Abstract
Background Huntington’s disease is characterised by a range of motor, psychiatric and cognitive symptoms. These present in different combinations through the disease course and impact on daily life and functioning. Huntington’s disease is caused by a dominant CAG repeat expansion in the HTT gene, and longer repeats are associated with earlier onset of motor symptoms.
Objectives To investigate the onset, prevalence and functional impact of motor and psychiatric symptoms of Huntington’s disease.
Methods We analysed clinical phenotype data from the European REGISTRY study for 6316 individuals with manifest Huntington’s disease. Onset and prevalence data for motor and psychiatric symptoms were extracted from the clinical history part of REGISTRY and the detailed Clinical Characteristics Questionnaire. Generalised linear models were constructed to assess relationships between symptoms and functional outcomes.
Results As age at first presentation of Huntington’s disease increases, the likelihood that the initial presenting symptom is motor also increases. This is not associated with pathogenic CAG repeat length. At a population level there were conserved relationships between symptoms across different repeat lengths, with depression often occurring early followed by motor and then cognitive symptoms. There were significant relationships between all individual psychiatric and cognitive symptoms and reduced functional capacity.
Conclusions There are conserved patterns of symptoms in HD that can be quantified. Psychiatric and behavioural symptoms significantly impair daily functioning and should be considered part of the disease trajectory at any age.
Competing Interest Statement
J.F.G.: Scientific Advisory Board member and has a financial interest in Triplet Therapeutics, Inc. His NIH-funded project is using genetic and genomic approaches to uncover other genes that significantly influence when diagnosable symptoms emerge and how rapidly they worsen in Huntington Disease. The company is developing new therapeutic approaches to address triplet repeat disorders such Huntington's Disease, Myotonic Dystrophy and spinocerebellar ataxias. His interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. G.B.L.: Consulting services, advisory board functions, clinical trial services and/or lectures for Allergan, Alnylam, Amarin, AOP Orphan Pharmaceuticals AG, Bayer Pharma AG, CHDI Foundation, GlaxoSmithKline, Hoffmann-LaRoche, Ipsen, ISIS Pharma, Lundbeck, Neurosearch Inc, Medesis, Medivation, Medtronic, NeuraMetrix, Novartis, Pfizer, Prana Biotechnology, Sangamo/Shire, Siena Biotech, Temmler Pharma GmbH and Teva Pharmaceuticals. He has received research grant support from the CHDI Foundation, the Bundesministerium fur Bildung und Forschung (BMBF), the Deutsche Forschungsgemeinschaft (DFG), the European Commission (EU-FP7, JPND). His study site Ulm has received compensation in the context of the observational Enroll-HD Study, TEVA, ISIS and Hoffmann-Roche and the Gossweiler Foundation. He receives royalties from the Oxford University Press and is employed by the State of Baden-Wurttemberg at the University of Ulm. A.E.R.: Chair of European Huntington's Disease Network (EHDN) executive committee, Global PI for Triplet Therapeutics L.J. is a member of the scientific advisory boards of LoQus23 Therapeutics and Triplet Therapeutics. T.H.M. is an associate member of the scientific advisory board of LoQus23 Therapeutics. B.Mc., J-M.L., M.E.M., M.O., N.M.W.: nothing to disclose
Footnotes
↵7 http://www.ehdn.org/wp-content/uploads/REGISTRY-contributors-full-list.pdf. See Appendix
Financial disclosures related to this manuscript: none
Funding sources: BMc was supported by a PhD studentship from Cardiff University School of Medicine. TM was supported by a Welsh Clinical Academic Track Fellowship, an MRC Clinical Training Fellowship (MR/P001629/1) and a Patrick Berthoud Charitable Trust Fellowship through the Association of British Neurologists. LJ, NW and PH were supported by an MRC Centre grant (MR/L010305/1).