FSHD1

FSHD1, or facioscapulohumeral muscular dystrophy type 1, is the most common form of FSHD. It typically presents with weakness of facial and scapular stabilizers, followed by proximal arm and foot dorsiflexion weakness. The onset is usually during adolescence or early adulthood, and progression is variable. Muscle wasting and scapular winging are common, and mild to moderate disability can occur over years.

The disease is caused by contraction of the D4Z4 macrosatellite repeat array on chromosome 4q35. In FSHD1, the repeat array is shortened to about 1–10 units on a permissive 4qA haplotype, which allows aberrant expression of the DUX4 gene in skeletal muscle. The pathogenesis involves epigenetic changes that derepress DUX4 expression. Normal individuals have 11–100 D4Z4 repeats on 4q35 and do not express DUX4 in muscle. The 4qA haplotype provides a functional polyadenylation signal necessary for pathogenic DUX4 mRNA.

Inheritance is autosomal dominant with incomplete penetrance; de novo cases occur. A positive test for FSHD1 requires both shortened D4Z4 repeats and a permissive 4qA haplotype, whereas a non-permissive 4qB haplotype does not cause disease despite contraction. FSHD2, a overlapping but distinct form, involves SMCHD1 variants leading to similar epigenetic derepression but without the characteristic D4Z4 contraction.

Diagnosis combines clinical assessment with molecular testing to measure D4Z4 repeat length and determine haplotype. Management is supportive and multidisciplinary, including physical and occupational therapy, braces or devices to aid mobility, and monitoring for respiratory or cardiac involvement. Genetic counseling is recommended due to autosomal dominant inheritance and variable expression.