Genetics of CMT/Editorial in Arch.Neurology

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Genetics of Charcot-Marie-Tooth Disease from Archives of

Neurology,2003;60:481-482

Editorial by E. Pleasure, MD ph Stokes, Jr, Research

Institute, The Children's Hospital of Philadelphia Room 517, Abramson

Research Building, 34th and Civic Center Boulevard Philadelphia, PA

19104

CHARCOT-MARIE-TOOTH DISEASE (CMT) rivals neurofibromatosis type 1 as the

most common genetic disorder affecting the peripheral nervous system. In

the United States, Western Europe, and Japan, the most frequent mutation

causing CMT is a reduplication of a 15-megabase segment of DNA on

chromosome 17.1 The mechanism by which this

duplication leads to dominantly inherited demyelinative polyneuropathy

(CMT1A) is likely via overexpression of the peripheral myelin protein 22

gene (PMP22), which is located on the duplicated chromosomal segment.2

Various mutations affecting the myelin protein zero (P0) or connexin 32

(Cx32) genes are also relatively common causes of CMT. P0 mutations

occur as either dominant or recessive genes; they primarily affect

myelin but in some instances show predominantly axonal abnormalities.1,

3 Cx32 mutations are inherited in an X-linked pattern and typically

yield mixed axonal and myelin sheath abnormalities.1 Mutations in these

and other genes that cause CMT are listed on the Web site

http://molgen-www.uia.ac.be/CMTMutations/.

Consanguinity is common in North Africa, thus favoring the phenotypic

expression of rare recessive mutations. As a consequence and in contrast

to the United States, Western Europe, and Japan, recessive forms of CMT

in that country outnumber the

autosomal-dominant and X-linked forms that predominate in the United

States.4 Genetic

analysis of families from North Africa has proved an efficient means by

which to discover novel CMT genotypes. Mutations in the gene encoding

ganglioside-induced

differentiation-associated protein 1 (GDAP1) were first reported in

connection with recessively inherited CMT in 2 articles that appeared

simultaneously

in Nature Genetics in January 2002. Baxter et al5 documented 3 GDAP1

mutations in 4

consanguineous Tunisian families that caused slowly progressive

demyelinative CMT. Cuesta et al6 described 3 Spanish families, 1 known

to be consanguineous, in which axonal neuropathy with vocal cord paresis

was caused by another nonoverlapping group of 3 GDAP1 mutations. These 2

articles reinforce the concept that mutations in single genes can cause

both myelinic and axonal forms of CMT, depending on the specific gene

alteration. The phenotypic diversity associated with GDAP1 mutations

pales in comparison with mutations of the lamin A/C gene (LMNA), which

encodes a nuclear envelope protein. Depending on site-specific LMNA

amino acid substitutions, patients may develop axonal CMT,

Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy,

dilated cardiomyopathy, mandibuloacral dysplasia, or familial partial

lipodystrophy.4

What is the practical significance of the ever-increasing number of

mutations that result in the CMT phenotype? Clinical recognition of CMT

is generally not

demanding given the characteristic clinical features and family history,

but in probands lacking a family history and/or with atypical features,

documentation of a mutation previously demonstrated to cause CMT is

diagnostic. The number of distinct CMT mutations has now grown to the

point that would justify the design and commercialization of a DNA chip

to permit simultaneous and efficient screening of genomic DNA from

patients with the CMT phenotype.

The article by Birouk et al,7 which originated in North Africa and

appears in this issue of the ARCHIVES, provides details of the clinical,

electrophysiological,

morphological, and genetic features of a single consanguineous family

with severe CMT

caused by a GDAP1 mutation (S194X) identical with 1 of the 3 documented

by Cuesta et

al.6 All affected members of this family had large reductions in the

amplitude of

compound motor action potentials, and in the 1 subject in whom nerve

conduction velocities could be elicited, the median nerve conduction

velocity was 40 m/s, higher than the 38-m/s cutoff often used to

discriminate between myelin sheath and axonal forms of CMT.1 Results of

a nerve biopsy showed a sharp reduction in the number of myelinated

fibers, a downward shift in the size spectrum of surviving myelinated

fibers, evidence of axonal sprouting, and a normal ratio of axon

diameter to axon + myelin sheath diameter. Thus, the results of both

electrophysiological and morphological studies were compatible with a

" pure " axonal polyneuropathy.

GDAP1, encoded by 6 exons that span 13.9 kilobases on chromosome 8q21,

is a

358–amino acid protein of unknown function with a sequence homologous to

the

glutathione S-transferase family of detoxifying proteins and is

expressed both in Schwann cells and the central nervous system.6 As the

number of GDAP1 mutations known to be associated with the CMT phenotype

grows, it will likely become clear, as it has with P0, that

nonoverlapping mutations cause predominantly myelinic vs axonal

abnormalities. We can then hope to relate specific alterations in the

tertiary

structure, interactions with other proteins, and biological functions of

GDAP1 resulting from these mutations to deleterious effects exerted

primarily on Schwann cells vs axons, and ultimately to devise effective

therapies for these 2 forms of GDAP1-linked CMT.

REFERENCES

1. Hattori N, Yamamoto M, Yoshihara T, et al. Demyelinating and

axonal features of Charcot-Marie-Tooth disease with mutations of

myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological

study of 205 Japanese patients. Brain. 2003;126:134-151.

2. Robaglia-Schlupp A, Pizant J, Norreel JC, et al. PMP22 overexpression

causes

dysmyelination in mice. Brain. 2002;125:2213-2221.

3. Hanemann CO, Gabreels-Festen AA, De Jonghe P. Axon damage in CMT due

to mutation in myelin protein P0. Neuromuscul Disord. 2001;11:753-756.

4. Chaouch M, Allal Y, De Sandre-Giovannoli A, et al. The phenotypic

manifestations of

autosomal recesive axonal Charcot-Marie-Tooth due to a mutation in lamin

A/C gene.

Neuromuscul Disord. 2003;13:60-67.

5. Baxter RV, Ben Othmane K, Rochelle JM, et al. Ganglioside-induced

differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth

disease type 4A/8q21. Nat Genet. 2002;30:21-22.

6. Cuesta A, Pedrola L, Sevilla T, et al. The gene encoding

ganglioside-induced

differentiation-associated protein 1 is mutated in axonal

Charcot-Marie-Tooth type 4A

disease. Nat Genet. 2002;30:22-25.

7. Birouk N, Azzedine H, Dubourg O, et al. Phenotypical features of a

Moroccan family

with autosomal recessive Charcot-Marie-Tooth disease associated with the

S194X

mutation in the GDAP1 gene. Arch Neurol. 2003;60:598-604.