Duchenne Muscular Dystrophy and Genetics

Skeletal Muscle Pathology

Muscular Dystrophies

• Muscular dystrophies are a group of inherited muscle disorders leading to progressive weakness and muscle wasting.
• Characterized by muscle fiber necrosis and regeneration.
• Three types: Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Myotonic Dystrophy.

Duchenne Muscular Dystrophy

• Etiology: X-linked, loss-of-function mutation of a structural protein called dystrophin.
• Epidemiology: 1 in 5,000 male births.
• Clinical Features:
  • Normal at birth, but early motor milestones are met, and walking is often delayed.
  • Clumsiness and inability to keep up with peers are the first indications of muscle weakness.
  • Weakness begins in pelvic girdle muscles and extends to shoulder girdle.
  • (+) Gower's sign: patients often have to push off the thighs to stand from sitting.
  • Pseudohypertrophy of lower leg.
  • Cognitive impairment and learning disability are common.
• Prognosis:
  • Eventual progression to wheelchair dependence (average age ~9.5 years).
  • Patients develop joint contractures, scoliosis, worsening respiratory reserve, and sleep hypoventilation.
  • Development of cardiomyopathies and arrhythmias can occur in older patients.
  • Mean age of death: 25-30 years of age (commonly from respiratory insufficiency, pulmonary infection, or heart failure).

Becker Muscular Dystrophy

• Etiology: X-linked mutation in dystrophin.
• Epidemiology: 1 in 30,000 male births.
• Clinical Features:
  • Onset later in childhood, adolescence, or adulthood.
  • Generally similar to Duchenne Muscular Dystrophy but less severe and with slower progression.
  • Patients are still at risk of developing dilated cardiomyopathy, but this is very rare.
• Prognosis: Near-normal life expectancy.

Myotonic Dystrophy

• Etiology: Autosomal dominant disorder caused by expansion of triplet repeats.
• Epidemiology: Affects 1 in 8,000 individuals.
• Pathogenesis: Not well understood, but may result from a "toxic" gain-of-function effect by the CGT triplet repeat expansion.
• Clinical Features:
  • Onset begins in adolescence or young adulthood.
  • Type I: Myotonia, weakness, and wasting of peripheral muscles and facial muscles.
  • Can also include: cardiomyopathy, intellectual disability, cataracts, and endocrine disorders.

Statin Myopathy

• Etiology: Caused by the cholesterol-lowering "statin" drugs.
• Pathogenesis: Blocking the rate-limiting step of cholesterol synthesis.

Myasthenia Gravis

• Etiology: Autoimmune condition associated with autoantibodies directed against acetylcholine receptors.
• Epidemiology: Prevalence of 150-200 per 1 million.
• Pathogenesis: Ab-Ach receptor complexes lead to a variety of problems, ultimately limiting the ability of the myofiber to respond to Ach at the neuromuscular junction.
• Clinical Features:
  • Fluctuating proximal muscle weakness.
  • Ptosis and diplopia are common initial findings.
  • Proximal muscle involvement, including diaphragm, neck, and facial muscles.
  • Weakness is usually worse with activity/exercise and improves with rest.
• Diagnosis & Treatment:
  • Diagnosis based on clinical history, physical exam findings, (+) antibody screen, and electrophysiologic studies.
  • Prognosis has improved significantly with current therapies.
  • Complications can include pneumonia, falls, and myasthenic crisis.

Skeletal Muscle Tumours

• Rhabdomyosarcoma:
  • Malignant mesenchymal tumour with skeletal muscle differentiation.
  • 4 subtypes: Alveolar, Embryonal, Pleomorphic, Spindle cell/sclerosis.
  • Epidemiology: Alveolar and embryonal rhabdomyosarcoma are the most common soft tissue sarcoma of childhood.
  • Etiology: Chromosomal translocations commonly found, typically involving transcription factor involved in skeletal muscle differentiation.
• Synovial Cell Sarcoma:
  • Most common soft tissue tumour in adolescents and young adults.
  • Epidemiology: 5-10% of all soft tissue sarcomas.
  • Etiology: Chromosomal translocation has been found in >90% of cases.

