Skip to main content

Advertisement

Springer Nature Link
Log in

Huntington’s Disease: Relationship Between Phenotype and Genotype

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disease with the typical manifestations of involuntary movements, psychiatric and behavior disorders, and cognitive impairment. It is caused by the dynamic mutation in CAG triplet repeat number in exon 1 of huntingtin (HTT) gene. The symptoms of HD especially the age at onset are related to the genetic characteristics, both the CAG triplet repeat and the modified factors. Here, we reviewed the recent advancement on the genotype-phenotype relationship of HD, mainly focus on the characteristics of different expanded CAG repeat number, genetic modifiers, and CCG repeat number in the 3′ end of CAG triplet repeat and their effects on the phenotype. We also reviewed the special forms of HD (juvenile HD, atypical onset HD, and homozygous HD) and their phenotype-genotype correlations. The review will aid clinicians to predict the onset age and disease course of HD, give the genetic counseling, and accelerate research into the HD mechanism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Gonzalez-Alegre P, Afifi AK (2006) Clinical characteristics of childhood-onset (juvenile) Huntington disease: report of 12 patients and review of the literature. J Child Neurol 21:223–9

    PubMed  Google Scholar 

  2. Milunsky JM, Maher TA, Loose BA, Darras BT, Ito M (2003) XL PCR for the detection of large trinucleotide expansions in juvenile Huntington’s disease. Clin Genet 64:70–3

    Article  CAS  PubMed  Google Scholar 

  3. Nicolas G, Devys D, Goldenberg A, Maltete D, Herve C, Hannequin D, Guyant-Marechal L (2011) Juvenile Huntington disease in an 18-month-old boy revealed by global developmental delay and reduced cerebellar volume. Am J Med Genet A 155A:815–8. doi:10.1002/ajmg.a.33911

    Article  PubMed  Google Scholar 

  4. Roos RA (2010) Huntington’s disease: a clinical review. Orphanet J Rare Dis 5:40. doi:10.1186/1750-1172-5-40

    Article  PubMed  PubMed Central  Google Scholar 

  5. Fisher ER, Hayden MR (2014) Multisource ascertainment of Huntington disease in Canada: prevalence and population at risk. Mov Disord 29:105–14. doi:10.1002/mds.25717

    Article  PubMed  Google Scholar 

  6. Squitieri F, Andrew SE, Goldberg YP, Kremer B, Spence N, Zeisler J, Nichol K, Theilmann J et al (1994) DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. Hum Mol Genet 3:2103–14

    Article  CAS  PubMed  Google Scholar 

  7. Warby SC, Montpetit A, Hayden AR, Carroll JB, Butland SL, Visscher H, Collins JA, Semaka A et al (2009) CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am J Hum Genet 84:351–66. doi:10.1016/j.ajhg.2009.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. The American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group (1998) ACMG/ASHG statement. Laboratory guidelines for Huntington disease genetic testing. Am J Hum Genet 62:1243–7

    Article  Google Scholar 

  9. Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C et al (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4:387–92. doi:10.1038/ng0893-387

    Article  CAS  PubMed  Google Scholar 

  10. Jiang H, Sun YM, Hao Y, Yan YP, Chen K, Xin SH, Tang YP, Li XH et al (2014) Huntingtin gene CAG repeat numbers in Chinese patients with Huntington’s disease and controls. Eur J Neurol 21:637–42. doi:10.1111/ene.12366

    Article  CAS  PubMed  Google Scholar 

  11. Lee JM, Ramos EM, Lee JH, Gillis T, Mysore JS, Hayden MR, Warby SC, Morrison P et al (2012) CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 78:690–5. doi:10.1212/WNL.0b013e318249f683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, Marder K, Penchaszadeh G et al (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci U S A 101:3498–503. doi:10.1073/pnas.0308679101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Claes S, Van Zand K, Legius E, Dom R, Malfroid M, Baro F, Godderis J, Cassiman JJ (1995) Correlations between triplet repeat expansion and clinical features in Huntington’s disease. Arch Neurol 52:749–53

    Article  CAS  PubMed  Google Scholar 

  14. Kieburtz K, MacDonald M, Shih C, Feigin A, Steinberg K, Bordwell K, Zimmerman C, Srinidhi J et al (1994) Trinucleotide repeat length and progression of illness in Huntington’s disease. J Med Genet 31:872–4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Furtado S, Suchowersky O, Rewcastle B, Graham L, Klimek ML, Garber A (1996) Relationship between trinucleotide repeats and neuropathological changes in Huntington’s disease. Ann Neurol 39:132–6. doi:10.1002/ana.410390120

