Limb girdle muscular dystrophy
Limb girdle muscular dystrophy (LGMD) is a progressive group of muscular dystrophies characterized by muscle weakness that typically starts in the proximal muscles of the shoulder and pelvic girdle. There are over twenty known subtypes of LGMD, which are classified based on their genetic inheritance patterns—either autosomal dominant or autosomal recessive. The condition is relatively rare, with prevalence estimates ranging from 1 in 14,500 to 1 in 123,000 individuals, and its clinical presentation can vary widely among genetic subtypes and affected individuals.
Diagnosing LGMD can be challenging due to its genetic and clinical variability, often requiring a combination of clinical assessments, laboratory tests, and genetic analysis. While there is currently no cure, treatment focuses on supportive care to enhance quality of life, including monitoring for cardiac and respiratory issues, maintaining muscle strength, and utilizing assistive devices. Research is ongoing into potential therapies, including gene therapy and pharmacological approaches, which aim to address the underlying genetic causes of the disorder. Genetic counseling and prenatal testing options are available for affected families, offering strategies for risk assessment and prevention.
Limb girdle muscular dystrophy
ALSO KNOWN AS: LGMD; severe childhood autosomal recessive muscular dystrophy (SCARMD)
DEFINITION Limb girdle muscular dystrophy (LGMD) is a group of progressive muscular dystrophies that share common clinical features. Currently, there are more than twenty subtypes of LGMD. They are subdivided by inheritance and by the genes involved. All types share symptoms of progressive weakness beginning in the proximal muscles of the shoulder and pelvic girdle.
Risk Factors
Limb girdle muscular dystrophy is both autosomal dominantly and recessively inherited; therefore, risk analysis can widely range depending on family history. Risks of 50 percent can be seen in families with autosomal dominant LGMD. Recessive forms also show increased risks, especially when families are consanguineous or geographically isolated, creating a founder effect. Collective LGMD prevalence is estimated to be from 1 in 14,500 to 1 in 123,000; however, it is difficult to assess, given that each type is relatively rare.
Etiology and Genetics
Currently, LGMD is subdivided by inheritance pattern. As of 2014, a total of thirty-one mutation loci causing LGMD have been identified, of which eight are autosomal dominant and twenty-three autosomal recessive; autosomal dominant LGMDs are designated type 1, while autosomal recessive LGMDs are type 2. Careful analysis of family history can help classify patients as type 1 or type 2. In families with a single affected individual, defining the inheritance pattern remains a challenge. LGMD1 and LGMD2 are further subdivided by the genes in which mutations are identified. A lettering system denoting the order of loci discovery (LGMD1A-H and LGMD2A-W) are further used to characterize patients with LGMD. Therefore, patients diagnosed with LGMD1B have an autosomal dominantly inherited mutation in the Lamin A/C (LMNA) gene. The genes that code for the LGMDs have multiple functions within the cell ranging from enzymes to structural proteins (cytoskeleton and sarcomere), making their functions important in all aspects of muscle pathophysiology.
Symptoms
Most patients with LGMD have symptoms of muscle weakness and/or muscle wasting beginning in the shoulder and pelvic girdles proximally, progressing down the limbs distally. Facial and extraocular muscles are usually spared, while cardiac involvement is seen in some subtypes. Disease onset, disease progression, and distribution of weakness are highly variable between genetic subtypes, between individuals, and within families. Genotype-phenotype correlations are difficult, as several genes show multiple phenotypes. Mutations in Caveolin 3 (LGMD1C) are associated with 5 phenotypes (LGMD, rippling muscle disease, hyperCKemia, familial hypertrophic cardiomyopathy, and distal myopathy).
Screening and Diagnosis
A definitive LGMD diagnosis, especially in sporadic patients, can be extremely difficult as a result of considerable clinical and genetic variability. The diagnosis may be achieved by using a combination of careful clinical evaluation, laboratory testing, and ethnicity. Careful clinical assessment to determine the pattern of weakness, onset of disease, and course severity provide valuble information to direct laboratory testing. Creatine kinase (CK), a muscle enzyme found in blood when muscle is diseased, is usually elevated in patients with LGMD. The level of elevation may help to determine the LGMD subtype. For example, patients diagnosed with LGMD2B (dysferlin gene mutation) have CK values more than one hundred times the normal limit. Notably, patients with other types of LGMD have normal-to-elevated CK levels, even within the same family. Muscle biopsy is another important laboratory test. Histologically, most LGMD patients have general dystrophic changes (degenerating/regenerating fibers, increased connective tissue, fiber size variation) making it impossible to glean subtype. Biopsy tissue can also be used for immunostaining or western blotting to look for specific muscle proteins. Genetic testing is the final step in determining the definitive LGMD diagnosis. By using the aforementioned studies, genetic testing options should be narrowed to prevent analysis of more than seventeen genes, which is expensive, laborious, and not always clinically available.
Treatment and Therapy
Currently, disease management is solely supportive use to increase survival and quality of life. Supportive therapies include monitoring heart and respiratory complications, maintaining muscle mass and strength, and use of assistive devices. Therapies that can slow, reverse, and restore the progressive effects of LGMD have been sought since the 1980s. Research is now focused on gene, cell-based, and pharmacological therapies.
Gene therapy, replacing a mutated gene with a functioning gene, has been successful in several animal models; human clinical trials focusing on LGMD2C and LGMD2D have had promising results, but both treatments are still in an early stage of development. Alternatively, pharmacological strategies are able to circumvent many limitations seen in gene and cell-based therapies. Corticosteroids have been shown to increase muscle mass, although the mechanism of action is poorly understood. Due to the large number of side effects with minimal benefit, this treatment is controversial for LGMD. Other pharmacologic approaches include agents designed to overcome premature stop codons, upregulate homologs of LGMD proteins causing a functional substitution, and increase muscle mass by inhibiting negative or enhancing positive regulators of muscle growth (such as myostatin-negative regulator). Given the promising animal models, one can anticipate potential for human trials.
Prevention and Outcomes
Genetic counseling, prenatal diagnosis, and preimplantation genetic diagnosis (PGD) are available to affected or at-risk family members for prevention of LGMD. Prenatal diagnosis and PGD are options in families and individuals when a molecular diagnosis has been determined. Genetic counseling is available for recurrence risk analysis with or without a molecular diagnosis.
Bibliography
Herson, Serge, et al. "A Phase I Trial of Adeno-Associated Virus Serotype 1-Gamma-Sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C." Brain 135.2 (2012): 483–92. Print.
Jones, R., Jr., D. Devivo, and B. Darras. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Philadelphia: Elsevier Science, 2003.
"Limb-Girdle Muscular Dystrophy." Genetics Home Reference. Natl. Lib. of Medicine, Apr. 2011. Web. 31 July 2014.
"Limb-Girdle Muscular Dystrophy (LGMD)." Cleveland Clinic, 12 Dec. 2023, my.clevelandclinic.org/health/diseases/limb-girdle-muscular-dystrophy-lgmd. Accessed 10 Sept. 2024.
"Limb-Girdle Muscular Dystrophy." Medline Plus, 1 Sept. 2019, medlineplus.gov/genetics/condition/limb-girdle-muscular-dystrophy/. Accessed 10 Sept. 2024.
Nigro, Vincenzo, and Marco Savarese. "Genetic Basis of Limb-Girdle Muscular Dystrophies: The 2014 Update." Acta Myologica 33.1 (2014): 1–12. Print.