Increased Severity over Generations of CMT 1A

[Guest guest]

(ANN April 17, 2008)

Increased Severity over Generations of Charcot-Marie-Tooth Disease

Type 1A

Israel Steiner, Marc Gotkine, Bettina Steiner-Birmanns, Iftah Biran,

Tel Aviv, Israel, Silverstein Shira, Dvora Abeliovich, Zohar Argov,

Jerusalem, Israel, Itzik Wirguin, Beer-Sheva, Israel

OBJECTIVE: To test the hypothesis that in a subgroup of CMT1A

patients there is clinical anticipation, namely an increase in

disease severity over generations.

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

known to be modified during inheritance.

DESIGN/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/RELEVANCE: 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.