Muscular Dystrophies

  • Duchenne
    • X-linked disorder typically due to frameshift or nonsense mutations → truncated or absent dystrophin protein (which links actin in cytoskeleton to the transmembrane proteins α and β dystrophiglycans on the extracellular matrix) → progressive myofiber damage. Weakness begins in pelvic girdle muscles and progresses superiorly. Asymmetric weakening of paraspinal muscles leading to kyphoscoliosis. Restrictive pulmonary function due to scoliosis (decreased vital capacity and total lung capacity. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle, with segmental degeneration and regeneration of myofibers with marked variation in size (atrophy and hypertrophy). Waddling gait.
    • Onset before 5 years of age. Wheelchair bound by age 12. Dilated cardiomyopathy is common cause of death.
    • Gower sign—patient uses upper extremities to help stand up. Classically seen in Duchenne muscular dystrophy, but also seen in other muscular dystrophies and inflammatory myopathies (eg, polymyositis).
    • Duchenne = deleted dystrophin
    • Dystrophin gene (DMD) is the largest protein-coding human gene → ↑chance of spontaneous mutation. Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle. It connects the intracellular cytoskeleton (actin) to the transmembrane proteins α- and β-dystroglycan, which are connected to the extracellular matrix (ECM).
    • Loss of dystrophin → myonecrosis.
    • ↑CK and aldolase; genetic testing confirms diagnosis.
  • Becker
    • X-linked disorder typically due to non-frameshift deletions in dystrophin gene (partially functional instead of truncated). Less severe than Duchenne. Onset in adolescence or early adulthood.
    • Deletions can cause both Duchenne and Becker muscular dystrophies. 2⁄3 of cases have large deletions spanning one or more exons.
  • Myotonic type 1
    • Autosomal dominant. CTG trinucleotide repeat expansion in the DMPK gene → abnormal expression of myotonin protein kinase → myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia.
    • Cataracts, Toupee (early balding in men), Gonadal atrophy.

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