    Article  CAS  PubMed  Google Scholar 

  16. Brandt J, Bylsma FW, Gross R, Stine OC, Ranen N, Ross CA (1996) Trinucleotide repeat length and clinical progression in Huntington’s disease. Neurology 46:527–31

    Article  CAS  PubMed  Google Scholar 

  17. Penney JB Jr, Vonsattel JP, MacDonald ME, Gusella JF, Myers RH (1997) CAG repeat number governs the development rate of pathology in Huntington’s disease. Ann Neurol 41:689–92. doi:10.1002/ana.410410521

    Article  PubMed  Google Scholar 

  18. Mahant N, McCusker EA, Byth K, Graham S (2003) Huntington’s disease: clinical correlates of disability and progression. Neurology 61:1085–92

    Article  CAS  PubMed  Google Scholar 

  19. Rosenblatt A, Liang KY, Zhou H, Abbott MH, Gourley LM, Margolis RL, Brandt J, Ross CA (2006) The association of CAG repeat length with clinical progression in Huntington disease. Neurology 66:1016–20. doi:10.1212/01.wnl.0000204230.16619.d9

    Article  CAS  PubMed  Google Scholar 

  20. Ravina B, Romer M, Constantinescu R, Biglan K, Brocht A, Kieburtz K, Shoulson I, McDermott MP (2008) The relationship between CAG repeat length and clinical progression in Huntington’s disease. Mov Disord 23:1223–7. doi:10.1002/mds.21988

    Article  PubMed  Google Scholar 

  21. De Rooij KE, De Koning Gans PA, Skraastad MI, Belfroid RD, Vegter-Van Der Vlis M, Roos RA, Bakker E, Van Ommen GJ et al (1993) Dynamic mutation in Dutch Huntington’s disease patients: increased paternal repeat instability extending to within the normal size range. J Med Genet 30:996–1002

    Article  PubMed  PubMed Central  Google Scholar 

  22. Goldberg YP, Kremer B, Andrew SE, Theilmann J, Graham RK, Squitieri F, Telenius H, Adam S et al (1993) Molecular analysis of new mutations for Huntington’s disease: intermediate alleles and sex of origin effects. Nat Genet 5:174–9. doi:10.1038/ng1093-174

    Article  CAS  PubMed  Google Scholar 

  23. Hendricks AE, Latourelle JC, Lunetta KL, Cupples LA, Wheeler V, MacDonald ME, Gusella JF, Myers RH (2009) Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27–35 CAG). Am J Med Genet A 149A:1375–81. doi:10.1002/ajmg.a.32901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Semaka A, Kay C, Doty C, Collins JA, Bijlsma EK, Richards F, Goldberg YP, Hayden MR (2013) CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease. J Med Genet 50:696–703. doi:10.1136/jmedgenet-2013-101796

    Article  CAS  PubMed  Google Scholar 

  25. 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 78:381–7. doi:10.1111/j.1399-0004.2010.01388.x

    Article  CAS  PubMed  Google Scholar 

  26. Brocklebank D, Gayan J, Andresen JM, Roberts SA, Young AB, Snodgrass SR, Penney JB, Ramos-Arroyo MA et al (2009) Repeat instability in the 27–39 CAG range of the HD gene in the Venezuelan kindreds: counseling implications. Am J Med Genet B Neuropsychiatr Genet 150B:425–9. doi:10.1002/ajmg.b.30826

    Article  CAS  PubMed  Google Scholar 

  27. Andrich J, Arning L, Wieczorek S, Kraus PH, Gold R, Saft C (2008) Huntington’s disease as caused by 34 CAG repeats. Mov Disord 23:879–81. doi:10.1002/mds.21958

    Article  PubMed  Google Scholar 

  28. Groen JL, de Bie RM, Foncke EM, Roos RA, Leenders KL, Tijssen MA (2010) Late-onset Huntington disease with intermediate CAG repeats: true or false? J Neurol Neurosurg Psychiatry 81:228–30. doi:10.1136/jnnp.2008.170902

    Article  PubMed  Google Scholar 

  29. Ha AD, Jankovic J (2011) Exploring the correlates of intermediate CAG repeats in Huntington disease. Postgrad Med 123:116–21. doi:10.3810/pgm.2011.09.2466

