Progressive muscular dystrophies

Muscular dystrophies are a group of progressive diseases that affect the musculoskeletal system. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive diseases, whereas limb-girdle muscular dystrophy (LGMD) may be either autosomal dominant or recessive, and facioscapulohumeral dystrophy (FSHD) is usually autosomal dominant. Muscular dystrophies are commonly due to mutations involving muscular genes (e.g., dystrophin-protein coding gene). Patients typically present with muscular complaints affecting specific muscle groups, particularly the pelvic girdle musculature. DMD is the most severe form of muscular dystrophy, with disease onset typically occurring at two to three years of age. BMD usually does not become evident before the age of 15. DMD progresses rapidly and typically leads to ambulatory inability by age 12. Diagnosis of DMD and BMD is established based on blood tests that show increased creatine kinase, whereas diagnosis of LGMD and FSHD is mainly based on genetic analysis. Treatment of muscular dystrophies is usually supportive and includes physiotherapy, assistive devices (e.g., wheelchair), and psychological support. The life expectancy for patients with DMD is approx. 30 years, whereas patients with BMD and LGMD have a longer life expectancy.

• Incidence
  • DMD: 1/3500
  • BMD: 1/30,000
• Sex: : only male individuals affected in DMD and BMD
• Age of onset
  • DMD: 2–5 years
  • BMD: adolescence or early adulthood, usually > 15 years

References:^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

• Inheritance pattern (DMD and BMD): X-linked recessive
• Chromosomal mutations affecting the dystrophin gene on the short arm of the X chromosome (Xp21)
  • DMD: frameshift deletion or nonsense mutation → shortened or absent dystrophin protein
  • BMD: in-frame deletion → partially functional dystrophin protein
  • In about two-thirds of DMD or BMD cases, deleted segments are as large as one or more exons.

References:^[1]

• Dystrophin protein: anchors the cytoskeleton of skeletal and cardiac muscle cells to the extracellular matrix by connecting cytoskeletal actin filaments to membrane-bound α- and β-dystroglycan, which are connected to extracellular laminin
• Dystrophin gene: largest known protein-coding gene in the human DNA
  • Because of its size, the dystrophin gene is at increased risk for spontaneous mutations.
  • Mutations affecting the dystrophin gene→ alterations of dystrophin protein structure → partial (BMD) or almost complete (DMD) impairment of protein function → disturbance of numerous cellular signaling pathways → necrosis of affected muscle cells → replacement with connective tissue and fatty tissue → affected muscles are weak even though they appear larger (“pseudohypertrophy”)
  • Errors in splicing in the DMD gene can also cause DMD. ^[3]

Duchenne is caused by Deleted Dystrophin.

Duchenne muscular dystrophy (DMD)

• Progressive muscle paresis and atrophy
  • Starts in the proximal lower limbs (pelvic girdle)
  • Extends to the upper body and distal limbs as the disease progresses
• Weak reflexes
• Waddling gait (i.e., Duchenne limp) with bilateral Trendelenburg sign
• Gower maneuver
  • The individual arrives at a standing position by supporting themselves on their thighs and then using the hands to “walk up” the body until they are upright.
  • Classic sign of DMD, but also occurs in inflammatory myopathies (e.g., dermatomyositis, polymyositis) and other muscular dystrophies (e.g., BMD)
• Calf pseudohypertrophy (see pathophysiology above)
• Scoliosis
• Inability to walk by approx. 12 years of age
• Cardiac and respiratory muscle involvement
  • Dilated cardiomyopathy: common cause of death
  • Cardiac arrhythmias
  • Respiratory insufficiency
• Cognitive impairment
• In late stages: nocturnal hypoventilation, dysphagia, vomit, diarrhea, and constipation; rarely intestinal pseudo-obstruction

Becker muscular dystrophy (BMD)

• Symptoms similar to those of DMD, but less severe
• Slower progression (patients often remain ambulatory into adult life)
• Heart involvement is more common compared to DMD.

“Becker is Better.”

• Blood tests
  • ↑↑ Creatine kinase in serum of almost all affected individuals (also, in > 50% of female carriers)
  • ↑ Serum aldolase
• Genetic analysis (confirmatory test): detect dystrophin gene mutation
• Muscle biopsy
  • Only performed if genetic analysis is inconclusive
  • Findings
    • Throughout the disease course: Muscle fiber diameter changes
    • Later in the disease course: necrosis of muscle tissue and replacement with connective and adipose tissue
    • DMD: absent dystrophin
    • BMD: reduced dystrophin

Facioscapulohumeral muscular dystrophy (FSHD) ^[4]

• Definition: a complex genetic disorder characterized by progressive muscle weakness of the face, scapula, upper arm
• Etiology
  • Inheritance: autosomal dominant (70–90%) or sporadic
  • Deletion of D4Z4 repeat units, each of which contains a copy of a double homeobox protein 4 gene (DUX4), in the 4q35 region
• Epidemiology: the third most common type of muscular dystrophy
• Clinical features
  • Progressive muscle weakness
    • Onset usually in childhood and adolescence
    • Asymmetrical involvement
    • Affects the face, scapula, and upper arms
    • Less commonly, the girdle and/or lower leg can be involved
  • Extramuscular manifestations: retinal vasculopathy, hearing loss
• Diagnosis: genetic testing to detect the D4Z4 short repeat array

Limb-girdle muscular dystrophy (LGMD) ^[5]

• Definition: a genetic disorder characterized by progressive muscle weakness that primarily affects the pelvic and shoulder girdle
• Etiology
  • Inheritance: either autosomal dominant (LGMD1) or autosomal recessive (LGMD2)
  • Many different mutations (e.g., in the calpain-3 gene).
• Epidemiology
  • Fourth most common muscular dystrophy (after dystrophinopaties, myotonic dystrophy, and FSHD)
  • Affects both sexes equally
• Clinical features
  • Onset in childhood or adolescence (LGMD 1 can also present in late adulthood)
  • Paresis and subsequent atrophy of the pelvic and shoulder girdle muscles
  • Normal intellect and absent distal muscle weakness
• Diagnosis
  • Elevated CK
  • Muscle biopsy shows a decrease in protease calpain 3
  • Genetic analysis to detect the underlying mutation

Other

• Polymyositis
• Spinal muscular atrophy
• Myotonic syndromes

The differential diagnoses listed here are not exhaustive.

Medical therapy

• DMD
  • Glucocorticoids (e.g., prednisone, deflazacort)
  • Eteplirsen ^[6]
    • An antisense oligonucleotide that binds to exon 51 of the dystrophin RNA prior to splicing, which leads to skipping of this exon
    • Results in production of truncated but functional dystrophin protein
    • Can only be used in individuals with mutations within exon 51 of the dystrophin gene
• BMD: Glucocorticoids may be used, although their efficacy is low.

Supportive therapy

• Physiotherapy to reinforce preserved muscles (including respiratory muscles training) and to prevent contractures
• Orthopedic assistive devices (wheelchair, walkers)
• Psychological support
• Ventilation support
• If necessary, surgical treatment of the contractures, correction of scoliosis

• DMD
  • Life expectancy is approx. 30 years.
  • Cardiac or respiratory failure is usually the cause of death.
• BMD
  • Life expectancy is 40–50 years.
  • Cardiac failure is typically responsible for the reduced life expectancy.