CMT Costa Rican family Research

[Guest guest]

(Abstract from Presentation at the American Academy of Neurology

Meeting, Honolulu, April 2003)

Charcot Marie Tooth Disease: Clinical Aspects of a Novel TYR145SER

Mutation in the Myelin Zero Gene

D. Heuss, C. Berghoff, Erlangen, Germany, M. Berghoff, Wuerzburg,

Germany, A. Leal, Erlangen, Germany, G. Del Valle, E. , R.

Barrantes, San , Costa Rica, A. Reis, B. Rautenstrauss, B.

Neundrfer, Erlangen, Germany

OBJECTIVE: To demonstrate the phenotype of an autosomal-dominant CMT of

a Costa Rican family who carry a not yet described Tyr145Ser mutation in

homo- and heterozygous states.

BACKGROUND: Mutations in the Myelin Protein Zero gene (MPZ, P0) cause

CMT1B disease (MIM 118200). The phenotypic variability of MPZ mutation

carriers includes also axonally pronounced peripheral neuropathies,

particularly due to a Thr124Met mutation in exon 3. These patients

additionally show pupillary anomalities and the disease is frequently

accompanied by deafness and dysphagia.

DESIGN/METHODS: Four patients (III:4, III:5, IV:1, IV:2) of a large

consanguineous family with CMT in Costa Rica with predominant Spanish

ancestry were evaluated by clinical examination and electrophysiological

studies. A sural nerve biopsy was performed in one patient. All 6 coding

MPZ exons were amplified, using primer sequences already published.

Sequencing was performed in both directions, using the same primers and

BigDye Terminator Kit version 3.0 with an ABI 3100 DNA Sequencer, and

analyzed with the SEQUENCE ANALYZER and SEQMAN II softwares.

RESULTS: Age at onset of neuropathic complaints was 38 (daughter) and 39

years (son) and 51 years in case of the mother. The father was still

without subjective complaints at the age of 65. Disease duration was 2

to 4 years (son and daughter, respectively) and 11 years for the mother.

All four family members showed severe distal sensory deficits for touch

and pain sensations, which were more pronounced in the lower limbs. The

mother and both children had mild sensory ataxia. Motor weakness and

wasting of distal muscles were present only in the children. Ankle jerks

were absent in all

family members. Pupillary abnormalities with a negative reaction to

light were

present in both siblings; the daughter also complained about progressive

deafness. The electrophysiological studies and sural nerve biopsy

revealed a demyelinating and axonal nerve degeneration. In MPZ exon 3 a

AC transition was found, causing a novel missense mutation Tyr145Ser;

individuals III:1, III:4, III:5 and III:6 are heterozygous, whereas the

individuals IV:1 and IV:2 are homozygous carriers. Healthy individuals

from the family do not present the mutation.

CONCLUSIONS: The phenotypic influence of this amino acid exchange seems

to be more moderate in heterozygous carriers, probably due to the

biochemical properties of the respective amino acids. However, the

homozygous exchange causes not only a more severe typical peripheral

neuropathy but moreover pupillary anomalies inidicating a not yet

understood role of MPZ in the pathogenesis of complex phenotypes.

Supported By: This study was supported by the Deutsche

Forschungsgemeinschaft (DFG) and Deutsche Gesellschaft fr Muskelkranke

(DGM, AFM) and by the ELAN funds.