CMT 1A: Inherited demyelinating neuropathies with micromutations of peripheral

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Brain. 2011 Jan 19. [Epub ahead of print]

Inherited demyelinating neuropathies with micromutations of peripheral myelin

protein 22 gene.

Taioli F, Cabrini I, Cavallaro T, Acler M, Fabrizi GM.

Department of Neurological, Neuropsychological, Morphological and Movement

Sciences, University of Verona, 37134 Verona, Italy.

Abstract

The peripheral myelin protein 22 gene (PMP22) encodes an intrinsic membrane

protein of compact myelin. Duplication or deletion of PMP22 causes the most

common autosomal dominant neuropathies, Charcot-Marie-Tooth disease type 1A or

hereditary neuropathy with liability to pressure palsies. Charcot-Marie-Tooth

disease type 1A is a hypertrophic de-remyelinating neuropathy manifesting with

peroneal muscular atrophy and uniform, marked, slowing of nerve conduction

velocities.

Hereditary neuropathy with liability to pressure palsies is a recurrent focal

neuropathy with sausage-like myelin thickening (tomacula) and non-uniform nerve

conduction velocity changes.

Missense or nonsense mutations also cause more severe Charcot-Marie-Tooth

disease type 1A forms of infancy or hereditary neuropathy with liability to

pressure palsies, but they are presumably very rare. We performed a mutational

scanning of PMP22 in 229 index patients (46 familial, 183 isolated) referred for

suspected inherited neuropathy.

The series included 125 cases with hereditary neuropathy with liability to

pressure palsies (mean age 42.5 years), 47 cases with Charcot-Marie-Tooth

disease type 1A (motor nerve conduction velocities at median nerve below

38 & #8201;m/s) (mean age 40.7 years) and 57 cases with Charcot-Marie-Tooth with

unknown nerve conduction velocities (mean age 43 years).

Preliminary molecular studies ruled out PMP22 duplication or deletion or

mutations in a comprehensive panel of Charcot-Marie-Tooth genes. Mutational

scanning of PMP22 was done by denaturing high performance liquid chromatography

and automated nucleotide sequencing.

To investigate the molecular basis of phenotype-to-genotype correlations, we

performed a transcriptional analysis of PMP22 using reverse-transcriptase

polymerase chain reaction and quantitative real-time polymerase chain reaction

in two phenotypically divergent nerve biopsies. Ten patients harboured eight

micromutations of PMP22 including four novel changes. In six familial and three

sporadic cases, detected mutations caused premature or delayed stop codons and

were associated with hereditary neuropathy with liability to pressure palsies;

the related pathological pictures ranged from classical tomaculous neuropathy to

a mild demyelinating neuropathy with atypical non-tomaculous myelin thickenings.

In a single family a c.179-2A & #8201;> & #8201;G mutation affecting the splice

acceptor site of intron 2 cosegregated with a Charcot-Marie-Tooth disease type

1A-like syndrome and a peculiar pathological picture of demyelinating neuropathy

without Charcot-Marie-Tooth disease type 1A-like classical onion bulbs or

tomacula.

Transcriptional analysis of a novel c.174_178 & #8201;+ & #8201;7delAAACGGTGAGGC

deletion involving exon 2 and intron 2 demonstrated an unstable mutant

transcript leading to a p.Asn59GlyfsX12 change; the mutation represented a null

allele and caused a typical tomaculous hereditary neuropathy with liability to

pressure palsies.

The Charcot-Marie-Tooth disease type 1-like c.179-2A & #8201;> & #8201;G allele led

to a stable transcript with an in-frame deletion of exon 3 (p.Glu60_Ala106del);

the predicted shorter protein could exert variable molecular effects.

In conclusion, micromutations of PMP22 cause a clinical and pathological

continuum of demyelinating neuropathies that may include atypical phenotypes.