What is Facioscapulohumeral (FSHD) muscular dystrophy?

Facioscapulohumeral Muscular Dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular disorder worldwide, characterized by progressive, asymmetric muscle weakness that typically begins in the face, shoulders, and upper arms before spreading to the trunk and lower extremities. 1

Clinical Presentation

• FSHD presents with slowly progressive asymmetric muscle weakness primarily affecting the facial, scapular, and upper arm muscles, though the name can be misleading as it often involves trunk and leg muscles as well 2
• Facial weakness manifests as difficulty whistling, drinking through a straw, or fully closing the eyes 2
• Shoulder girdle weakness presents as scapular winging, difficulty raising arms overhead, and clavicular flattening 3
• Disease progression is highly variable - approximately 20% of patients eventually become wheelchair-bound 1
• Extramuscular manifestations may occur in some patients, including hearing loss and retinal abnormalities 1

Genetic Basis

• FSHD is predominantly an autosomal dominant disorder linked to chromosome 4q35 (designated FSHD1A) 4
• The condition is caused by aberrant expression of the double homeobox protein 4 (DUX4) gene in skeletal muscle 1
• In FSHD1A (95% of cases), the disease is associated with a deletion of D4Z4 tandem repeats, resulting in an EcoRI fragment smaller than 35kb (normal range: 50-300kb) 4
• Approximately 5-10% of FSHD families have a form unlinked to 4q35 (designated FSHD1B), demonstrating genetic heterogeneity 3, 4
• The severity and age of onset correlate with the size of the deletion at the 4q35 locus - larger deletions typically result in earlier onset and more severe disease 4

Diagnosis

• Clinical diagnosis is based on the characteristic pattern of muscle weakness:
  • Facial weakness (inability to fully close eyes, whistle, or smile) 2
  • Scapular winging and shoulder girdle weakness 3
  • Asymmetric muscle involvement 2
• Confirmation is through genetic testing looking for D4Z4 repeat contractions on chromosome 4q35 4
• Muscle biopsy shows myopathic changes without inflammatory or mitochondrial pathology 3
• Electromyography typically shows myopathic patterns 2

Disease Progression and Prognosis

• FSHD has a highly variable disease course - some patients have mild symptoms while others experience significant disability 2
• The condition is slowly progressive, with most patients remaining ambulatory throughout their lives, though approximately 20% eventually require wheelchairs 1
• Respiratory complications are less common than in other muscular dystrophies but can occur in advanced disease 5
• Life expectancy is generally not significantly reduced, though quality of life may be substantially impacted 2

Management Approaches

• Currently, there is no established consensus on disease-modifying treatments for FSHD 5
• Management focuses on symptomatic treatment and rehabilitation:
  • Physical therapy to maintain muscle strength and prevent contractures 6
  • Submaximal and aerobic exercise is recommended over excessive resistive exercise 6
  • Gentle strengthening within physiological limits to avoid overexertion 6
  • Functional training focusing on activities that enhance self-care skills and mobility 6

Emerging Treatments

• Several medications have been investigated in clinical trials:
  • Albuterol showed statistically significant improvement in elbow flexor muscle strength in three out of four clinical trials 5
  • Vitamin C, vitamin E, zinc gluconate, and selenomethionine demonstrated significant improvement in quadriceps muscle function 5
  • Diltiazem and MYO-029 showed no significant improvement in function, strength, or muscle mass 5
• Genetic approaches targeting DUX4 expression using oligonucleotide and genome editing technologies are under development 1
• Losmapimod, currently in clinical trials, has shown promising preliminary results 5

Common Pitfalls in Management

• Excessive resistive and eccentric exercise can worsen muscle damage 6
• Overwork weakness can lead to further deterioration of muscle function 6
• Mild or early FSHD can be difficult to recognize, leading to diagnostic delays 2
• Inadequate monitoring of cardiorespiratory response during exercise can be harmful 6

FSHD represents a significant clinical challenge due to its variable presentation and progression. Early recognition of the characteristic pattern of muscle weakness can facilitate prompt diagnosis and appropriate management to maintain function and quality of life.