Facioscapulohumeral muscular dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a common type of adult muscular dystrophy and is divided into types 1 and 2 based on genetic mutation. Clinically, both FSHD types often show asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms followed by the distal then proximal lower extremities. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both types share a common downstream mechanism, making it possible for future disease-directed therapies to be effective for both FSHD types.

Keywords: D4Z4 deletion; DUX4; Facioscapulohumeral muscular dystrophy; Muscular dystrophy; SMCHD1 mutation.

Figure 1

Pathological mechanism in FSHD. In normal individuals the chromatin is tightly wound keeping DUX4 in a repressed state. In FSHD1 deletion of a critical number of D4Z4 repeats opens up the chromatin structure allowing DUX4 to be expressed. However this only occurs when the D4Z4 deletion occurs on a permissive genetic background, the A allele, which contains a polyadenylation sequence which stabilizes the nascent DUX4 transcripts. In FSHD2 patients do not have deletions in the D4Z4 region, but do have decreased methylation, which in approximately 2/3 of patients is associated with mutations in the SMCHD1 gene. Decreased methylation also causes an opening of chromatin structure, and when this occurs on a permissive genetic background containing the A allele, DUX4 can be expressed. In both expression of DUX4 is believed to cause disease in a toxic gain-of-function fashion.