Limb-girdle muscular dystrophy (LGMD) is a descriptive term applied to a clinically and genetically heterogeneous group of childhood- or adult-onset muscular dystrophies. LGMD is characterized by weakness and wasting restricted to the limb musculature, proximal greater than distal. Most individuals with LGMD show relative sparing of the heart and 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. Serum creatine kinase (CK) levels in individuals with LGMD are usually elevated, and muscle biopsy reveals dystrophic changes. Immunohistochemistry (IHC) testing of a muscle biopsy sample can be used to determine the presence or absence of specific proteins, and confirmatory genetic testing is available in some cases. LGMDs are distinct from the much more common X-linked dystrophinopathies, which include Duchenne and Becker muscular dystrophy (DMD/BMD).
LGMD 2A, also referred to as calpainopathy, is likely the most frequent form of LGMD, although there are geographic differences in frequency. Average age of onset is 8-15 years of age. Onset usually occurs in the lower extremities with proximal weakness, followed by weakness in the upper extremities some years later. Other features include scapular winging, difficulties running and walking, toe walking, waddling gait, slight hyperlordosis, and muscle atrophy with only rare hypertrophy. There is no cardiac involvement. LGMD 2A is slowly and steadily progressive, with loss of ambulation occurring approximately 20 years after onset. Intra- and interfamilial variability has been observed. Serum CK levels can be normal but are often 5-80 times normal and calpain-3 is usually, but not always, absent by IHC. Secondary deficiency of calpain-3 can also be seen in several other muscular dystrophies. LGMD 2A is inherited in an autosomal recessive manner.
Mutations in the CAPN3 gene (15q15.1-q21.1) cause LGMD 2A.
For patients with suspected LGMD 2A, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.
- Bonnemann, C. Limb-girdle muscular dystrophy in childhood. Pediatric Annals. 2005; 34(7):569-577.
- GeneTests: Calpainopathy: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=lgmd2a.
- GeneTests: Limb-Girdle Muscular Dystrophy Overview: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=lgmd-overview.
- Guglieri, M. et al. Limb-girdle muscular dystrophies. Curr Opin Neurol. 2008; 21:576-584.
This test is indicated for:
- Confirmation of a clinical diagnosis of LGMD 2A in individuals who have tested negative for sequence analysis
- Carrier testing in adults with a family history of LGMD 2A who have tested negative for sequence analysis
DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.
Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations. Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.
Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.
- Sequence analysis of the CAPN3 gene is available and is required before deletion/duplication analysis.
- Sequence and deletion/duplication analysis panels are available for 11 LGMD genes.
- Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.