Increased severity over generations of CMT 1A

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J Neurol. 2008 Apr 30

Increased severity over generations of Charcot-Marie-Tooth disease

type 1A.

Steiner I, Gotkine M, Steiner-Birmanns B, Biran I, Silverstein S,

Abeliovich D, Argov Z, Wirguin I.

Neurological Sciences Unit, Hadassah University Hospital, Mount

Scopus, 24035, Jerusalem, 91240, Israel

BACKGROUND : Charcot- Marie-Tooth type 1A (CMT1A) is an autosomal

dominant polyneuropathy due to a 1.5 Mb tandem duplication in

chromosome 17p11.2, containing the PMP22 gene. This mutation is not

modified during inheritance.

OBJECTIVES : We set forth to test the hypothesis that in a subgroup

of CMT1A patients there is clinical anticipation, namely an increase

in disease severity over generations.

METHODS : Thirty-nine CMT1A mutation-positive patients in 16 families

and 23 parent-offspring pairs were evaluated. This included 14

families with 2 generations and 2 families with 3 generations. Age of

presentation was assessed by interviewing the patients and clinical

severity was measured using the CMT neuropathy score (CMTNS).

RESULTS : In 21/23 parent-child pairs and 14/16 families, there was

an earlier age of presentation in children of genetically affected

parents. The mean age of onset in the progeny was 12.61 years

compared to 41.22 years in the parent generation, (p < 0.001).Mean

severity in the younger generation was slightly higher than that of

the parent generation. When corrected for the age difference, the

trend for a worse phenotype in the younger generation became

statistically significant (p < 0.02,Wilcoxon signed rank test).

CONCLUSIONS : Our findings suggest that in a subgroup of CMT1A

patients there is an increase in clinical severity over generations.

The mechanism responsible for this observation remains unknown. Our

findings should be validated on a larger cohort of CMT1A families.