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Hereditary motor and sensory neuropathies, commonly referred to as Charcot-Marie-Tooth disease (CMT), are among the most common inherited neurological diseases, with an overall prevalence of about 1–4/10 000.1 Clinically, the hereditary motor and sensory neuropathies are characterised by progressive muscular and sensory loss in the distal extremities with chronic distal weakness, deformation of the feet (pes cavus), and loss of deep tendon reflexes.2 Two main subgroups have been defined on the basis of electrophysiological and histopathological characteristics: the demyelinating form (CMT1) and the axonal form (CMT2). CMT1 can be distinguished from CMT2 by measuring motor nerve conduction velocities in the median nerve: patients affected by CMT1 show reduced velocities (<38 m/s), whereas those affected by CMT2 show velocities of ⩾38 m/s, the normal value being ⩾48 m/s. Recently, a new group of CMT has been described, referred to as intermediate CMT3,4; in this, nerve conduction velocities overlap CMT1 and CMT2, and nerve biopsies present characteristics of both demyelination and axonal loss.
CMT is also characterised by great genetic heterogeneity, with more than 30 loci and 19 genes identified to date5,6 (inherited peripheral neuropathy mutation database, IPNMDB, http://www.molgen.ua.ac.be/CMTMutations). All modes of inheritance have been reported: autosomal dominant, autosomal recessive, and X linked. Autosomal recessive demyelinating forms (CMT4) are, in most cases, less frequent, of earlier onset, and more severe than the autosomal dominant CMT forms (CMT1), with a fast progression to severe disability leading to a higher frequency of wheelchair dependency early in life.7 To date, at least seven demyelinating forms with autosomal recessive inheritance have been identified:
CMT4A (MIM 214400) at chromosome 8q13–q21.18,9 caused by mutations in the ganglioside induced differentiation associated protein 1 gene (GDAP1, MIM 606598),10,11 together with mixed demyelinating and axonal autosomal recessive phenotypes …
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