Axonal Charcot-Marie-Tooth disease
The fog is only slowly lifting
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Research in molecular genetics is clarifying the underlying defects in Charcot-Marie-Tooth disease (CMT), a genetically heterogeneous group of inherited neuropathies with similar clinical phenotypes. Length-dependent axonal degeneration is the likely basis for the manifestations of the typical CMT phenotype, characterized by wasting and weakness of distal limb muscles, usually accompanied by distal sensory loss, skeletal deformities, and decreased or absent reflexes. An important milestone was the recognition of two main forms: CMT1, characterized by primary demyelination with slowed nerve conduction velocities (NCVs, by definition < 38 m/sec); and CMT2, in which the axon is the primary disease target and NCVs are preserved or only mildly slowed (> 38 m/sec in upper limb motor nerves).1 However, cases not conforming to this dichotomization are found with increasing frequency.
The most common CMT types are CMT1A, associated with duplication of the peripheral myelin protein 22 gene (PMP22), accounting for 40 to 50% of all CMT cases; and X-linked CMTX (7 to 10% of cases), intermediate between CMT1 and CMT2 and associated with mutations in the GJB1/Cx32 gene encoding connexin 32.2,3
Ten causative genes for axonal (CMT2) Charcot-Marie-Tooth have been identified in recent years: mitofusin 2 (MFN2); small GTPase late endosomal protein RAB7 (RAB7); neurofilament light chain (NEFL); glycyl-tRNA synthetase (GARS); heat-shock 27-kDa protein 1 (HSPB1); heat-shock 22-kDa protein 8 (HSBP8); myelin protein zero (MPZ); Berardinelli-Seip congenital lipodystrophy 2 (BSCL2); ganglioside-induced differentiation-associated protein 1 (GDAP1); and lamin A/C nuclear …
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