Fibromyalgia

• Epidemiology: Can occur in patients of either sex or any age, but most commonly presents in young-adult to middle-aged females.
• Etiology & Pathogenesis: Not known, but considered a neurosensory disorder characterized by abnormalities in pain processing by the CNS.
• Diagnostic Criteria:
  • Widespread pain index (WPI) and self-administered patient questionnaire.
  • Diagnosis is based on WPI and a score of 13 or greater on the polysymptomatic distress scale.

Chronic Fatigue Syndrome

• Epidemiology: Not specified.
• Etiology & Pathogenesis: Not specified.
• Clinical Features: Not specified.
• Diagnostic Criteria: Not specified.

Duchenne Muscular Dystrophy

• Pathology:
  • Muscle biopsy shows variable muscle fiber size, clusters of regenerating muscle fibers, and slight endomysial fibrosis
  • Muscle fascicular architecture is initially preserved but becomes abnormal over time with muscle remodeling
• Clinical Features:
  • Normal at birth, but early motor milestones are met, and walking is often delayed
  • Clumsiness and inability to keep up with peers are first indications of muscle weakness
  • Weakness begins in pelvic girdle muscles and extends to shoulder girdle
  • (+) Gower's sign: patient often has to push off the thighs to stand from sitting
  • Pseudohypertrophy of lower leg
  • Cognitive impairment and learning disability are common
• Prognosis:
  • Eventual progression to wheelchair dependence at an average age of 9.5 years
  • Development of joint contractures, scoliosis, worsening respiratory reserve, and sleep hypoventilation
  • Development of cardiomyopathies and arrhythmias can occur in older patients due to the impact of dystrophin on cardiac muscle
  • Mean age of death is 25-30 years old, commonly due to respiratory insufficiency, pulmonary infection, or heart failure

Becker Muscular Dystrophy

• Etiology:
  • X-linked mutation in dystrophin, resulting in a truncated dystrophin protein that retains partial function
  • Milder phenotype than Duchenne muscular dystrophy with a later age of onset
• Epidemiology:
  • Less common than Duchenne muscular dystrophy, with an incidence of 1 in 30,000 live male births
• Clinical Features:
  • Onset later in childhood, adolescence, or adulthood
  • Generally similar to Duchenne muscular dystrophy but with a slower progression
  • Patients are still at risk of developing dilated cardiomyopathy, but this is rare compared to Duchenne muscular dystrophy
• Prognosis:
  • Near-normal life expectancy

Myotonic Dystrophy

• Etiology:
  • Autosomal dominant disorder caused by expansion of triplet repeats
  • Type 1: expansion of CGT trinucleotide repeat within the myotonic dystrophy protein kinase (DMPK) gene
  • Type 2: CCTG repeat expansion within the gene nucleic acid-binding protein (CNBP) gene
• Epidemiology:
  • Affects 1 in 8,000 individuals
• Pathogenesis:
  • Not well understood, but type 1 may result in a "toxic" gain-of-function effect by the CGT triplet repeat expansion, disrupting splicing of mRNA transcripts of other proteins, including the transcript of a chloride channel (CLC1)
  • Lack of CLC1 may explain myotonia
• Clinical Features:
  • Onset begins in adolescence or young adulthood
  • Type 1:
    • Myotonia, weakness, and wasting of peripheral muscles and facial muscles
    • Can also include cardiomyopathy, intellectual disability, cataracts, and endocrine disorders
  • Type 2:
    • CNBP gene codes for a zinc-finger DNA-binding protein

