The majority of these (evolving over years) prove to be genetic, either inherited or one of the infrequent sporadic mutations that are responsible for the inherited types. The observations of Dyck and coworkers (1981), referred to in the introduction to this chapter, are of interest in this respect. In a series of 205 patients who were referred to the Mayo Clinic with neuropathies of unknown cause, 86 were found to have an inherited form of disease. The proportion is presumably higher now that panels of genetic testing are available. With appropriate genealogic data, the diagnoses of the peroneal muscular atrophy of Charcot-Marie-Tooth disease can usually be made on clinical grounds alone (high arches, distal foreleg atrophy, chronicity, etc.). Sporadic cases are more difficult. Some of the patients who have consulted us in adulthood for an obscure polyneuropathy report having had operations on their feet and toes for these reasons, but the connection to a genetic neuropathy had not been previously made. Additional hints are frequent sprained ankles and the need to tape the ankles during adolescence in order to run or participate in sports. Dyck and associates (1981) found that direct examinations of the patients’ siblings, children, parents, and other close relatives were often successful in revealing a hereditary basis for the neuropathy. The absence of ankle reflexes or foot deformities in relatives discloses the diagnosis.
DNA testing for the main forms of Charcot-Marie-Tooth disease is available from commercial laboratories and has increased the diagnostic certainty. A comment has already been made regarding the utility of such testing and the small number of mutations that give rise to over one-third of cases of inherited sensorimotor neuropathy. As already alluded to, individuals with a chronic demyelinating neuropathy, pes cavus or hammer toes, and a likely autosomal dominant pattern of inheritance probably have CMT1A and sequencing for PMP22 duplication may be undertaken. If there is male-to-male transmission, CMT1X is likely and the GJB1 gene may be investigated. If both genes lack causative mutations in a demyelinating case, CMT1B is possible, especially if motor nerve conduction velocities are very slow (below 15 m/s), and the MPZ gene is suspect. Whether testing beyond this, which would include the SIMPLE, PMP22, and EGR2 genes that occur in low frequency with CMT1A, is worthwhile depends on the clinical circumstances. Some cases of axonal, CMT2, will have one of several very low-frequency mutations that have been delineated. Numerous easily accessible algorithms for genetic testing have been published, similar to the guidance in the article by Saporta and colleagues, that are based on inheritance, nerve conduction velocity, and clinical features and we have not reproduced them here.
Slowly progressive polyneuropathy with features of central nervous system degeneration, particularly cerebellar ataxia, most often has a genetic basis, but a small number are found to be the result of a genetic metabolic disorder such as a leukodystrophy.
In contrast, a few young patients have come to our attention in whom a gradually progressive polyneuropathy that evolved over almost a decade turned out to be an acquired chronic inflammatory demyelinating condition rather than the expected genetic type. The absence of a family history of neuropathy and of high arches and heterogeneous slowing of both nerve conduction velocities and reductions in motor amplitudes on the nerve conduction studies provided hints to the acquired nature of the condition.
Finally, it should be conceded again that even after the most assiduous clinical and laboratory investigation, a substantial proportion of chronic neuropathies remain unexplained.
Diagnosis of Recurrent or Relapsing Polyneuropathy