Abstract
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 wellbehaved 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.
Original language | English (US) |
---|---|
Pages (from-to) | 690-695 |
Number of pages | 6 |
Journal | Neurology |
Volume | 78 |
Issue number | 10 |
DOIs | |
State | Published - Mar 6 2012 |
ASJC Scopus subject areas
- Clinical Neurology
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CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. / Lee, J. M.; Ramos, E. M.; Lee, J. H.; Gillis, T.; Mysore, J. S.; Hayden, M. R.; Warby, S. C.; Morrison, P.; Nance, M.; Ross, C. A.; Margolis, R. L.; Squitieri, F.; Orobello, S.; Di Donato, S.; Gomez-Tortosa, E.; Ayuso, C.; Suchowersky, O.; Trent, R. J.A.; McCusker, E.; Novelletto, A.; Frontali, M.; Jones, R.; Ashizawa, T.; Frank, S.; Saint-Hilaire, M. H.; Hersch, S. M.; Rosas, H. D.; Lucente, D.; Harrison, M. B.; Zanko, A.; Abramson, R. K.; Marder, K.; Sequeiros, J.; Paulsen, J. S.; Landwehrmeyer, G. B.; Myers, R. H.; MacDonald, M. E.; Gusella, J. F.
In: Neurology, Vol. 78, No. 10, 06.03.2012, p. 690-695.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion
AU - Lee, J. M.
AU - Ramos, E. M.
AU - Lee, J. H.
AU - Gillis, T.
AU - Mysore, J. S.
AU - Hayden, M. R.
AU - Warby, S. C.
AU - Morrison, P.
AU - Nance, M.
AU - Ross, C. A.
AU - Margolis, R. L.
AU - Squitieri, F.
AU - Orobello, S.
AU - Di Donato, S.
AU - Gomez-Tortosa, E.
AU - Ayuso, C.
AU - Suchowersky, O.
AU - Trent, R. J.A.
AU - McCusker, E.
AU - Novelletto, A.
AU - Frontali, M.
AU - Jones, R.
AU - Ashizawa, T.
AU - Frank, S.
AU - Saint-Hilaire, M. H.
AU - Hersch, S. M.
AU - Rosas, H. D.
AU - Lucente, D.
AU - Harrison, M. B.
AU - Zanko, A.
AU - Abramson, R. K.
AU - Marder, K.
AU - Sequeiros, J.
AU - Paulsen, J. S.
AU - Landwehrmeyer, G. B.
AU - Myers, R. H.
AU - MacDonald, M. E.
AU - Gusella, J. F.
N1 - Funding Information: Supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (“Huntington's Disease Center Without Walls”; NS016367 ), the CHDI Foundation, Inc., and the Huntington's Disease Society of America's Coalition for the Cure. J.H.L. received a fellowship from the National Research Foundation of Korea and E.M.R. received a scholarship from the Fundação para a Ciência e a Tecnologia of Portugal (FCT). PREDICT-HD is supported by NINDS grant NS040068 . Both PREDICT-HD and COHORT are also supported by the CHDI Foundation, Inc. and REGISTRY is supported by the High Q Foundation. Funding Information: Dr. J-M. Lee reports no disclosures. Dr. Ramos received a scholarship from FCT (SFRH/BD/44335/2008) . Dr. J.-H. Lee received support from the National Research Foundation of Korea (NRF-2009–352-E0010) . Dr. Gillis and Dr. Mysore report no disclosures. Dr. Hayden serves as Editor-in-Chief of Clinical Genetics. Dr. Warby reports no disclosures. Dr. Morrison is a section editor of The Oncologist. Dr. Nance received honoraria from the Huntington's Disease Society of America HD Training Course for Physicians, the American Academy of Neurology Genetics in Neurology lecture and lectures at Augsburg College, royalties from Oxford University Press for Juvenile Huntington's Disease 2009, reimbursement for NIH Study Section service and the Parkinson Study Group Scientific Review Board, Center of Excellence support from the Huntington Disease Society of America and the National Parkinson Foundation, and grant support from Santhera Pharmaceuticals, NeuroSearch, Medivation/Pfizer, Schwarz Biosciences, IMPAX Pharmaceuticals, Neuraltus Pharmaceuticals and Teva Pharmaceuticals, National Institutes of Health NINDS grants NS044466, NS036630, NS040068, NS052592, and NS060118 , NCCAM grant AT000613 and NHGRI grant HG02449 , and grants from the CHDI Foundation (HP Therapeutics), the High Q Foundation, and the Michael J. Fox Foundation/Northwestern Dixon Foundation, and declares spousal participation in Speaker's bureaus: Roche, Sanford. Dr. Ross received research funding from National Institutes of Health NINDS grants NS16375, NS055252, NS060118, and NS069422 . Dr. Margolis received research funding from National Institutes of Health NINDS grant NS016375, Medivation/Pfizer, CHDI Foundation Inc., and Forest Laboratories and was a consultant to AstraZeneca. Dr. Squitieri and Dr. Orobello report no disclosures. Dr. Di Donato was on the Scientific Advisory Board of the Fondazione Mariani Onlus, Milan, Italy, and a consultant Advisor for Preclinical Research and International Relationships of the Scientific Direction of the Fondazione IRCSS Instituto Neurologico Carlo Besta, Milan, Italy, and received support from the Ministero della Salute, Italy, and from the Fondazione Cariplo, Milan, Italy. Dr. Gomez-Tortosa reports no disclosures. Dr. Ayuso has received research support from CIBERER, ISCIII, Madrid, Spain. Dr. Suchowersky was an Advisory Board Member for Allergan, Biovail and Novartis, on the editorial boards of the Canadian Journal of Neurological Sciences and Nature Reviews Neurology, and received support from