Limb-Girdle Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics: Limb-girdle muscular dystrophy (LGMD) is a purely descriptive term, generally reserved for childhood- or adult-onset muscular dystrophies that are distinct from the much more common X-linked dystrophinopathies. LGMDs are typically nonsyndromic, with clinical involvement typically limited to skeletal muscle. Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal, and muscle degeneration/regeneration on muscle biopsy. Most individuals with LGMD show relative sparing of the bulbar muscles, although exceptions occur, depending on the genetic subtype. Onset, progression, and distribution of the weakness and wasting vary considerably among individuals and genetic subtypes.

Diagnosis/testing: The limb-girdle muscular dystrophies typically show degeneration/regeneration (dystrophic changes) on muscle biopsy, which is usually associated with elevated serum creatine kinase concentration. For any male or female suspected of having limb-girdle muscular dystrophy, it is necessary to first rule out an X-linked dystrophinopathy. Biochemical testing (i.e., protein testing by immunostaining or immunblotting) performed on a muscle biopsy can establish the diagnosis of the following LGMD types: sarcoglycanopathy, calpainopathy, dysferlinopathy, and O-linked glycosylation defects (also known as dystroglycanopathy). In some cases, demonstration of complete or partial deficiencies for any particular protein can then be followed by mutation studies of the corresponding gene. Pathogenic variants in a number of genes have been associated with types of LGMD.

Genetic counseling: The term LGMD1 (including, e.g., LGMD1A, LGMD1B) refers to genetic types showing dominant inheritance, whereas LGMD2 refers to types with autosomal recessive inheritance. Pathogenic variants at more than 50 loci have been reported, making accurate diagnosis and genetic counseling a challenge. In most instances, the proband represents a simplex case, and the families can be counseled for recurrence risks associated with rare autosomal recessive conditions, which leaves a "significant" risk only for the sibs of the proband. If the causative pathogenic variant(s) have been identified in the family, prenatal testing for pregnancies at increased risk is possible.

Management: No definitive treatments for the limb-girdle muscular dystrophies exist. Management should be tailored as much as possible to each individual and each specific LGMD type. Management to prolong survival and improve quality of life includes weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and prevent contractures, use of mechanical aids to help ambulation and mobility, surgical intervention for orthopedic complications, use of respiratory aids when indicated, monitoring for cardiomyopathy in LGMD types with cardiac involvement, and social and emotional support and stimulation.