Journal
NEUROLOGY
Volume 78, Issue 10, Pages 690-695Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e318249f683
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Funding
- National Institute of Neurological Disorders and Stroke (NINDS) [NS016367]
- CHDI Foundation, Inc.
- Huntington's Disease Society of America
- National Research Foundation of Korea [NRF-2009-352E0010]
- Fundacao para e a Tecnologia of Portugal (FCT) [SFRH/BD/44335/2008]
- National Institutes of Health NINDS [NS016367, NS024279, NS032765, NS033648, NS040068, NS044466, NS036630, NS052592, NS060118, NS16375, NS055252., NS069422, NS016375, NS044431, NS068897, NS050095]
- High Q Foundation
- National Parkinson Foundation
- Santhera Pharmaceuticals
- Medivation/Pfizer
- Neuro-Search
- Schwarz Biosciences
- IMPAX Pharmaceuticals
- Neuraltus Pharmaceuticals
- Teva Pharmaceuticals
- National Institutes of Health NCCAM [AT000613]
- NHGRI [HG02449]
- Michael J. Fox Foundation/Northwestern Dixon Foundation
- Forest Laboratory
- Ministero della Salute, Italy
- Fondazione Cariplo, Milan, Italy
- CIBERER, ISCIII, Madrid, Spain
- Abbott Laboratories
- Australian Research Council LIED [LE0989147, LE100100130]
- Italian Drug Agency (AIFA) [FARM659PTX]
- Lundbeck Pharmaceuticals
- Bayer
- EMD Serono
- Michael J. Fox Foundation
- National Institutes of Health NICHD [HD062550, HD06528]
- South Carolina Council [18120 FL00]
- Fullerton Foundation
- Amarin Corporation
- NeuroSearch Sweden AB
- Medivation
- NCRR [RR024156, PO412196-G]
- Parkinson Study Group
- European Commission
- European Union
- High Q Foundation/CHDI Foundation
- Jerry MacDonald Huntington Research Fund
- NIGMS [GM061354]
- Simons Foundation
- MRC [G1001257, G0800784] Funding Source: UKRI
- Medical Research Council [G0800784B, G1001257, G0800784] Funding Source: researchfish
- National Institute for Health Research [CL-2009-18-005] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [SFRH/BD/44335/2008] Funding Source: FCT
- Australian Research Council [LE0989147, LE100100130] Funding Source: Australian Research Council
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Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e. g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology (R) 2012; 78: 690-695
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