Abbott Laboratories, from National Institutes of Health NINDS grant NS044431 , and from the CHDI Foundation, Inc. Dr. Trent reports royalties for the book Molecular Medicine, 3 rd edition (Elsevier) and support from Australian Research Council LIED grants LE0989147 and LE100100130 . Dr. McCusker is on the editorial board of Tremor and Hyperkinetic Movements. Dr. Novelletto reports no disclosures. Dr. Frontali received support from Italian Drug Agency (AIFA) grant FARM659PTX. Dr. Jones received support from the National Institutes of Health NINDS grants NS040068 and NS060118 and from the High Q Foundation and the Huntington's Disease Society of America. Dr. Ashizawa received support from the National Institutes of Health NINDS grant NS068897. Dr. Frank consulted for and received support from Lundbeck Pharmaceuticals. Dr. Saint-Hilaire was on the Steering Committee of the Safinamide (MOTION) study of EMD Serono, lectured at the meetings of the Movement Disorder Society and the American Academy of Neurology, is a member of the speaker's bureau of Teva Pharmaceuticals, and received support from Bayer, EMD Serono, and Teva Pharmaceuticals, National Institutes of Health NINDS grant NS050095 , and NHGRI grant HG02449 , and from the Michael J. Fox Foundation. Dr. Hersch was a consultant to Link Medicine and Alnylam Pharmaceuticals and received support from the National Institutes of Health NCCAM grant AT000613 , NINDS grant NS071789 , and from the Huntington's Disease Society of America. Dr. Rosas and Dr. Lucente report no disclosures. Dr. Harrison received support from National Institutes of Health NCCAM grant AT000613 , from the CHDI Foundation, Inc., and from the Huntington's Disease Society of America. Dr. Zanko reports no disclosures. Dr. Abramson received support from National Institutes of Health NICHD grant HD062550 , South Carolina Council on Disabilities grant 18120 FL00 , and a grant from the Fullerton Foundation. Dr. Marder served on the editorial board of Neurology® and as an editor of Current Neurology and Neuroscience and received support from Amarin Corporation, NeuroSearch Sweden AB, and Medivation, and from National Institutes of Health NINDS grant NS036630 , NCRR grant RR024156, and PO412196-G from NHGRI grant HG02449 at the University of Rochester as well as from the Parkinson Disease Foundation, the Huntington's Disease Society of America, the Parkinson Study Group, the Michael J. Fox Foundation, and the CHDI Foundation, Inc. Dr. Sequeiros was a compensated speaker for the Fundacion Jimenez Diaz, served on the editorial boards of Clinical Genetics, the Journal of Community Genetics, and the Journal of Biomedicine and Biotechnology, and received research support from the FCT “Financiamento Plurianual de Unidades de investigação” and from the European Commission FP6 Network of Excellence EuroGentest: Genetics Testing in Europe. Dr. Paulsen received funding from National Institutes of Health NINDS grant NS040068 and from the CHDI Foundation, Inc. Dr. Landwehrmeyer received a speaker honorarium/reimbursement from DGNP-Temmler Pharma, royalties from Neurologie Compact (Verlag) and Juvenile HD (Oxford Press), consulting support from the CHDI Foundation, Inc., clinical trial support from Medivation and Neurosearch, and support from the European Union (FP7 Paddington) and the High Q Foundation/CHDI Foundation. Dr. Myers received funding from National Institutes of Health NINDS grant NS016367 and from the Jerry MacDonald Huntington Research Fund. Dr. MacDonald serves as an Associate Editor of PLoS Genetics, is on the Board of Directors of the Huntington's Disease Society of America, and received support from National Institutes of Health NINDS grants NS016367, NS032765, and NS033648 and from the Huntington's Disease Society of America and the CHDI Foundation, Inc. Dr. Gusella is on the Scientific Advisory Board of Quest Diagnostics, Inc., is on the editorial boards of DNA and Cell Biology, Neurobiology of Disease, Neurogenetics, Biomed Central Neuroscience, Biomed Central Biology, and Molecular Autism, and received support from National Institutes of Health NINDS grants NS016367, NS024279, and NS069422 , NIGMS grant GM061354 , and NICHD grant HD06528 and from the Simons Foundation Autism Research Initiative, Autism Speaks, CHDI Foundation, Inc., and the Huntington's Disease Society of America.
PY - 2012/3/6
Y1 - 2012/3/6
N2 - 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 wellbehaved 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.
AB - 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 wellbehaved 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.
UR - http://www.scopus.com/inward/record.url?scp=84858074593&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84858074593&partnerID=8YFLogxK
U2 - 10.1212/WNL.0b013e318249f683
DO - 10.1212/WNL.0b013e318249f683
M3 - Article
C2 - 22323755
AN - SCOPUS:84858074593
VL - 78
SP - 690
EP - 695
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 10
ER -