The genetic complexity of CMT necessitates a rational approach for clinical genetic testing. Factors to consider when initiating genetic testing should include careful evaluation of (1) the availability of clinical testing, (2) the yield of a specific molecular test, (3) the aim of establishing a molecular diagnosis and (4) the frequency of de novo mutations.
Evidence-based data from 12 population-based studies from various ethnic backgrounds10, 11, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
established the contribution of 5 genes/genomic rearrangements to disease burden: PMP22
point mutations. Electrophysiological classification (demyelinating versus axonal neuropathy) markedly improves the diagnostic yield (). In families, with informative pedigrees to determine the inheritance pattern, further targeting of the diagnostic testing can be achieved.19, 25
Mutation frequencies for CMT and related neuropathies
Duplication of a chromosomal segment harboring PMP22
(ie, the CMT1A duplication)26
represents 43% of the total CMT cases, whereas the yield of duplication detection rises to 70% in CMT1. The deletion of the same chromosomal segment results in HNPP.27
Although the deletion has not been reported in any other phenotype, the yield of deletion testing is over 90% in this distinctive phenotype.
mutations are the next most common culprits in inherited neuropathy. In informative pedigrees a dominant inheritance pattern and lack of male-to-male transmission points to this gene on the X chromosome. Because electrophysiology frequently suggests the intermediate form, molecular testing for Cx32
is appropriate in both CMT1 (after duplication testing) and CMT2. In the CMT1 group, MPZ
mutations are the next most common, followed by the rare genes.25
In the CMT2 group, Cx32
mutations are followed by MPZ
mutations in frequency; however, recent data, though not population based, suggest that MFN2
mutations may be one of the most common causes of CMT2.28, 29, 30
The high frequency of de novo
mutations in duplication/deletion (37–90%)10, 12
and in point mutations11
illustrates that genetic disease is commonly sporadic in presentation. The absence of a family history does not exclude CMT and related peripheral neuropathies. In fact, in a patient presenting with chronic polyneuropathy in the absence of other signs and symptoms, after the most common systemic and treatable causes, such as diabetes, uremia and nutritional deficiency, genetic causes are more common than autoimmune or paraneoplastic neuropathy. A rational diagnostic approach is presented in . In pediatric cases, which are more severe and when reproductive plans may depend on the genetic information, complete evaluation with panel testing is warranted.
Suggested testing scheme in hereditary sensory and motor polyneuropathy for patients with and without a family history of CMT based on the genotype–phenotype correlations and frequency data in 12 population-based studies.