Journal of Neurology

, Volume 262, Issue 12, pp 2691–2698 | Cite as

Motor onset and diagnosis in Huntington disease using the diagnostic confidence level

  • Dawei Liu
  • Jeffrey D. Long
  • Ying Zhang
  • Lynn A. Raymond
  • Karen Marder
  • Anne Rosser
  • Elizabeth A. McCusker
  • James A. Mills
  • Jane S. Paulsen
  • The PREDICT-HD Investigators and Coordinators of the Huntington Study Group
Original Communication


Huntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive deterioration, and psychiatric symptoms, with progressive motor impairments being a prominent feature. The primary objectives of this study are to delineate the disease course of motor function in HD, to provide estimates of the onset of motor impairments and motor diagnosis, and to examine the effects of genetic and demographic variables on the progression of motor impairments. Data from an international multisite, longitudinal observational study of 905 prodromal HD participants with cytosine–adenine–guanine (CAG) repeats of at least 36 and with at least two visits during the followup period from 2001 to 2012 was examined for changes in the diagnostic confidence level from the Unified Huntington’s Disease Rating Scale. HD progression from unimpaired to impaired motor function, as well as the progression from motor impairment to diagnosis, was associated with the linear effect of age and CAG repeat length. Specifically, for every 1-year increase in age, the risk of transition in diagnostic confidence level increased by 11 % (95 % CI 7–15 %) and for one repeat length increase in CAG, the risk of transition in diagnostic confidence level increased by 47 % (95 % CI 27–69 %). Findings show that CAG repeat length and age increased the likelihood of the first onset of motor impairment as well as the age at diagnosis. Results suggest that more accurate estimates of HD onset age can be obtained by incorporating the current status of diagnostic confidence level into predictive models.


Huntington disease Hidden Markov model Diagnostic confidence level Prediction Diagnosis Onset 



This research is supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (5R01NS040068) awarded to Jane Paulsen; CHDI Foundation, Inc (A6266; A2015) awarded to Jane Paulsen; and Cognitive and Functional Brain Changes in Preclinical Huntington’s Disease (HD) (5R01NS054893) awarded to Jane Paulsen. We thank the PREDICT-HD sites, the study participants, the National Research Roster for Huntington Disease Patients and Families, the Huntington’s Disease Society of America, and the Huntington Study Group. This publication was supported by the National Center for Advancing Translational Sciences, and the National Institutes of Health (NIH), through Grant 2 UL1 TR000442-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

PREDICT-HD Investigators, Coordinators, Motor Raters, Cognitive Raters

Isabella De Soriano, Courtney Shadrick, and Amanda Miller (University of Iowa, Iowa City, IA, USA); Edmond Chiu, Joy Preston, Anita Goh, Stephanie Antonopoulos, and Samantha Loi (St. Vincent’s Hospital, The University of Melbourne, Kew, VIC, Australia); Phyllis Chua and Angela Komiti (The University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia); Lynn Raymond, Joji Decolongon, Mannie Fan, and Allison Coleman (University of British Columbia, Vancouver, BC, Canada); Christopher A. Ross, Mark Varvaris, Maryjane Ong, and Nadine Yoritomo (Johns Hopkins University, Baltimore, MD, USA); William M. Mallonee and Greg Suter (Hereditary Neurological Disease Centre, Wichita, KS, USA); Ali Samii, Emily P. Freney, and Alma Macaraeg (University of Washington and VA Puget Sound Health Care System, Seattle, WA, USA); Randi Jones, Cathy Wood-Siverio, and Stewart A. Factor (Emory University School of Medicine, Atlanta, GA, USA); Roger A. Barker, Sarah Mason, and Natalie Valle Guzman (John van Geest Centre for Brain Repair, Cambridge, UK); Elizabeth McCusker, Jane Griffith, Clement Loy, Jillian McMillan, and David Gunn (Westmead Hospital, Sydney, NSW, Australia); Michael Orth, Sigurd Süβmuth, Katrin Barth, Sonja Trautmann, Daniela Schwenk, and Carolin Eschenbach (University of Ulm, Ulm, Germany); Kimberly Quaid, Melissa Wesson, and Joanne Wojcieszek (Indiana University School of Medicine, Indianapolis, IN, USA); Mark Guttman, Alanna Sheinberg, Albie Law, and Irita Karmalkar (Centre for Addiction and Mental Health, University of Toronto, Markham, ON, Canada); Susan Perlman and Brian Clemente (UCLA Medical Center, Los Angeles, CA, USA); Michael D. Geschwind, Sharon Sha, Joseph Winer, and Gabriela Satris (University of California, San Francisco, San Francisco, CA, USA); Tom Warner and Maggie Burrows (National Hospital for Neurology and Neurosurgery, London, UK); Anne Rosser, Kathy Price, and Sarah Hunt (Cardiff University, Cardiff, Wales, UK); Frederick Marshall, Amy Chesire, Mary Wodarski, and Charlyne Hickey (University of Rochester, Rochester, NY, USA); Peter Panegyres, Joseph Lee, Maria Tedesco, and Brenton Maxwell (Neurosciences Unit, Graylands, Selby-Lemnos & Special Care Health Services, Perth, WA, Australia); Joel Perlmutter, Stacey Barton, and Shineeka Smith (Washington University, St. Louis, MO, USA); Zosia Miedzybrodzka, Daniela Rae, Vivien Vaughan, and Mariella D’Alessandro (Clinical Genetics Centre, Aberdeen, Scotland, UK); David Craufurd, Judith Bek, and Elizabeth Howard (University of Manchester, Manchester, UK); Pietro Mazzoni, Karen Marder, and Paula Wasserman (Columbia University Medical Center, New York, NY, USA); Rajeev Kumar, Diane Erickson, Christina Reeves, and Breanna Nickels (Colorado Neurological Institute, Englewood, CO, USA); Vicki Wheelock, Lisa Kjer, Amanda Martin, and Sarah Farias (University of California, Davis, Sacramento, CA, USA); Wayne Martin, Oksana Suchowersky, Pamela King, Marguerite Wieler, and Satwinder Sran (University of Alberta, Edmonton, AB, Canada); and Anwar Ahmed, Stephen Rao, Christine Reece, Alex Bura, and Lyla Mourany (Cleveland Clinic Foundation, Cleveland, OH, USA).

