Limb-Girdle Muscular Dystrophy (LGMD) Type 2A: CAPN3 Gene Deletion/Duplication

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Condition Description

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.

Visit www.ThinkGenetic.com for patient-friendly information on limb-girdle muscular dystrophy.

References:

  • 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.

Genes (1)

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Indications

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

Methodology

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.



Please note that a "backbone" of probes across the entire genome are included on the array for analytical and quality control purposes. Rarely, off-target copy number variants causative of disease may be identified that may or may not be related to the patient's phenotype. Only known pathogenic off-target copy number variants will be reported. Off-target copy number variants of unknown clinical significance will not be reported.

Detection

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.

Specimen Requirements

Submit only 1 of the following specimen types

Preferred specimen type: Whole Blood

Type: Whole Blood

Specimen Requirements:

In EDTA (purple top) or ACD (yellow top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva

Specimen Requirements:

OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

Special Instructions

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 Emory Genetics Laboratory, 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.

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