Facioscapulohumeral muscular dystrophy type 2: an update on the clinical, genetic, and molecular findings

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a common genetic disease of the skeletal muscle with a characteristic pattern of weakness. Facioscapulohumeral muscular dystrophy type 2 (FSHD2) accounts for approximately 5% of all cases of FSHD and describes patients without a D4Z4 repeat contraction on chromosome 4. Phenotypically FSHD2 shows virtually no difference from FSHD1 and both forms of FSHD arise via a common downstream mechanism of epigenetic derepression of the transcription factor DUX4 in skeletal muscle cells. This results in expression of DUX4 and target genes leading to skeletal muscle toxicity. Over the past decade, major progress has been made in our understanding of the genetic and epigenetic architecture that underlies FSHD2 pathogenesis, as well as the clinical manifestations and disease progression. These include the finding that FSHD2 is a digenic disease and that mutations in the genes SMCHD1, DNMT3B, and more recently LRIF1, can cause FSHD2. FSHD2 is complex and it is important that clinicians keep abreast of recent developments; this review aims to serve as an update of the clinical, genetic, and molecular research into this condition.