Executive Committee

Principal Investigator Jane S. Paulsen, Jeffrey D. Long, Hans J. Johnson, Thomas Brashers-Krug, Phil Danzer, Amanda Miller, H. Jeremy Bockholt, and Kelsey Montross.

Scientific Consultants

Deborah Harrington (University of California, San Diego); Holly Westervelt (Rhode Island Hospital/Alpert Medical School of Brown University); Elizabeth Aylward (Seattle Children’s Research Institute); Stephen Rao (Cleveland Clinic); David J. Moser, Janet Williams, Nancy Downing, Vincent A. Magnotta, Hans J. Johnson, Thomas Brashers-Krug, Jatin Vaidya, Daniel O’Leary, and Eun Young Kim (University of Iowa).

Core Sections

Biostatistics: Jeffrey D. Long, Ji-In Kim, Spencer Lourens (University of Iowa); Ying Zhang and Wenjing Lu (University of Indiana).

Ethics: Cheryl Erwin (Texas Tech University Health Sciences Center); Thomas Brashers-Krug, Janet Williams (University of Iowa); and Martha Nance (University of Minnesota).

Biomedical Informatics: H. Jeremy Bockholt, Jason Evans, and Roland Zschiegner (University of Iowa).

Compliance with ethical standards

Conflicts of interest

J. Paulsen is the principal investigator for PREDICT-HD and has therefore received grant funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke as detailed above. J. Paulsen has also served on an advisory board for Lundbeck, LLC, and has a consulting agreement with ProPhase, LLC. J. Long has a consulting agreement with NeuroPhage, LLC. All other authors declare no conflicts of interest.

Ethical standards

PREDICT-HD was approved by the institutional review boards at the University of Iowa and each participating site, and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from each participant.

Supplementary material

415_2015_7900_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 21 kb)


