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.

Keywords: DUX4; Facioscapulohumeral muscular dystrophy; SMCHD1; biomarker; epigenetic; treatment.

Fig. 1

This figure displays the spectrum of the genetic mechanisms in FSHD. Normal: in healthy individuals, both copies of 4q35 contain 11 to 100 repeats with normal methylation or, rarely, a contraction with hypomethylation on a nonpermissive B allele. In this figure, we display only 1 copy of 4q35 with a permissive A allele, which is necessary to cause FSHD. In FSHD1, 1 copy of the 4q35 is contracted with hypomethylation of the D4Z4 repeat array. In patients with 1 to 6 repeats, the repeat number is associated with disease severity. In patients with 7 to 10 repeats, nonpenetrance is more common and epigenetic factors (such as mutations in SMCHD1) play a larger role. In FSHD2, 1 copy of the 4q35 contains 11 to 20 repeats. A mutation in SMCHD1 or DNMT3B gene is present and D4Z4 repeat arrays are hypomethylated on both 4q35 copies

Fig. 2

This figure demonstrates several different approaches for targeted treatment: modifying epigenetic repression of DUX4, targeting DUX4 mRNA, DUX4 protein, or cellular downstream effects of DUX4 expression