FSHD2

FSHD2, or facioscapulohumeral muscular dystrophy type 2, is a form of FSHD caused by mutations in the SMCHD1 gene that lead to reduced epigenetic silencing of the D4Z4 macrosatellite on chromosome 4q35. Unlike FSHD1, which results from contraction of the D4Z4 repeats, FSHD2 typically involves normal or near-normal D4Z4 repeat lengths but increased expression of the toxic DUX4 gene due to hypomethylation of D4Z4.

Genetics and inheritance in FSHD2 are autosomal dominant with variable penetrance. SMCHD1 mutations can be inherited or arise de novo. A permissive 4qA haplotype, which provides a functional polyadenylation signal for DUX4, is usually required for disease manifestation. The combination of SMCHD1 dysfunction, D4Z4 hypomethylation, and a 4qA haplotype allows DUX4 to be expressed in muscle cells, driving pathogenic effects.

Clinically, FSHD2 resembles FSHD1, with facial weakness and scapulohumeral weakness often progressing to affect shoulder girdle and pelvic muscles. Onset is typically in adolescence or adulthood, with considerable variability in severity and progression.

Diagnosis uses a combination of clinical features and genetic testing: SMCHD1 sequencing to identify pathogenic variants, assessment of D4Z4 methylation, and analysis of 4q35 haplotypes. D4Z4 repeat length alone is not sufficient for FSHD2 diagnosis.

Management is supportive and multidisciplinary, focusing on physical therapy, orthopedic care, respiratory support when needed, and genetic counseling. Research continues into the epigenetic mechanisms and potential therapies targeting DUX4 expression. FSHD2 accounts for a minority of FSHD cases, with estimates around a subset of affected families.

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