  1. 1.
    Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983. doi: 10.1016/0092-8674(93)90585-E CrossRefGoogle Scholar
  2. 2.
    Walker FO (2007) Huntington’s disease. Lancet 369:218–228. doi: 10.1016/S0140-6736(07)60111-1 CrossRefPubMedGoogle Scholar
  3. 3.
    Roos RA (2010) Huntington’s disease: a clinical review. Orphanet J Rare Dis 5:40. doi: 10.1186/1750-1172-5-40 PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Huntington Study Group (1996) Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 11:136–142. doi: 10.1002/mds.870110204 CrossRefGoogle Scholar
  5. 5.
    Penney JB Jr, Young AB, Shoulson I et al (1990) Huntington’s disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals. Mov Disord 5:93–99. doi: 10.1002/mds.870050202 CrossRefPubMedGoogle Scholar
  6. 6.
    Louis ED, Lee P, Quinn L, Marder K (1999) Dystonia in Huntington’s disease: prevalence and clinical characteristics. Mov Disord 14:95–101CrossRefPubMedGoogle Scholar
  7. 7.
    Kirkwood SC, Siemers E, Bond C, Conneally PM, Christian JC, Foroud T (2000) Confirmation of subtle motor changes among presymptomatic carriers of the Huntington disease gene. Arch Neurol 57:1040–1044. doi: 10.1001/archneur.57.7.1040 CrossRefPubMedGoogle Scholar
  8. 8.
    Garcia Ruiz PJ, Hernandez J, Cantarero S, Bartolome M, Sanchez Bernardos V, Garcia de Yebenez J (2002) Bradykinesia in Huntington’s disease. A prospective, follow-up study. J Neurol 249:437–440. doi: 10.1007/s004150200035 CrossRefPubMedGoogle Scholar
  9. 9.
    Blekher TM, Yee RD, Kirkwood SC, Hake AM, Stout JC, Weaver MR, Foroud TM (2004) Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington’s disease. Vision Res 44:2729–2736. doi: 10.1016/j.visres.2004.06.006 CrossRefPubMedGoogle Scholar
  10. 10.
    Biglan KM, Zhang Y, Long JD, Geschwind M, Kang GA, Killoran A, Lu W, McCusker E, Mills JA, Raymond LA, Testa C, Wojcieszek J, Paulsen JS, PREDICT-HD Investigators of the Huntington Study Group (2013) Refining the diagnosis of Huntington disease: the PREDICT-HD study. Front Aging Neurosci 5:12. doi: 10.3389/fnagi.2013.00012 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Biglan KM, Ross CA, Langbehn DR, Aylward EH, Stout JC, Queller S, Carlozzi NE, Duff K, Beglinger LJ, Paulsen JS, PREDICT-HD Investigators of the Huntington Study Group (2009) Motor abnormalities in premanifest persons with Huntington’s disease: the PREDICT-HD study. Mov Disord 24:1763–1772. doi: 10.1002/mds.22601 PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA, Graham RK, Hayden MR (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 4:398–403. doi: 10.1038/ng0893-398 CrossRefPubMedGoogle Scholar
  13. 13.
    Stine OC, Pleasant N, Franz ML, Abbott MH, Folstein SE, Ross CA (1993) Correlation between the onset age of Huntington’s disease and length of the trinucleotide repeat in IT-15. Hum Mol Genet 2:1547–1549. doi: 10.1093/hmg/2.10.1547 CrossRefPubMedGoogle Scholar
  14. 14.
    Lucotte G, Turpin JC, Riess O, Epplen JT, Siedlaczk I, Loirat F, Hazout S (1995) Confidence intervals for predicted age of onset, given the size of (CAG)n repeat, in Huntington’s disease. Hum Genet 95:231–232. doi: 10.1007/BF00209410 CrossRefPubMedGoogle Scholar
  15. 15.
    Foroud T, Gray J, Ivashina J, Conneally PM (1999) Differences in duration of Huntington’s disease based on age at onset. J Neurol Neurosurg Psychiatry 66:52–56. doi: 10.1136/jnnp.66.1.52 PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Squitieri F, Sabbadini G, Mandich P, Gellera C, Di Maria E, Bellone E, Castellotti B, Nargi E, de Grazia U, Frontali M, Novelletto A (2000) Family and molecular data for a fine analysis of age at onset in Huntington disease. Am J Med Genet 95:366–373. doi: 10.1002/1096-8628(20001211)95:4<366::AID-AJMG13>3.0.CO;2-2 CrossRefPubMedGoogle Scholar
  17. 17.
    Langbehn DR, Hayden MR, Paulsen JS, PREDICT-HD Investigators of the Huntington Study Group (2010) CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. Am J Med Genet B Neuropsychiatr Genet 153B:397–408. doi: 10.1002/ajmg.b.30992 PubMedCentralPubMedGoogle Scholar
  18. 18.
    Andresen JM, Gayan J, Cherny SS, Brocklebank D, Alkorta-Aranburu G, Addis EA, Cardon LR, Housman DE, Wexler NS (2007) Replication of twelve association studies for Huntington’s disease residual age of onset in large Venezuelan kindreds. J Med Genet 44:44–50. doi: 10.1136/jmg.2006.045153 PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Paulsen JS, Magnotta VA, Mikos AE, Paulson HL, Penziner E, Andreasen NC, Nopoulos PC (2006) Brain structure in preclinical Huntington’s disease. Biol Psychiatry 59:57–63. doi: 10.1016/j.biopsych.2005.06.003 CrossRefPubMedGoogle Scholar
