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Limb-Girdle Muscular Dystrophy, Genetic Testing

Limb-girdle muscular dystrophy (LGMD) refers to a group of inherited neuromuscular disorders characterized by weakness and wasting of the muscles, particularly those around the hips and shoulders (limb-girdle muscles). There are several subtypes of LGMD, each associated with specific genetic mutations. The prevalence of LGMD is estimated to be between 2 and 10 cases per 100.000 individuals.

Limb-girdle muscular dystrophy genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Critical features of Limb-Girdle Muscular Dystrophy include:

  • Proximal Muscle Weakness: The hallmark feature of LGMD is weakness in the proximal muscles, which are the muscles around the shoulders and hips. This weakness can lead to difficulty with activities such as standing up from a seated position, climbing stairs, and raising the arms overhead.
  • Progressive Muscle Wasting: Over time, affected individuals may experience progressive muscle wasting, leading to a loss of muscle mass.
  • Variable Age of Onset: The age of onset and the rate of disease progression can vary widely among different subtypes of LGMD. Symptoms may appear in childhood, adolescence, or adulthood.
  • Distribution of Weakness: While the weakness typically starts in the limb-girdle muscles, it can later extend to affect muscles in other body parts.
  • Elevated Creatine Kinase (CK) Levels: Blood tests may reveal elevated creatine kinase (CK) levels, an enzyme released into the bloodstream when muscles are damaged.
  • Genetic Heterogeneity: LGMD is genetically heterogeneous, meaning it can result from gene mutations. To date, multiple genes associated with different subtypes of LGMD have been identified.
  • Autosomal Recessive and Dominant Inheritance: The inheritance pattern of LGMD can be autosomal recessive or autosomal dominant, depending on the specific subtype. In autosomal recessive cases, individuals inherit two mutated copies of the responsible gene (one from each parent). In contrast, in autosomal dominant cases, a single copy of the mutated gene is sufficient to cause the condition.
  • Cardiac Involvement: Some subtypes of LGMD may involve the heart muscles, leading to cardiomyopathy and other cardiac complications.

There are more than 30 subtypes of LGMD, each associated with a specific genetic cause. Genetic testing is essential for diagnosing the specific subtype and guiding management and treatment decisions. While there is currently no cure for LGMD, management involves supportive care, physical therapy, and in some cases, medications to address specific symptoms.

Due to LGMD's heterogeneity, individuals with the condition may benefit from a multidisciplinary approach involving neurologists, physical therapists, and other healthcare professionals. Genetic counseling is important for affected individuals and their families to understand the inheritance pattern and assess the risk of having affected children.

More Information

To date, 5 autosomal dominant and 26 autosomal recessive limb-girdle dystrophy subtypes have been identified. We analyze pathogenic variants in subtypes 2A, 2D, 2E, and 2I. For these four subtypes of autosomal recessive limb-girdle dystrophies, cases of compound heterozygotes, i.e., individuals presenting two different pathogenic variants in the same gene, have been described.

Some of these dystrophies occur in the genes coding for sarcoglycans and dystroglycans or other molecules interacting with these proteins, which are especially abundant in muscle cells. Sarcoglycans and dystroglycans are essential for maintaining stable plasma membrane and extracellular matrix binding in skeletal and cardiac muscle tissue cells.

Limb-girdle muscular dystrophy subtype 2A or type 1 is caused by pathogenic variants in the gene coding for the enzyme calpain-3 (CAPN3). The c.550del variant is the most common in European populations.

Limb-girdle muscular dystrophy subtype 2D or R3 is a progressive genetic myopathy caused by mutations in the human alpha-sarcoglycan gene (SGCA). The c.229C>T variant produces an altered protein that does not reach its correct cellular location in the plasma membrane.

Limb-girdle muscular dystrophy subtype 2E or R4 is an autosomal recessive inherited form of the disease caused by mutations in the beta-sarcoglycan gene (SGCB). The most frequent pathogenic variant identified in patients with subtype 2E or R4 is c.341C>T. It is suggested that this variant may affect the intracellular trafficking of sarcoglycans. The c.452C>G variant is characteristic of the Amish population and leads to a drastic reduction in the expression of the SGCB gene encoding for sarcoglycan beta.

Limb-girdle muscular dystrophy subtype 2I, C5 or R9, is caused by pathogenic variants of the FKRP gene coding for the fukutin protein involved in dystroglycan processing. The c.826C>A variant in FKRP reduces alpha-dystroglycan expression in skeletal muscle. Cases have been described that may present early with a Duchenne-like phenotype (including cardiomyopathy) to cases of patients with milder symptoms and with a more favorable long-term prognosis.

Limb-girdle muscular dystrophy genetic testing analyzes the 30 most frequent pathogenic mutations of the CAPN3 gene, the 5 most frequent pathogenic mutations of the FKRP gene, the 7 most frequent pathogenic mutations of the SGCA gene, and the 2 most frequent pathogenic mutations of the SGCB gene.

The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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