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LGMD Type 2A Screening

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Condition Description Indications
Detection Special Instructions

 

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.  Average age of onset is 8-15 years.
  • 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 usually occurs in the lower extremities with proximal weakness, followed by weakness in the upper extremities some years later.
  • LGMD type 2A is inherited in an autosomal recessive manner and also referred to as calpainopathy. This is likely the most frequent form of LGMD.
  • LGMD 2A is caused by mutation in the gene encoding for calpain-3 resulting in total or partial loss of protein.
  • Serum creatine kinase (CK) levels in individuals with LGMD are usually elevated and muscle biopsy reveals dystrophic changes.
  • 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.
  • Agarwal community from Indian origin has shown two founder mutations in caplain gene.

Gene & Mutation

Mutations in CAPN3 gene (15q15.1-q21.1) cause LGMD 2A (intron18/exon19 & exon 22) commonly known as Agarwal founder mutation responsible to cause LGMD 2A.

Indications
This test is indicated for:
  • Confirmation of a clinical diagnosis of LGMD 2A based on two founder mutations.

  • Carrier testing in adults with a family history of LGMD 2A and First-degree relatives of patients with genetically confirmed mutation desirous of counseling.

  • Patient with LGMD phenotype, like raised creatine kinase (CK) and electromyography suggestive of myopathy.

Methodology

Sanger Sequencing:  Two most significant target regions are amplified on the patient’s genomic DNA using polymerase chain reaction and subjected to bi-directional direct DNA Sanger sequencing for mutation detection.

Detection

  • Screening of CAPN3 based on two founder pathogenic mutations.
  • Results of molecular analysis should be interpreted in the context of the patient's biochemical /phenotype.
  • For patients with suspected LGMD 2A, are recommended for founder mutation screening as the first step. For patients in whom mutations are not identified are suggested to go for full gene and/or deletion/duplication analysis by next generation sequencing.

Specimen Requirements

Type: EDTA Whole Blood;  Infants (2 years): 1-2 ml Blood;  Children & Adults: 5-10 ml Blood.

Special Instructions

  • Submit patients consent form along with the samples.
  • Biochemical diagnostic test results, if available.
  • Refrigerate until time of shipment. Ship the sample at 4-80C with overnight delivery

  • TAT applicable from the date of receipt of sample @ECGI