Categories
Gene

PMP22

Hereditary Neuropathy with Liability to Pressure Palsies

Familial Recurrent Polyneuropathy; Tomaculous Neuropathy

It is the responsibility of the ordering physician to ensure that informed consent has been obtained from the patient/legal guardian before ordering genetic testing. Please review the following Pre-Test Counselling Information with your patient before requesting any of our genetic tests.

Clinical Features

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop, typically with a family history consistent with autosomal dominant inheritance. Prolonged distal nerve conduction latencies is found on electrophysiologic studies of all individuals, symptomatic or not.

Genetics

In the majority of cases (80%), HNPP is caused a 1.5 Mb contiguous gene deletion at 17p11.2, which includes the PMP22 gene. In the remaining 20%, the condition is caused by a point mutation in the PMP22 gene. Inheritance is autosomal dominant, although 20% of cases arise due to de novo mutations.

Indications for Testing

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

Description of this Assay

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.

Sensitivity and Limitations

This test only detects PMP22 gene deletions and duplications (PMP22 gene duplications cause Charcot-Marie-Tooth type 1A). Since 20% of patients with HNPP have the condition due to a point mutation in the gene, a negative result does not exclude the diagnosis of HNPP. In cases where the clinical suspicion is high, consideration may be given to PMP22 gene sequencing in an out of province laboratory. Please see our Out of Province Testing Protocol for further information.

Turnaround Time

Routine

6 weeks

Specimen Requirements

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). 

Test Price and Billing

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.

Cautions

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.