Highmark Commercial Medical Policy - Pennsylvania
Medical Policy: L-151-006
Topic: Charcot-Marie-Tooth Neuropathy Testing Panel
Section: Laboratory
Effective Date: July 1, 2018
Issue Date: July 2, 2018
Last Reviewed: March 2018

Charcot-Marie-Tooth neuropathy (CMT) is a group of inherited genetic conditions characterized by chronic motor and sensory polyneuropathy. Onset is typically before 30 years of age. The key finding in CMT is symmetric, slowly progressive distal motor neuropathy (feet and/or hands). This is expressed as distal muscle weakness/wasting and atrophy with sensory loss, depressed reflexes and foot deformities (including pes cavus and hammer toes). Molecular genetic testing can be used to establish a specific diagnosis, which aids in understanding the prognosis and risk assessment for family members. CMT is the most common inherited neurological disorder. The prevalence of all CMT types is 1 in 3,300.

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

Known Familial Mutation Analysis may be considered medically necessary when the following criteria are met:

Procedure Codes
81325 , 81403 , 81404 , 81405 , 81406 , 81479


PMP22 Deletion/Duplication Analysis may be considered medically necessary when the following criteria are met:

Procedure Codes
81324, 81479


CMT Neuropathy Multigene Panel may be considered medically necessary when the following criteria are met:

Procedure Codes
81448

Professional Statements and Societal Positions


  • Evidence-based guidelines from the American Academy of Neurology (2009) recommend testing for CMT, but with a tiered approach:


    • "Genetic testing should be conducted for the accurate diagnosis and classification of hereditary neuropathies." (level A recommendation = "established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population"). 

    •  "Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype. Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening." (level C recommendation = possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population").

    • "There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype." (level U recommendation = "data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven").


  • Comprehensive CMT panels test most known genes related to CMT simultaneously, but this is not usually necessary or cost-effective, and therefore not recommended.

  • DiVincenzo et al. [2014] described their experience testing more than 17,000 patients for CMT using a commercially available comprehensive panel of 14 genes. Overall, they identified a mutation in 18.5% of patients. Notably they state that “Among patients with a positive genetic finding in a CMT-related gene, 94.9% were positive in one of four genes ( PMP22 , GJB1 , MPZ , or MFN2 ). The results of our study in a population in over 17,000 individuals support the initial genetic testing of four genes ( PMP22 , GJB1 , MPZ , and MFN2 ) followed by an evaluation of rarer genetic causes in the diagnostic evaluation of CMT.”

  • In an expert-authored review, the following genetic testing strategies are recommended:


    • “In families with at least two-generation involvement, known male-to-male transmission, and very slow NCVs (<15 m/sec):”


      • “First, obtain testing for the PMP22 duplication (CMT1A).”

      • “If normal, follow with testing of MPZ (CMT1B) and single-nucleotide variants in PMP2 (CMT1E).”

      • “If both are normal, test for LITAF (CMT1C) and EGR2 (CMT1D).”


    • “In families with at least two-generation involvement and slow NCVs (15-35 m/sec), but without male-to-male transmission, molecular genetic testing of PMP22 (CMT1A), GJB1 (CMTX), MPZ (CMT1B), and LITAF (CMT1C) should be performed sequentially.”

    • “In families with probable X-linked inheritance of the CMT phenotype, molecular genetic testing of GJB1 (CMTX) is appropriate to confirm the diagnosis.”

    • “In individuals with the CMT2 phenotype, MFN2 (CMT2A2) can be tested first followed by testing of MPZ (CMT2I/2J) and GJB1 (CMTX1). Other rarer causes include GDAP1 (CMT2H/2K), NEFL (CMT2E/1F), and EGR2 (CMT1D).”

    • Regarding cases of early childhood onset: “[…] pathogenic variants in MPZ, PMP22, and EGR2 should be evaluated first as they were most frequent in those individuals with hypotonia and breathing difficulties. Testing of FGD4, PRX, MTMR2, SBF2, SH3TC2, and GDAP1 is indicated in individuals with early foot deformities and delay in motor milestones after an uneventful neonatal period.”

    • For individuals with a negative family history (e.g., a simplex case):


      • “Molecular genetic testing of PMP22dup (CMT1A), MPZ (CMT1B), and GJB1 (CMTX) should be performed on males and females who have no family history of neuropathy because de novo duplications of the 17p11 region (causing CMT1A) are common and because females who have a GJB1 pathogenic variant (causing CMTX1) may be asymptomatic.”

      • “If no pathogenic variant is identified in any of these three genes testing for rarer subtypes can be considered.”

      • “Early-onset severe CMT may be caused by mutation of PMP22 (CMT1A or 1E), GDAP1 (CMT4A), EGR2 (CMT4E), PRX (CMT4F), SH3TC2 (CMT4C), FDG4 (CMT4H), or MTMR2 (CMT4B1).”


    • “An alternative genetic testing strategy is use of a multi-gene panel that includes genes associated with CMT and other genes of interest…A reasonable testing approach is to first test for pathogenic variant(s) in the single most likely gene that best fits the phenotype (e.g., CMT1A or CMT2A). If such testing does not identify the pathogenic variant(s), then proceed to a genetic neuropathy panel followed by exome sequencing if appropriate.”

    • “Testing of asymptomatic at-risk children is discouraged.”




Place of Service: Outpatient

Charcot-Marie-Tooth neuropathy testing panel is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.


The policy position applies to all commercial lines of business


Denial Statements

Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

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Medical policies do not constitute medical advice, nor are they intended to govern the practice of medicine. They are intended to reflect Highmark's reimbursement and coverage guidelines. Coverage for services may vary for individual members, based on the terms of the benefit contract.

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