Limb-Girdle Muscular Dystrophy

LGMD is a group of disorders caused by a variety of gene mutations (e.g., CAPN3, DYSF, SGC, TPNO3) that encode proteins responsible for muscle function and repair (e.g., Calpain-3, dysferlin, sarcoyglycan). These gene mutations cause a deficiency in proteins required for healthy muscle development. There are two major forms of muscular dystrophy: LGMD1 and LGMD2, and they are classified based on inheritance patterns. LGMD1 is inherited in an autosomal dominant pattern, meaning only one mutated allele is required to cause disease. LGMD2 is inherited in an autosomal recessive pattern, meaning two mutated alleles are required to cause disease. In recent years nomenclature has been established, many subtypes have been discovered, and nomenclature has changed. Thus, LGMD1 may sometimes be referred to as LGMD D (dominant) and LGMD2 as LGMD R (recessive). 

Autosomal recessive forms of LGMD are more common than autosomal dominant forms. The autosomal recessive forms are more commonly diagnosed in childhood, whereas the autosomal dominant forms are more likely to occur in the later decades of life. Additionally, the autosomal dominant form progresses at a slower rate.

Diagnosis of LGMD begins with a thorough review of symptoms, medical history, and family history. Since LGMD is inherited, a thorough family history can help determine whether the individual has the autosomal recessive or autosomal dominant form. A focused neuro-musculoskeletal exam helps determine specific patterns of weakness and areas of muscle atrophy. A laboratory blood test evaluating serum creatine kinase (CK) levels can also support the diagnosis of LGMD. Creatine kinase is an intracellular enzyme that is present in skeletal muscle, myocardium (i.e., heart muscle), and the brain. When it is present in the serum, it suggests that there is muscle damage. Creatine kinase elevations are typically much higher in autosomal recessive types of LGMD compared to their autosomal dominant counterparts. 

Electromyography, which is a test that measures the electrical activity of muscles in response to nerve stimulation, can also be performed. Electromyography (EMG) may reveal myopathic changes with small polyphasic potentials in LGMD. In rare instances where there is cardiac involvement, further specialized testing which includes an electrocardiogram (EKG) and echocardiogram (ECHO) can be performed to evaluate the heart’s electrical conductivity and structural integrity, respectively.  

The diagnosis is confirmed when there is clinical suspicion for LGMD and when molecular testing via DNA sequencing identifies a pathogenic variant that is implicated in LGMD. If a genetic test is unequivocal, then a muscle biopsy of the affected tissue can provide a histopathologic diagnosis. Pathology often reveals dystrophic changes with degeneration and regeneration of muscle fibers, the presence of fibrosis, and a whorled appearance of muscle fibers. 

Treatment of LGMD consists of supportive care measures aimed at improving the individual’s quality of life. A multidisciplinary treatment team consisting of physical and occupational therapists, cardiologists, orthopedics, neurologists, and geneticists can help ensure individuals receive comprehensive care. Referral to a physical and occupational therapist can help individuals increase mobility and maintain their functional status. A treatment plan may consist of stretching exercises to help prevent contractures from immobility. If there is cardiac involvement, a referral to a cardiologist can be helpful in co-managing cardiac-related symptoms (e.g., heart failure, shortness of breath).  

Currently, there are no Food and Drug Administration (FDA) approved treatments, therefore, participation in a clinical trial is an option. Gene replacement therapies (i.e., treatments that aim to replace the missing/deficient gene) yield promise but the safety and efficacy of these treatments are still under investigation. Genetic testing and counseling can be offered to individuals and their families to understand the risk of passing the gene to future offspring.  The prognosis of LGMD differs depending on the specific subtype, but most subtypes present with a slow, progressive, clinical course.