Genetic evaluation of inherited motor/sensory neuropathy

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Suppl Clin Neurophysiol. 2004;57:228-42.

Genetic evaluation of inherited motor/sensory neuropathy.

Chance PF.

Neurogenetics Laboratory, Division of Genetics and Developmental

Medicine, Box 356320, Department of Pediatrics, University of

Washington School of Medicine, Seattle, WA 98195, USA.

Inherited disorders of peripheral nerves represent a common group of

neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is

a genetically heterogeneous group of chronic demyelinating

polyneuropathies with loci mapping to chromosome 17 (CMT1A),

chromosome 1 (CMT1B), chromosome 16 (CMT1C) and chromosome 10

(CMT1D). CMT1A is most often associated with a tandem 1.5-megabase

(Mb) duplication in chromosome 17p11.2-p12. In rare patients it may

result from a point mutation in the peripheral myelin protein-22

(PMP22) gene.

CMT1B is associated with point mutations in the myelin protein zero

(Po or MPZ) gene.

Mutations in the SIMPLE gene cause CMT1C, and CMT1D is the result of

mutations in the early response 2 (ERG2 or Krox-20) gene.

An X-linked form of CMT1 (CMT1X) maps to Xq13 and is associated with

mutations in the connexin32 (Cx32) gene.

Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy

that maps to chromosome 1p35-p36 (CMT2A), chromosome 3q13-q22

(CMT2B), chromosome 7p14 (CMT2D), chromosome 8p21 (CMT2E), chromosome

1q22-q23 (CMT2F) or chromosome 3q13 (CMT2G).

Two X-linked forms of CMT2 have been reported (CMT2XA and CMT2XB),

but the genes remain unidentified.

An area that has recently expanded is the identification of autosomal

recessive forms of CMT type 1 and 2. Of the eight recessive forms of

CMT1 that have been identified to date, only two have been fully

characterized at the molecular level (CMT1 AR B 1 and CMT1 AR D).

Point mutations were found in the myotubularin-related protein-2

(MTM2) gene for CMT1 AR B1. CMT1 AR D is the result of point

mutations in the N-myc downstream-regulated gene 1 (NDRG1).

Dejerine-Sottas disease (DSD), also called hereditary motor and

sensory neuropathy type III (HMSNIII), is a severe, infantile-onset

demyelinating polyneuropathy syndrome that may be associated with

point mutations in either the PMP22 gene, PO gene, EGR2 gene or the

PRX gene (for the recessive form). It shares considerable clinical

and pathological features with CMT1.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an

autosomal dominant disorder that results in a recurrent, episodic

demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion

in chromosome 17p11.2-p12 that results in reduced expression of the

PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion

syndromes that originate from unequal crossover during germ cell

meiosis. Other rare forms of demyelinating peripheral neuropathies

map to chromosome 8q, 10q and 11q.