Facioscapulohumeral Muscular Dystrophy

FSHD is caused by contraction of the D4Z4 repeat region on chromosome 4q35, which normally has 11-150 repeats. Individuals with fewer than 11 repeats have FSHD1. In FSHD1, the smaller repeat array leads to aberrant chromatin opening and expression of the normally silenced DUX4 gene. DUX4 produces a toxic transcription factor that triggers a cascade of molecular events including oxidative stress, abnormal gene expression, cellular apoptosis, and inflammation. FSHD2 results from mutations in epigenetic regulators like SMCHD1 that affect D4Z4 methylation. Both pathways converge on DUX4 ectopic expression in muscle. FSHD shows distinctive asymmetric weakness pattern, often manifesting first in facial muscles with difficulty smiling or closing eyes completely, followed by shoulder girdle weakness with characteristic scapular winging. Upper arm muscles weaken more than forearms, and lower extremities are affected in 20% of patients with advanced disease. Disease progression is highly variable, with some patients remaining stable for years while others progress rapidly to significant disability. About 20% of FSHD patients become severely disabled, requiring wheelchairs. Pain syndromes are common and can precede weakness. Respiratory involvement is unusual but possible in advanced disease.