Molecular Genetics of Autosomal-Recessive Axonal Charcot-Marie-Tooth Neuropathies

Abstract

Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families with CMT. On the other hand, in countries with a high prevalence of consanguinity this mode of inheritance accounts, likely, for the vast majority of CMT phenotypes. Like dominant forms, autosomal-recessive forms are generally subdivided into demyelinating forms (autosomal-recessive CMT1: ARCMT1 or CMT4) and axonal forms (ARCMT2). Until now, demyelinating ARCMT were more extensively studied at the genetic level than the axonal forms. Although the latter are undoubtedly the rarest forms among the heterogeneous group of CMT, three distinct forms have been genetically mapped and recent studies in the past 4 yr provided evidence that their respective causing genes have been characterized. Indeed, gene defects in encoding A-type lamins (LMNA), encoding Ganglioside-induced Differentiation-Associated Protein-1 (GDAP1) and encoding the mediator of RNA polymerase II transcription, subunit 25 homolog (MED25) have been identified in ARCMT2 subtypes. Given the clinical, electrophysiological and histological heterogeneity of CMT2, it is likely that unreported forms of ARCMT2, related to novel genes, remain to be discovered, leading to an even more complex classification. However, our goal in this review is to provide the reader with a clear view on the known genes and mechanisms involved in ARCMT2 and their associated phenotypes.

Charcot‐Marie‐Tooth Disease: A Clinico‐genetic Confrontation

“…CMT4C4 or AR‐CMT2K is caused by mutations in GDAP1 on chromosome 8q13–21.1 (Cuesta et al, 2002; Birouk et al, 2003; Bernard et al, 2006) that can also result in autosomal recessive demyelinating CMT. Autosomal recessive GDAP1‐linked intermediate type A (CMTRIA) has been also described (Nelis et al, 2002; Senderek et al, 2003a).…”

Late‐onset Charcot‐Marie‐Tooth type 2 disease with hearing impairment associated with a novel Pro105Thr mutation in the MPZ gene

“…The frequency of axonal form of Charcot‐Marie‐Tooth disease (CMT2) remains unknown. To date 17 loci in autosomal dominant (14) and in autosomal recessive (3) CMT2 have been mapped [Bernard et al, 2006; Zuchner and Vance, 2006]. Among 11 genes identified in AD‐CMT2, the Mitofusin 2 gene has been shown to be mutated in 11% of CMT2 cases [Verhoeven et al, 2006].…”

Novel mutation in the membrane metalloendopeptidase gene in a patient with the autosomal recessive form of Charcot–Marie–Tooth disease

“…A total of 11 causative genes for AR‐CMT2 have been identified to date. The diagnostic rate of patients with AR‐CMT2, however, is low because of the genetic heterogeneity of the disease . Recently, the membrane metalloendopeptidase gene ( MME ) has been identified as a causative gene for AR‐CMT2T .…”