MOLECULAR-GENETICS OF CHARCOT-MARIE-TOOTH DISEASE AND RELATED NEUROPATHIES

Collectively, the inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot - Marie - Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17(CMT1A), chromosome 1 (CMT1B), the X chromosome (CMTX) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5 megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P-0) gene. The molecular defect in CMT1C is unknown. X-linked Charcot - Marie - Tooth neuropathy (CMTX) is associated with mutations in the connexin32 gene. Charcot - Marie - Tooth neuropathy type II (CMT2) is an axonal neuropathy, also of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A). Dejerine - Sottas disease, also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene or the P-0 gene. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5 Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. CMT1A and HNPP are apparent reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis.