Hereditary Motor and Sensory Neuropathy 1A

Charcot-Marie-Tooth disease is a chronic motor and/or sensory neuropathy typically characterized by distal muscle weakness, sensory loss, and pes cavus deformity. Charcot-Marie-Tooth Type 1A (CMT1A) accounts for ~75% of Charcot-Marie-Tooth type 1 (CMT1), and CMT1 accounts for nearly half of all Charcot-Marie-Tooth disease.

CMT1A is caused by an 1.5 Mb duplication in 17p11.2, which results in the inheritance of three copies of the PMP22 gene. Inheritance is autosomal dominant; 20 – 33% of cases are due to de novo duplications. Rare cases of homozygous duplications (resulting in a total of four copies of PMP22) have been described and, in general, manifest a more severe phenotype than the typical three-copy cases.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of CMT1.
2. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):
   1. Pregnancies to couples in which one person has confirmed CMT1A .
3. Presymptomatic testing
   1. Adults at risk of inheriting CMT1A from a parent may be referred for presymptomatic testing for CMT1A.
   2. Requests to test asymptomatic children who are at risk of developing CMT1A are only accepted following genetic counselling by a recognized genetic service.

Multiplex ligation-dependent probe amplification (MLPA) analysis is carried out with the P033-B2 probe mix (MRC-Holland) to determine the gene dosage (i.e. number of copies) of the PMP22 gene. Note: This assay will detect both CMT1A and HNPP.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: NOT ACCEPTED

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., point mutations in the coding region, promoter mutations, and regulatory element mutations). In rare cases, a point mutation could be detected.

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.