  20. 20.
    Paulsen JS, Langbehn DR, Stout JC, Aylward E, Ross CA, Nance M, Guttman M, Johnson S, MacDonald M, Beglinger LJ, Duff K, Kayson E, Biglan K, Shoulson I, Oakes D, Hayden M, PREDICT-HD Investigators and Coordinators of the Huntington Study Group (2008) Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry 79:874–880. doi: 10.1136/jnnp.2007.128728 PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Paulsen JS, Long JD, Johnson HJ, Aylward EH, Ross CA, Williams JK, Nance MA, Erwin CJ, Westervelt HJ, Harrington DL, Bockholt HJ, Zhang Y, McCusker EA, Chiu EM, Panegyres PK, PREDICT-HD Investigators and Coordinators of the Huntington Study Group (2014) Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: a decade of the PREDICT-HD study. Front Aging Neurosci 6:78. doi: 10.3389/fnagi.2014.00078 PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Paulsen JS, Hayden M, Stout JC, Langbehn DR, Aylward E, Ross CA, Guttman M, Nance M, Kieburtz K, Oakes D, Shoulson I, Kayson E, Johnson S, Penziner E, Predict-HD Investigators of the Huntington Study Group (2006) Preparing for preventive clinical trials: the Predict-HD study. Arch Neurol 63:883–890. doi: 10.1001/archneur.63.6.883 CrossRefPubMedGoogle Scholar
  23. 23.
    Warner JP, Barron LH, Brock DJ (1993) A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington’s disease chromosomes. Mol Cell Probes 7:235–239. doi: 10.1006/mcpr.1993.1034 CrossRefPubMedGoogle Scholar
  24. 24.
    Witjes-Ane MN, Mertens B, van Vugt JP, Bachoud-Levi AC, van Ommen GJ, Roos RA (2007) Longitudinal evaluation of “presymptomatic” carriers of Huntington’s disease. J Neuropsychiatry Clin Neurosci 19:310–317. doi: 10.1176/appi.neuropsych.19.3.310 CrossRefPubMedGoogle Scholar
  25. 25.
    Hogarth P, Kayson E, Kieburtz K, Marder K, Oakes D, Rosas D, Shoulson I, Wexler NS, Young AB, Zhao H (2005) Interrater agreement in the assessment of motor manifestations of Huntington’s disease. Mov Disord 20:293–297. doi: 10.1002/mds.20332 CrossRefPubMedGoogle Scholar
  26. 26.
    Rabiner LR (1989) A tutorial on hidden Markov models and selected applications in speech recognition. Proc IEEE 77:257–286. doi: 10.1109/5.18626 CrossRefGoogle Scholar
  27. 27.
    Zucchini W, MacDonald IL (2009) Hidden Markov models for time series : an introduction using R. CRC Press, Boca RatonCrossRefGoogle Scholar
  28. 28.
    Jackson CH (2011) Multi-state models for panel data: the msm package for R. J Stat Softw 38:1–28. doi: 10.18637/jss.v038.i08 CrossRefGoogle Scholar
  29. 29.
    Rubinsztein DC, Leggo J, Coles R et al (1996) Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet 59:16–22PubMedCentralPubMedGoogle Scholar
  30. 30.
    Sequeiros J, Ramos EM, Cerqueira J, Costa MC, Sousa A, Pinto-Basto J, Alonso I (2010) Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population. Clin Genet 78:381–387. doi: 10.1111/j.1399-0004.2010.01388.x CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Dawei Liu
    • 1
    • 2
  • Jeffrey D. Long
    • 1
    • 3
  • Ying Zhang
    • 4
  • Lynn A. Raymond
    • 5
  • Karen Marder
    • 6
    • 7
  • Anne Rosser
    • 8
    • 9
  • Elizabeth A. McCusker
    • 10
  • James A. Mills
    • 1
  • Jane S. Paulsen
    • 1
    • 11
    • 12
  • The PREDICT-HD Investigators and Coordinators of the Huntington Study Group
  1. 1.Department of PsychiatryCarver College of Medicine, The University of IowaIowa CityUSA
  2. 2.BiogenCambridgeUSA
  3. 3.Department of BiostatisticsCollege of Public Health, The University of Iowa, S160 CPHBIowa CityUSA
  4. 4.Department of BiostatisticsIndiana University Fairbanks School of Public HealthIndianapolisUSA
  5. 5.Department of Psychiatry and Brain Research CentreUniversity of British ColumbiaVancouverCanada
  6. 6.Department of Neurology, Gertrude H. Sergievsky Center, Taub Institute on Alzheimers Disease and the Aging BrainColumbia University College of Physicians and SurgeonsNew YorkUSA
  7. 7.Department of PsychiatryColumbia University Medical CenterNew YorkUSA
  8. 8.Institute for Psychological Medicine and Clinical NeurosciencesCardiff University School of MedicineCardiffUK
  9. 9.School of BiosciencesCardiff UniversityCardiffUK
  10. 10.Department of NeurologyWestmead Hospital, The University of SydneyWestmeadAustralia
  11. 11.Department of Neurology, Carver College of MedicineThe University of IowaIowa CityUSA
  12. 12.Department of PsychologyThe University of IowaIowa CityUSA

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