Genetics of peripheral neuropathies and hereditary ataxias

: Charcot-Marie-Tooth disease (CMT) is a hereditary motor-sensory neuropathy with a large genetic heterogeneity. Type 1 (CMT1), or demyelinating CMT, and type 2 (CMT2), or neuronal CMT, are two genetically and clinically distinct entities. CMT1 is the more prevalent and better understood of the two from a genetic standpoint. At least three genes have been shown to be implicated: the 22Kda (PMP22) gene for peripheral myelin protein located in the 17p11.2 chromosome (the CMT1A locus), the P0 myelin protein gene located in the 1q23 chromosome (the CMT1B locus), and the connexin 32 (Cx32) gene located in the Xq13 chromosome (CMTX locus). The most common mutation in CMT1, found in 70% of cases, is a tandem duplication of 1,500 kb at the CMT1A locus. Point mutations have also been described in the PMP22 gene and in P0 and Cx32. Dejerine-Sortas syndrome (DSS) is caused by point mutations in PMP22 and P0 genes, whereas familial neuropathy with liability to pressure palsies (FNPP) or tomacular neuropathy are caused mainly by deletion of 1,500 kb at the CMT1A locus, although point mutations have also been described in the PMP22 gene. Altogether, we can say that CMT1, DSS and FNPP are different clinical expressions of the same genetic pathology and reflect a phenotypic spectrum of related myelin disorders. Hereditary ataxias constitute a wide ranging and heterogeneous set of clinical entities with different ages of onset, patterns of system involvement and type of inheritance. The most common form is Friedreich's ataxia, a autosomally recessive inherited disease whose gene is located in the 9q13 chromosome, though it has not yet been isolated. This disease has various clinical presentations, which does not imply genetic heterogeneity. Dominant autosomal cerebellar ataxias, on the other hand, are extremely heterogeneous. Seven genetic loci have been described, some of which are associated to cerebellar plus forms and expanded unstable triplet sequences of CAG in SCA1 and SCA3/MJD. One locus has been described for the "pure cerebellar form" (ACAD type III) (locus SCA5) and another for the form with retinopathy (ACAD type II) (locus SCA7).