CMT Neuropathies Autosomal-Recessive Molecular Genetics

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Neuromolecular Med. 2006;8(1-2):87-106.

Molecular genetics of autosomal-recessive axonal charcot-marie-tooth

neuropathies.

Bernard R, De Sandre-Giovannoli A, Delague V, Levy N.

Departement de Genetique Medicale Hopital d'enfants de la Timone,

Marseille, France; and Inserm U491 Genetique Medicale et

Developpement, Faculte de Medecine de Marseille, Universite de la

Mediterranee, Marseille, France.

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.