Observing Huntington's Disease: the European Huntington's Disease Network's REGISTRY

Michael Orth, Olivia J Handley, Carsten Schwenke, Stephen B Dunnett, David Craufurd, Aileen K Ho, Edward Wild, Sarah J Tabrizi, G Bernhard Landwehrmeyer, Investigators of the European Huntington's Disease Network

Abstract

Background: Huntington's disease (HD) is a rare triplet repeat (CAG) disorder. Advanced, multi-centre, multi-national research frameworks are needed to study simultaneously multiple complementary aspects of HD. This includes the natural history of HD, its management and the collection of clinical information and biosamples for research.

Methods: We report on cross-sectional data of the first 1766 participants in REGISTRY, the European Huntington's Disease Network's (EHDN), multi-lingual, multi-national prospective observational study of HD in Europe. Data collection (demographics, phenotype, genotype, medication, co-morbidities, biosamples) followed a standard protocol.

Results: Phenotype, and the HD genotype, of manifest HD participants across different European regions was similar. Motor onset was most common (48%) with a non-motor onset in more than a third of participants. Motor signs increased, and cognitive abilities and functional capacity declined as the disease burden (CAGn-35.5) X age) increased. A life-time history of behavioural symptoms was common, but the behavioural score was not related to disease burden. One fifth of participants had severe psychiatric problems, e.g. suicidal ideation and attempts, and/or irritability/aggression, with psychosis being less common. Participants on anti-dyskinetic medication had a higher motor and lower cognitive score, were older, and more prone to physical trauma. A higher motor and a lower cognitive score predicted more advanced disease.

Conclusions: The unparalleled collection of clinical data and biomaterials within the EHDN's REGISTRY can expedite the search for disease modifiers (genetic and environmental) of age at onset and disease progression that could be harnessed for the development of novel treatments.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3037015/bin/orth-fig-1.jpg
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3037015/bin/orth-fig-2.jpg
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3037015/bin/orth-fig-3.jpg

References

    1. Huntington G. On chorea. Med Surg Reporter 1872;26:320-1.
    1. Walker FO. Huntington's disease. Lancet 2007;369:218-28.
    1. The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72:971-83.
    1. Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci 2007;30:575-621.
    1. Handley OJ, Naji JJ, Dunnett SB, Rosser AE. Pharmaceutical, cellular and genetic therapies for Huntington's disease. Clin Sci (Lond) 2006;110:73-88.
    1. Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. Mov Disord 1996;11:136-42.
    1. Shoulson I. Huntington disease: functional capacities in patients treated with neuroleptic and antidepressant drugs. Neurology 1981;31:1333-5.
    1. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561-71.
    1. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
    1. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36® Health Survey Manual and Interpretation Guide. Boston, MA: New England Medical Center, The Health Institute; 1993.
    1. Beecham J, Knapp M. Costing psychiatric interventions. In: Thornicroft G, ed. Measuring Mental Health Needs. 2nd ed. London: Gaskell; 2001.
    1. Novak M, Guest C. Application of a multidimensional caregiver burden inventory. Gerontologist 1989;29:798-803.
    1. Beck JC, Beiswanger CM, John EM, Satariano E, West D. Successful transformation of cryopreserved lymphocytes: a resource for epidemiological studies. Cancer Epidemiol Biomarkers Prev 2001;10:551-4.
    1. Bernacki SH, Stankovic AK, Williams LO, et al. Establishment of stably EBV-transformed cell lines from residual clinical blood samples for use in performance evaluation and quality assurance in molecular genetic testing. J Mol Diagn 2003;5:227-30.
    1. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.
    1. Warner JP, Barron LH, Brock DJ. A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington's disease chromosomes. Mol Cell Probes 1993;7:235-9.
    1. Riess O, Noerremoelle A, Soerensen SA, Epplen JT. Improved PCR conditions for the stretch of (CAG)n repeats causing Huntington's disease. Hum Mol Genet 1993;2:637.
    1. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159-74.
    1. Quarrell O, Brewer HM, Squitieri F, Barker RA, Nance M, Landwehrmeyer GB. Juvenile Huntington's Disease. Oxford: Oxford University Press; 2009.
    1. Penney JB, Jr., Vonsattel JP, MacDonald ME, Gusella JF, Myers RH. CAG repeat number governs the development rate of pathology in Huntington's disease. Ann Neurol 1997;41:689-92.
    1. Harper PS. The epidemiology of Huntington's disease. In: Bates G, Harper PS, Jones L, eds. Huntington's disease. Oxford: Oxford University Press; 2002:159-97.
    1. Wexler NS, Lorimer J, Porter J, et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci U S A 2004;101:3498-503. Epub 2004 Mar 1.
    1. Seldin MF, Shigeta R, Villoslada P, et al. European population substructure: clustering of northern and southern populations. PLoS Genet 2006;2:e143. Epub 2006 Jul 25.
    1. Ranen NG, Stine OC, Abbott MH, et al. Anticipation and instability of IT-15 (CAG)n repeats in parent- offspring pairs with Huntington disease. Am J Hum Genet 1995;57:593-602.
    1. Brinkman RR, Mezei MM, Theilmann J, Almqvist E, Hayden MR. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 1997;60:1202-10.
    1. Rosenblatt A, Liang KY, Zhou H, et al. The association of CAG repeat length with clinical progression in Huntington disease. Neurology 2006;66:1016-20.
    1. Starkstein SE, Leentjens AF. The nosological position of apathy in clinical practice. J Neurol Neurosurg Psychiatry 2008;79:1088-92. Epub 2008 Jan 10.
    1. Robert P, Onyike CU, Leentjens AF, et al. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur Psychiatry 2009;24:98-104. Epub 2009 Feb 7.
    1. Hobart J, Cano S, Zajicek J, Thompson A. Rating Scales as outcome measures for clinical trials in neurology: problems, solution, and recommendations. Lancet Neurology 2007;6:1094-105.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa