What is FSH (Facioscapulohumeral) muscular dystrophy?

Facioscapulohumeral Muscular Dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common muscular dystrophy, characterized by progressive asymmetric muscle weakness primarily affecting the face, shoulders, and upper arms, with later involvement of trunk and lower extremity muscles. 1, 2

Genetic Basis and Pathophysiology

• FSHD is caused by aberrant expression of the double homeobox protein 4 (DUX4) gene in skeletal muscle, which occurs through two different genetic mechanisms 1, 3:

  • FSHD type 1 (FSHD1): Results from a deletion on chromosome 4q leading to hypomethylation and derepression of DUX4 3
  • FSHD type 2 (FSHD2): Caused by mutations in SMCHD1 with resulting hypomethylation of the same subtelomeric region of chromosome 4q and derepression of DUX4 3

• DUX4 is a transcription factor that, when abnormally expressed in skeletal muscle, dysregulates numerous signaling pathways leading to cytotoxicity 4

Clinical Presentation

• Characteristic pattern of weakness 2, 3:

  • Facial weakness (inability to fully close eyes, smile, whistle, or drink through a straw)
  • Scapular winging and shoulder girdle weakness (difficulty raising arms above shoulder height)
  • Upper arm weakness (biceps and triceps)
  • Progressive involvement of trunk and lower extremity muscles

• Key clinical features 2, 3:

  • Asymmetric muscle involvement (often right/left differences)
  • Descending pattern of weakness (face → shoulders → upper arms → trunk → lower limbs)
  • Preservation of extraocular and bulbar muscles
  • Approximately 20% of patients become wheelchair-dependent 4

• Disease onset and progression 2, 3:

  • Typical onset in adolescence or early adulthood
  • Highly variable disease course and severity, even within families
  • Some patients have mild disease with minimal functional impairment
  • Others experience significant disability with more rapid progression

Extramuscular Manifestations

• Hearing loss (high-frequency sensorineural) 3
• Retinal vascular abnormalities 3
• Cardiac abnormalities (less common than in other muscular dystrophies) 3
• Respiratory insufficiency (in advanced cases) 3

Diagnosis

• Clinical recognition of the characteristic pattern of weakness 2

• Genetic testing to confirm diagnosis 3:

  • For FSHD1: Testing for D4Z4 repeat contraction on chromosome 4q35
  • For FSHD2: Testing for SMCHD1 mutations if FSHD1 testing is negative but clinical suspicion remains high

• Supporting diagnostic tests 3:

  • Creatine kinase (CK) levels: Normal to moderately elevated (typically less than 5× normal)
  • Electromyography: Myopathic changes
  • Muscle MRI: Characteristic pattern of muscle involvement
  • Muscle biopsy: Nonspecific dystrophic changes (rarely performed for diagnosis)

Current Management

• Currently, there is no established disease-modifying treatment for FSHD, with management focused on supportive care and symptom management. 5, 3

• Physical therapy and rehabilitation 3:

  • Tailored exercise programs to maintain strength and function
  • Avoidance of excessive high-resistance training
  • Stretching to prevent contractures

• Orthotic devices 3:

  • Ankle-foot orthoses for foot drop
  • Scapular fixation devices for scapular winging

• Pain management 3:

  • Analgesics for musculoskeletal pain
  • Physical modalities (heat, massage)

• Respiratory assessment and support in advanced cases 3

Emerging Treatments

• Several therapeutic approaches are under investigation 4, 5, 3:

  • Antisense oligonucleotides targeting DUX4 mRNA
  • Gene therapy approaches
  • Small molecule inhibitors of DUX4 expression or activity

• Clinical trials of potential treatments 5:

  • Losmapimod (p38 MAPK inhibitor) has shown promising results in early trials
  • Albuterol demonstrated improvement in elbow flexor strength in three out of four clinical trials
  • Antioxidant combinations (vitamin C, vitamin E, zinc gluconate, and selenomethionine) showed improvement in quadriceps muscle function
  • Diltiazem and MYO-029 (myostatin inhibitor) did not demonstrate significant benefits

Prognosis

• Life expectancy is generally normal 3
• Disease progression is highly variable 2, 3:
  • Some patients have minimal functional impairment throughout life
  • Others experience significant disability requiring mobility aids
  • Approximately 20% become wheelchair-dependent 4

Genetic Counseling

• FSHD is inherited in an autosomal dominant pattern 3
• Genetic counseling is important for affected individuals and families 3
• Prenatal and preimplantation genetic diagnosis are available options 3