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.
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 CMT1Apatients 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 CMT1Apatients 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.
Authors: M E Shy; J Blake; K Krajewski; D R Fuerst; M Laura; A F Hahn; J Li; R A Lewis; M Reilly Journal: Neurology Date: 2005-04-12 Impact factor: 9.910
Authors: M E MacDonald; J P Vonsattel; J Shrinidhi; N N Couropmitree; L A Cupples; E D Bird; J F Gusella; R H Myers Journal: Neurology Date: 1999-10-12 Impact factor: 9.910
Authors: Adriana P Rebelo; Alexander J Abrams; Ellen Cottenie; Alejandro Horga; Michael Gonzalez; Dana M Bis; Avencia Sanchez-Mejias; Milena Pinto; Elena Buglo; Kasey Markel; Jeffrey Prince; Matilde Laura; Henry Houlden; Julian Blake; Cathy Woodward; Mary G Sweeney; Janice L Holton; Michael Hanna; Julia E Dallman; Michaela Auer-Grumbach; Mary M Reilly; Stephan Zuchner Journal: Am J Hum Genet Date: 2016-03-31 Impact factor: 11.025
Authors: Ah J Lee; Da E Nam; Yu J Choi; Seung W Noh; Soo H Nam; Hye J Lee; Seung J Kim; Gyun J Song; Byung-Ok Choi; Ki W Chung Journal: Mol Genet Genomic Med Date: 2020-07-09 Impact factor: 2.183
Authors: Barbara W van Paassen; Anneke J van der Kooi; Karin Y van Spaendonck-Zwarts; Camiel Verhamme; Frank Baas; Marianne de Visser Journal: Orphanet J Rare Dis Date: 2014-03-19 Impact factor: 4.123