Progressive Muscular Dystrophies
General Considerations
Definition
Characteristics of progressive muscular dystrophy: (1) myopathy (by clinical, histologic, and EMG criteria); (2) all symptoms are effects of muscle weakness; (3) symptoms become progressively worse; (4) histologic changes imply degeneration and regeneration of muscle, but no abnormal storage of a metabolic product is evident; (5) inheritable condition, even if no other cases identified in a particular family.
Other features: pathophysiologic basis of weakness unknown; no specific therapy exists.
Classification
Based on clinical, genetic characteristics. Three main types (Table 126.1): Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), and myotonic muscular dystrophy (MMD). Fourth category, limb-girdle muscular dystrophy (LGMD) being depleted with improved diagnosis of metabolic, congenital, inflammatory myopathies and refined with discovery of new mutations.
Pathogenesis
Progressive muscular dystrophies result from diverse defects in proteins of different muscle cell compartments.
Investigations
DNA diagnosis available for Duchenne, Becker, facioscapulohumeral, scapuloperoneal, myotonic, and about half of LGMDs.
Table 126.1 Features of the Most Common Muscular Dystrophies | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diagnosis sometimes confirmed by immunohistochemistry or Western blot of muscle tissue, or sequencing white blood cell DNA.
Muscle biopsy: 1) can improve prognostic accuracy in some syndromes; 2) needed for histochemical, electrophoresis of abnormal proteins (such as dystrophin) if no defining mutation found in a limb-girdle syndrome; 3) needed to characterize most congenital, metabolic myopathies.
Serum CK determination, ECG included for all patients with any kind of myopathy.
Specific Conditions
X-Linked Muscular Dystrophies (Duchenne, Becker)
Definitions
Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD).
Mutations in gene for dystrophin at Xp21 (dystrophinopathies). X-linked recessive inheritance (manifest in boys). Carriers (girls and women) may have mild symptoms or high CK.
Prevalence and Incidence
Duchenne: incidence 1 in 3,500 male births; prevalence 1 in 18,000 boys. Becker: one in 20,000.
Pathogenesis
Dystrophin: cytoskeletal protein located at plasma membrane, associated with glycoproteins linking cytoskeleton to plasma membrane.
Mutation in dystrophin gene leads to absence of dystrophin in DMD; smaller size, reduced levels in BMD. Sarcolemma unstable in contraction and relaxation, liable to breakage, excessive influx of calcium, causing muscle necrosis.
Deletions in Xp21 in 66%; point mutations in others. New mutations in 33%.
Specific Features
Duchenne Muscular Dystrophy
See Table 126.1. Proximal weakness with delayed walking, difficulty running, toe-walking, waddling gait. Progression to
overt symptoms before age 5: difficulty walking, climbing stairs, rising from chairs. Exaggerated lordosis, falls, use of arms to push up on rising from ground (Gower sign). Calf hypertrophy. Knee jerks lost before ankle jerks.
overt symptoms before age 5: difficulty walking, climbing stairs, rising from chairs. Exaggerated lordosis, falls, use of arms to push up on rising from ground (Gower sign). Calf hypertrophy. Knee jerks lost before ankle jerks.
Speech, swallowing, ocular movements spared. Wheelchair by age 9 to 12. Scoliosis, contractures at elbows and knees.
Onset of respiratory function decline around age 8. Mechanical ventilation by age 20.
ECG abnormal in most patients. Often cardiomyopathy with congestive heart failure. Mental retardation in 33%.
Other possible manifestations: intestinal hypomotility, acute gastric dilatation; osteoporosis; intellectual impairment.
Anesthetic catastrophes may occur (analogous to malignant hyperthermia): hyperkalemia, extremely high CK levels, acidosis, cardiac failure, hyperthermia, rigidity. Risk decreased by avoiding inhaled general anesthetics, depolarizing muscle relaxants.
Becker Muscular Dystrophy
Two differences from Duchenne: age at onset (usually after age 12); rate of progression slower (walk after age 12, often later). Otherwise syndrome nearly identical.
Intermediate Phenotype
Ambulatory after age 12; wheelchair bound before age 16. Anti-gravity strength in neck flexors preserved longer than typical DMD patients.
Manifesting carriers: DMD X-linked recessive. Women carrying gene show mild limb weakness, calf hypertrophy, cardiomyopathy or high serum CK levels.
Investigations
Serum CK elevated (usually at least 20 times normal). DNA test for Xp21 mutation.
EMG: myopathic pattern.
Dystrophin assay by immunoprecipitation of muscle proteins from biopsy or immunocytochemistry on frozen muscle section.
Diagnosis
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