    Article  PubMed  Google Scholar 

  30. Herishanu YO, Parvari R, Pollack Y, Shelef I, Marom B, Martino T, Cannella M, Squitieri F (2009) Huntington disease in subjects from an Israeli Karaite community carrying alleles of intermediate and expanded CAG repeats in the HTT gene: Huntington disease or phenocopy? J Neurol Sci 277:143–6. doi:10.1016/j.jns.2008.11.005

    Article  CAS  PubMed  Google Scholar 

  31. Kenney C, Powell S, Jankovic J (2007) Autopsy-proven Huntington’s disease with 29 trinucleotide repeats. Mov Disord 22:127–30. doi:10.1002/mds.21195

    Article  PubMed  Google Scholar 

  32. Squitieri F, Esmaeilzadeh M, Ciarmiello A, Jankovic J (2011) Caudate glucose hypometabolism in a subject carrying an unstable allele of intermediate CAG(33) repeat length in the Huntington’s disease gene. Mov Disord 26:925–7. doi:10.1002/mds.23623

    Article  PubMed  Google Scholar 

  33. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ, Chotai K, Connarty M 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(1):16–22

  34. Killoran A, Biglan KM, Jankovic J, Eberly S, Kayson E, Oakes D, Young AB, Shoulson I (2013) Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS. Neurology 80:2022–7. doi:10.1212/WNL.0b013e318294b304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Panegyres PK, Goh JG (2011) The neurology and natural history of patients with indeterminate CAG repeat length mutations of the Huntington disease gene. J Neurol Sci 301:14–20. doi:10.1016/j.jns.2010.11.015

    Article  CAS  PubMed  Google Scholar 

  36. Quarrell OW, Rigby AS, Barron L, Crow Y, Dalton A, Dennis N, Fryer AE, Heydon F et al (2007) Reduced penetrance alleles for Huntington’s disease: a multi-centre direct observational study. J Med Genet 44:e68. doi:10.1136/jmg.2006.045120

    Article  PubMed  PubMed Central  Google Scholar 

  37. Tang Y, Wang Y, Yang P, Liu Y, Wang B, Podolsky R, McIndoe R, Wang CY (2006) Intergeneration CAG expansion and contraction in a Chinese HD family. Am J Med Genet B Neuropsychiatr Genet 141B:242–4. doi:10.1002/ajmg.b.30261

    Article  CAS  PubMed  Google Scholar 

  38. Metzger S, Rong J, Nguyen HP, Cape A, Tomiuk J, Soehn AS, Propping P, Freudenberg-Hua Y et al (2008) Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington’s disease. Hum Mol Genet 17:1137–46. doi:10.1093/hmg/ddn003

    Article  CAS  PubMed  Google Scholar 

  39. Karadima G, Dimovasili C, Koutsis G, Vassilopoulos D, Panas M (2012) Age at onset in Huntington’s disease: replication study on the association of HAP1. Parkinsonism Relat Disord 18:1027–8. doi:10.1016/j.parkreldis.2012.05.020

    Article  PubMed  Google Scholar 

  40. Taherzadeh-Fard E, Saft C, Andrich J, Wieczorek S, Arning L (2009) PGC-1alpha as modifier of onset age in Huntington disease. Mol Neurodegener 4:10. doi:10.1186/1750-1326-4-10

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chergui K, Bouron A, Normand E, Mulle C (2000) Functional GluR6 kainate receptors in the striatum: indirect downregulation of synaptic transmission. J Neurosci 20:2175–82

    CAS  PubMed  Google Scholar 

  42. Diguet E, Fernagut PO, Normand E, Centelles L, Mulle C, Tison F (2004) Experimental basis for the putative role of GluR6/kainate glutamate receptor subunit in Huntington’s disease natural history. Neurobiol Dis 15:667–75. doi:10.1016/j.nbd.2003.12.010

    Article  CAS  PubMed  Google Scholar 

  43. MacDonald ME, Vonsattel JP, Shrinidhi J, Couropmitree NN, Cupples LA, Bird ED, Gusella JF, Myers RH (1999) Evidence for the GluR6 gene associated with younger onset age of Huntington’s disease. Neurology 53:1330–2

    Article  CAS  PubMed  Google Scholar 

  44. Rubinsztein DC, Leggo J, Chiano M, Dodge A, Norbury G, Rosser E, Craufurd D (1997) Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc Natl Acad Sci U S A 94:3872–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Andresen JM, Gayan J, Cherny SS, Brocklebank D, Alkorta-Aranburu G, Addis EA, Group US-VCR, Cardon LR et al (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

