Dysferlinopathy

Clinical characteristics: Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes: Miyoshi muscular dystrophy (MMD) and limb-girdle muscular dystrophy type 2B (LGMD2B); and two minor phenotypes: asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT).

1. MMD (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.

2. 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 in this spectrum are scapuloperoneal syndrome and congenital muscular dystrophy.

3. Asymptomatic hyperCKemia is characterized by marked elevation of serum CK concentration only.

4. DMAT is characterized by early and predominant distal muscle weakness, particularly of the muscles of the anterior compartment of the legs.

Diagnosis/testing: The diagnosis of dysferlinopathy is established in a proband with suggestive findings and biallelic pathogenic variants in DYSF identified by molecular genetic testing.

Management: Treatment of manifestations: There is no approved therapy for dysferlinopathy. Treatment is symptomatic only. Management should be tailored to the individual and the specific subtype. Individualized management may include physical therapy, use of mechanical aids, surgical intervention for orthopedic complications, respiratory aids, and social and emotional support.

Surveillance: Annual monitoring of muscle strength, physical function, activities of daily living, joint range of motion, balance, and respiratory function, and for evidence of cardiomyopathy for individuals with cardiac involvement.

Agents/circumstances to avoid: Weight control to avoid obesity.

Genetic counseling: Dysferlinopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DYSF pathogenic variant, each sib of an affected individual has at conception 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 the DYSF pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.