Clinical characteristics: Dysferlinopathy includes a spectrum of muscle disease characterized by two main phenotypes: Miyoshi myopathy with primarily distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B) with primarily proximal weakness. Miyoshi myopathy (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes are scapuloperoneal syndrome, distal myopathy with anterior tibial onset, elevated serum CK concentration only, and congenital muscular dystrophy.
Diagnosis/testing: Diagnosis depends on a combination of muscle biopsy and molecular genetic testing. Muscle biopsy western immunoblotting almost always indicates a primary dysferlinopathy. DYSF, which encodes the protein dysferlin, is the only gene in which pathogenic variants are known to cause dysferlinopathy.
Management: Treatment of manifestations: Individualized management may include physical therapy, use of mechanical aids, surgical intervention for orthopedic complications, respiratory aids, and social and emotional support. Prevention of secondary complications: Stretching exercises to prevent contractures. Surveillance: Annual monitoring of muscle strength, joint range of motion, and respiratory function; and for evidence of cardiomyopathy for subtypes with cardiac involvement. Agents/circumstances to avoid: Weight control to avoid obesity; avoidance of steroid treatment.
Genetic counseling: Dysferlinopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
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