    Article  CAS  PubMed  Google Scholar 

  46. Dhaenens CM, Burnouf S, Simonin C, Van Brussel E, Duhamel A, Defebvre L, Duru C, Vuillaume I et al (2009) A genetic variation in the ADORA2A gene modifies age at onset in Huntington’s disease. Neurobiol Dis 35:474–6. doi:10.1016/j.nbd.2009.06.009

    Article  CAS  PubMed  Google Scholar 

  47. Sando SB, Melquist S, Cannon A, Hutton ML, Sletvold O, Saltvedt I, White LR, Lydersen S et al (2008) APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from central Norway. BMC Neurol 8:9. doi:10.1186/1471-2377-8-9

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kehoe P, Krawczak M, Harper PS, Owen MJ, Jones AL (1999) Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J Med Genet 36:108–11

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Panas M, Avramopoulos D, Karadima G, Petersen MB, Vassilopoulos D (1999) Apolipoprotein E and presenilin-1 genotypes in Huntington’s disease. J Neurol 246:574–7

    Article  CAS  PubMed  Google Scholar 

  50. Kalman J, Juhasz A, Majtenyi K, Rimanoczy A, Jakab K, Gardian G, Rasko I, Janka Z (2000) Apolipoprotein E polymorphism in Pick’s disease and in Huntington’s disease. Neurobiol Aging 21:555–8

    Article  CAS  PubMed  Google Scholar 

  51. Panegyres PK, Beilby J, Bulsara M, Toufexis K, Wong C (2006) A study of potential interactive genetic factors in Huntington’s disease. Eur Neurol 55:189–92. doi:10.1159/000093867

    Article  PubMed  Google Scholar 

  52. Saft C, Andrich JE, Brune N, Gencik M, Kraus PH, Przuntek H, Epplen JT (2004) Apolipoprotein E genotypes do not influence the age of onset in Huntington’s disease. J Neurol Neurosurg Psychiatry 75:1692–6. doi:10.1136/jnnp.2003.022756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Holbert S, Denghien I, Kiechle T, Rosenblatt A, Wellington C, Hayden MR, Margolis RL, Ross CA et al (2001) The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington’s disease pathogenesis. Proc Natl Acad Sci U S A 98:1811–6. doi:10.1073/pnas.041566798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Metzger S, Saukko M, Van Che H, Tong L, Puder Y, Riess O, Nguyen HP (2010) Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum Genet 128:453–9. doi:10.1007/s00439-010-0873-9

    Article  CAS  PubMed  Google Scholar 

  55. Soyal SM, Felder TK, Auer S, Hahne P, Oberkofler H, Witting A, Paulmichl M, Landwehrmeyer GB et al (2012) A greatly extended PPARGC1A genomic locus encodes several new brain-specific isoforms and influences Huntington disease age of onset. Hum Mol Genet 21:3461–73. doi:10.1093/hmg/dds177

    Article  CAS  PubMed  Google Scholar 

  56. Xu EH, Tang Y, Li D, Jia JP (2009) Polymorphism of HD and UCHL-1 genes in Huntington’s disease. J Clin Neurosci 16:1473–7. doi:10.1016/j.jocn.2009.03.027

    Article  CAS  PubMed  Google Scholar 

  57. Kloster E, Saft C, Epplen JT, Arning L (2013) CNR1 variation is associated with the age at onset in Huntington disease. Eur J Med Genet 56:416–9. doi:10.1016/j.ejmg.2013.05.007

    Article  PubMed  Google Scholar 

  58. Li JL, Hayden MR, Almqvist EW, Brinkman RR, Durr A, Dode C, Morrison PJ, Suchowersky O et al (2003) A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. Am J Hum Genet 73:682–7. doi:10.1086/378133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Li JL, Hayden MR, Warby SC, Durr A, Morrison PJ, Nance M, Ross CA, Margolis RL et al (2006) Genome-wide significance for a modifier of age at neurological onset in Huntington’s disease at 6q23-24: the HD MAPS study. BMC Med Genet 7:71. doi:10.1186/1471-2350-7-71

    Article  PubMed  PubMed Central  Google Scholar 

  60. Gayan J, Brocklebank D, Andresen JM, Alkorta-Aranburu G, Zameel Cader M, Roberts SA, Cherny SS, Wexler NS et al (2008) Genomewide linkage scan reveals novel loci modifying age of onset of Huntington’s disease in the Venezuelan HD kindreds. Genet Epidemiol 32:445–53. doi:10.1002/gepi.20317

