Genetic features and genetic testing Aspects of the genetic causes of these diseases were addressed in the introductory comments and here it is emphasized that a few basic principles apply. First, only a small number of cases of Charcot-Marie-Tooth disease arise as de novo mutations (Hoogendijk et al). Second, different mutations in the same gene can give rise to more than one type of disease. Third, only four genes (PMP22, MPZ, GJB1, and MFN2) account for 92 percent of cases of CMT and this allows efficient testing in practice.
The most prevalent form of the disease is CMT1A, which displays an autosomal dominant pattern of inheritance with almost complete penetrance; it is due to duplication of PMP 22 on chromosome 17p. Less often, CMT1 is autosomal recessive and even less frequently, X-linked dominant or X-linked recessive (see Table 43-6). Two common mutations in chromosomes 1 or 17 cannot be easily distinguished from one another on clinical grounds, but they have distinctive EMG features. The condition of hereditary liability to pressure palsies (HNPP) also displays an aberration on chromosome 17, but in the form of a deletion rather than a duplication of the gene for PMP22. This disease is discussed further on under “Brachial Plexus Neuropathies.” The X-linked variant is the result of a mutation of the gene for connexin-32, another component of myelin. In a large proportion of CMT2 cases, the genetic basis cannot be established with current clinically available genetic testing. Undoubtedly, further studies of genes and gene products will continue to advance our understanding of the inherited neuropathies. For example, the study by Lupski and colleagues using whole genome sequencing has identified heretofore unknown compound heterozygous alleles that produce CMT phenotypes, most rare, but demonstrating that the frequency of unidentified mutations will be continuously be reduced.
Based on the finding that only a few mutations are implicated in the majority of cases of CMT, various algorithms have been designed, taking into account the degree of slowing of motor nerve conduction velocity and clinical features. For example, PMP22 testing is a reasonable first step if the patient has the typical clinical appearance of CMT1A and motor nerve conductions are slower than 38 m/s. If this shows no mutation and there is male-to-male transmission, screening for CMTX1 is performed, or if autosomal inheritance, for MPZ mutations (CMT1B). If these are unrevealing, a third step may be screening for point mutations in PMP22, SIMPLE, and EGR2. If the nerve conduction velocities are severely slowed, below 15 m/s, PMP22 duplication or MPZ mutations are likely to be present. Those with intermediate conduction velocities, between 35 and 45 m/s are likely to have CMT1X or CMT1B and mutations in the corresponding genes. It is worth again noting that only a third of CMT2 cases will have mutations found by current methods. These prescriptions for testing will change as new sequencing methods are introduced.