Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect.

C harcot-Marie-Tooth (CMT) disease is a motor and sensory neuropathy with clinical and genetic heterogeneity. Patients usually present in the first or second decade of life with distal muscle atrophy in the legs, areflexia, foot deformity (mainly pes cavus), and steppage gait. In most cases, hands are also involved as the disease progresses. CMT is the most frequent inherited neuropathy, with a prevalence in Spain of 28 in 100 000. Based on electrophysiological studies and histopathologic findings in nerve biopsies, CMT has been subcategorised into two main and distinct neuropathies: (i) demyelinating CMT (CMT1, MIM 118200) associated with reduction in a nerve conduction velocities (NCVs) in all nerves and segmental demyelination and remyelination (‘‘onion bulbs’’); and (ii) axonal CMT (CMT2, MIM 118220) associated with normal or almost normal NCVs and loss of myelinated axons. Other phenotypes are associated with motor and sensory nerve involvement: Déjérine-Sottas neuropathy (DSN, MIM 145900) is a severe demyelinating neuropathy with onset in infancy, delayed motor milestones, and NCVs less than 10 m/s; congenital hypomyelinating neuropathy (CHN, MIM 605253) is a dysmyelinating neuropathy characterised by infantile hypotonia, distal muscle weakness, and marked reduction of NCVs; hereditary neuropathy with liability to pressure palsies (HNPP, MIM 162500) is a milder sensory and motor neuropathy with periodic episodes of numbness, muscular weakness, and atrophy. Genetic heterogeneity is characteristic of the disease not just because of the large number of genes and loci associated with CMT (currently 21 genes), but also because the disease may segregate with different Mendelian patterns. The most frequent pattern of inheritance is autosomal dominant, but autosomal recessive and X linked segregation are also observed. The relationship of the type of CMT, demyelinating or axonal, with specific genes is not perfect. For instance, MPZ mutations are usually manifested clinically as an autosomal dominant demyelinating neuropathy, CMT1B. 7 However, some mutations inMPZ have also been found in patients with axonal neuropathy (CMT2-P0). 8 9 Moreover, some patients with mutation in MPZ expressed the disease as either DSN or CHN. 11 On the other hand, mutations in the same gene may be expressed with a different Mendelian pattern. Mutations in the PMP22 gene are expressed as dominant mutations, but there are some mutations in PMP22 that convey an autosomal recessive trait. 13 CMT disease caused by mutations in the gangliosideinduced differentiation-associated protein 1 (GDAP1) gene is a severe autosomal recessive neuropathy originally reported in families with either demyelinating CMT4A neuropathy (MIM 214400) 15 or axonal neuropathy with vocal cord paresis (MIM 607706), which maps to the CMT4A locus on Key points