Increased severity over generations of Charcot-Marie-Tooth disease type 1A.
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.


OBJECTIVE
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.
Steiner
I
I
Neurological Sciences Unit, Hadassah University Hospital, Mount Scopus, 24035, Jerusalem 91240, Israel. isteiner@md2.huji.ac.il
Gotkine
M
M
Steiner-Birmanns
B
B
Biran
I
I
Silverstein
S
S
Abeliovich
D
D
Argov
Z
Z
Wirguin
I
I
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D020132:Anticipation, Genetic; D002607:Charcot-Marie-Tooth Disease / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004185:Disability Evaluation; D005006:Ethnicity / Q000235:genetics; D005190:Family; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009185:Myelin Proteins / Q000235:genetics*; D010525:Peripheral Nerves / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D012720:Severity of Illness Index
D005819:Genetic Markers; D009185:Myelin Proteins; C073687:PMP22 protein, human