TY - CHAP M1 - Book, Section TI - Charcot-Marie-Tooth Peripheral Neuropathies and Related Disorders A1 - Lupski, James R. A1 - Garcia, Carlos A. A2 - Valle, David L. A2 - Antonarakis, Stylianos A2 - Ballabio, Andrea A2 - Beaudet, Arthur L. A2 - Mitchell, Grant A. Y1 - 2019 N1 - 10.1036/ommbid.264 T2 - The Online Metabolic and Molecular Bases of Inherited Disease AB - Charcot-Marie-Tooth (CMT) (MIM 118220) polyneuropathy syndrome represents a clinically and genetically heterogeneous group of disorders of the peripheral nerve. Two major types are distinguished by measuring motor nerve conduction velocities (NCV). CMT1 is a demyelinating neuropathy characterized by symmetrically slowed motor NCV (usually 85 percent of patients with HNPP. The CMT1A duplication and HNPP deletion result from unequal crossing over and reciprocal homologous recombination involving a 24-kb repeat—CMT1A region-specific low-copy repeats (CMT1A-REP)—that flanks the 1.5-Mb region. A meiotic recombination hotspot occurs within CMT1A-REP. The majority of the de novo duplication and deletion events occur in meiosis of the male germ cells.The CMT1A and HNPP phenotypes result from a gene dosage effect. CMT1A is due to trisomic overexpression of the peripheral myelin protein-22 gene (PMP22)whereas HNPP results from monosomic underexpression of PMP22. In rare patients without the CMT1A duplication or HNPP deletion, PMP22 point mutations can cause disease. Null alleles or haploinsufficiency cause HNPP, while gain-of-function or dominant-negative missense amino acid substitution results in CMT1A or DSS.Mutations in myelin protein zero (MPZ), connexin 32 (Cx32)or gap junction protein β1 (GJB1), and early growth response 2 (EGR2, the human Krox-20 homologue) genes can also cause CMT1 (MPZ, Cx32, EGR2), DSS (MPZ, EGR2), or CHN (MPZ, ... SN - PB - McGraw-Hill Education CY - New York, NY M3 - doi: 10.1036/ommbid.264 Y2 - 2024/11/07 UR - ommbid.mhmedical.com/content.aspx?aid=1181479189 ER -