FSHD

FSHD, or facioscapulohumeral muscular dystrophy, is the most common inherited muscular dystrophy of adulthood. It comprises two genetic forms, FSHD1 and FSHD2, both marked by progressive weakness of facial and shoulder girdle muscles with variable involvement of other muscle groups.

FSHD1 is caused by contraction of a repeated 4q35 D4Z4 segment on the chromosome to 1–10 units in individuals with a permissive 4qA haplotype. This contraction leads to aberrant expression of the DUX4 gene in skeletal muscle, triggering degeneration. FSHD2 results from mutations in SMCHD1 (and rarely DNMT3B) that cause hypomethylation of 4q35 and enable DUX4 expression even without a shortened D4Z4 array. Both forms involve a pathogenic mechanism focused on DUX4-driven muscle damage. Inheritance is autosomal dominant with variable penetrance; de novo cases occur.

Clinical features typically begin in adolescence or early adulthood but can appear later. Early signs include weakness of facial muscles (affecting eye closure and smiling) and scapulohumeral muscle weakness leading to scapular winging and difficulty lifting the arms. Distal leg weakness and foot drop may develop later. Disease progression is usually slow and highly variable, with many individuals maintaining ambulation for decades and others experiencing more rapid decline.

Diagnosis relies on clinical assessment supported by genetic testing. Testing differentiates FSHD1 (D4Z4 contraction with a permissive haplotype) from FSHD2 (SMCHD1 or DNMT3B involvement with permissive haplotype). Muscle MRI and electromyography can aid assessment.

Management is supportive; there is no cure. Multidisciplinary care includes physical and occupational therapy to maintain strength and prevent contractures, respiratory support if needed, bracing or surgical stabilization for scoliosis or scapular winging, and pain management. Genetic counseling is important, given dominant inheritance. Research focuses on therapies to suppress DUX4 expression and protect muscle from its toxic effects.