Myasthenia Gravis

• Etiology:
  • Autoimmune condition associated with autoantibodies directed against acetylcholine receptors
  • Strong association between anti-Ach receptor autoantibodies and thymic abnormalities (thymoma or thymic hyperplasia)
• Epidemiology:
  • Prevalence of 150-200 per 1 million
  • In young adults, more commonly found in females, and in older adults, more commonly found in males
• Pathogenesis and Pathophysiology:
  • Autoantibodies against the post-synaptic acetylcholine receptors (nicotinic receptors)
  • Ab-Ach receptor complexes lead to a variety of problems, ultimately limiting the ability of the myofiber to respond to Ach at the neuromuscular junction
• Clinical Features:
  • Fluctuating proximal muscle weakness
  • Ptosis and diplopia are common initial findings
  • Proximal muscle involvement, including diaphragm, neck, and facial muscles
  • Weakness is usually worse with activity/exercise and improves with rest
• Diagnosis and Treatment:
  • Based on clinical history, physical exam findings, (+) antibody screen, and electrophysiologic studies
  • Prognosis has improved significantly with current therapies
  • Complications can include pneumonia, falls, and myasthenic crisis
  • Treatment includes acetylcholinesterase inhibitors, plasmapheresis, and immunosuppressive drugs, and thymectomy for patients with a thymoma

Skeletal Muscle Tumors

• Nearly all skeletal muscle tumors are malignant
  • Occur in younger patients, usually with an onset before age 20
• Rhabdomyosarcoma:
  • Malignant mesenchymal tumor with skeletal muscle differentiation
  • 4 subtypes: Alveolar, Embryonal, Pleomorphic, and Spindle cell/sclerosis
  • Epidemiology:
    • Alveolar and embryonal rhabdomyosarcoma are the most common soft tissue sarcoma of childhood
    • Incidence of 6/1,000,000/year in children under 15 years
  • Etiology:
    • Chromosomal translocations commonly found, typically involving transcription factor (PAX) involved in skeletal muscle differentiation
  • Clinical Features:
    • Tumor is detected as a mass, sometimes painful, and metastases tend to cause respiratory difficulties, bone pain, and bone marrow failure
    • Tumors can occur anywhere in the body, including head and neck, extremities, and genitourinary tract
  • Treatment and Prognosis:
    • Tumors are aggressive, with a poor survival rate in older children/adults and those with metastatic disease
    • Younger children with localized disease have a survival rate of about 80% 5 years after diagnosis
• Synovial Cell Sarcoma:
  • Epidemiology:
    • Most common soft tissue tumor in adolescents and young adults
    • Represents 5-10% of all soft tissue sarcomas
    • Incidence: 2.75 per 100,000
  • Etiology:
    • Chromosomal translocation has been found in >90% of cases (fusion of SYT and SSX genes)
    • Origin and pathophysiology are unclear
  • Clinical Features:
    • Usually, a history of a long-standing nodule
    • Present for years, then increases rapidly in size over a few months
    • Tumor spreads along fascial planes, much more widespread than apparent on initial evaluation
    • Mass is often painless and deep
    • Usually situated around the knee, hands, and feet

Fibromyalgia

• Syndrome of persistent widespread pain, stiffness, fatigue, disrupted sleep, and cognitive difficulties
  • Often accompanied by anxiety/depression and impairment of activities of daily living
• Epidemiology:
  • Can occur in patients of either sex or any age, but most commonly presents in young-adult to middle-aged females
• Etiology and Pathogenesis:
  • Unknown
  • Now considered a neurosensory disorder characterized by abnormalities in pain processing by the CNS
  • Considered a central sensitivity syndrome
• Diagnostic Criteria:
  • Diagnosis is based on widespread pain index (WPI) and self-administered patient questionnaire
  • Widespread pain index – score of 0-19
  • Self-administered patient questionnaire – score of 0-12
  • WPI/Section 1 is combined with total points for sections 2 & 3 to yield a score out of 0-31 (Polysymptomatic distress scale)
  • A score of 13 or greater, with symptoms being present at a similar level or severity for at least 3 months, and not explained by another disorder, is diagnostic of fibromyalgia

Test your knowledge of Duchenne Muscular Dystrophy, its causes, characteristics, and diagnosis. Learn about the effects of mutations in the dystrophin gene and the role of X-chromosome inactivation in female carriers.