathy: Contributions of Non-Coding RNAs to Muscle Damage and Recovery

“…Facioscapulohumeral muscular dystrophy (FSHD; OMIM 158900) typically presents before age 20 with weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot. Weakness is slowly progressive and of variable severity [3]. Myotonic dystrophy (MD), the most common form of muscular dystrophy that begins in adulthood, is a chronic, slowly progressive, multi-system disease with symptoms including loss of muscle strength and fatigue [4].…”