    Article  PubMed  Google Scholar 

  61. Genetic Modifiers of Huntington’s Disease C (2015) Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell 162:516–26. doi: 10.1016/j.cell.2015.07.003

  62. Gusella JF, MacDonald ME (2009) Huntington’s disease: the case for genetic modifiers. Genome Med 1:80. doi:10.1186/gm80

    Article  PubMed  PubMed Central  Google Scholar 

  63. Gusella JF, MacDonald ME, Lee JM (2014) Genetic modifiers of Huntington’s disease. Mov Disord 29:1359–65. doi:10.1002/mds.26001

    Article  CAS  PubMed  Google Scholar 

  64. Joshi PK, Esko T, Mattsson H, Eklund N, Gandin I, Nutile T, Jackson AU, Schurmann C et al (2015) Directional dominance on stature and cognition in diverse human populations. Nature 523:459–62. doi:10.1038/nature14618

    Article  PubMed  PubMed Central  Google Scholar 

  65. Bhattacharyya A, Thakur AK, Chellgren VM, Thiagarajan G, Williams AD, Chellgren BW, Creamer TP, Wetzel R (2006) Oligoproline effects on polyglutamine conformation and aggregation. J Mol Biol 355:524–35. doi:10.1016/j.jmb.2005.10.053

    Article  CAS  PubMed  Google Scholar 

  66. Rockabrand E, Slepko N, Pantalone A, Nukala VN, Kazantsev A, Marsh JL, Sullivan PG, Steffan JS et al (2007) The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet 16:61–77. doi:10.1093/hmg/ddl440

    Article  CAS  PubMed  Google Scholar 

  67. Morovvati S, Nakagawa M, Osame M, Karami A (2008) Analysis of CCG repeats in Huntingtin gene among HD patients and normal populations in Japan. Arch Med Res 39:131–3. doi:10.1016/j.arcmed.2007.06.015

    Article  CAS  PubMed  Google Scholar 

  68. Vuillaume I, Vermersch P, Destee A, Petit H, Sablonniere B (1998) Genetic polymorphisms adjacent to the CAG repeat influence clinical features at onset in Huntington’s disease. J Neurol Neurosurg Psychiatry 64:758–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang BR, Tian J, Yan YP, Yin XZ, Zhao GH, Wu ZY, Gu WH, Xia K et al (2012) CCG polymorphisms in the huntingtin gene have no effect on the pathogenesis of patients with Huntington’s disease in mainland Chinese families. J Neurol Sci 312:92–6. doi:10.1016/j.jns.2011.08.015

    Article  CAS  PubMed  Google Scholar 

  70. Agostinho Lde A, Rocha CF, Medina-Acosta E, Barboza HN, da Silva AF, Pereira SP, da Silva IS, Paradela ER et al (2012) Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease. J Hum Genet 57:796–803. doi:10.1038/jhg.2012.120

    Article  PubMed  Google Scholar 

  71. Masuda N, Goto J, Murayama N, Watanabe M, Kondo I, Kanazawa I (1995) Analysis of triplet repeats in the huntingtin gene in Japanese families affected with Huntington’s disease. J Med Genet 32:701–5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pramanik S, Basu P, Gangopadhaya PK, Sinha KK, Jha DK, Sinha S, Das SK, Maity BK et al (2000) Analysis of CAG and CCG repeats in Huntingtin gene among HD patients and normal populations of India. Eur J Hum Genet 8:678–82. doi:10.1038/sj.ejhg.5200515

    Article  CAS  PubMed  Google Scholar 

  73. Saleem Q, Roy S, Murgood U, Saxena R, Verma IC, Anand A, Muthane U, Jain S et al (2003) Molecular analysis of Huntington’s disease and linked polymorphisms in the Indian population. Acta Neurol Scand 108:281–6

    Article  CAS  PubMed  Google Scholar 

  74. Liu ZJ, Sun YM, Ni W, Dong Y, Shi SS, Wu ZY (2013) Clinical features of Chinese patients with Huntington’s disease carrying CAG repeats beyond 60 within HTT gene. Clin Genet. doi:10.1111/cge.12120

    PubMed Central  Google Scholar 

  75. Osborne JP, Munson P, Burman D (1982) Huntington’s chorea. Report of 3 cases and review of the literature. Arch Dis Child 57:99–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ramaswamy S, McBride JL, Kordower JH (2007) Animal models of Huntington’s disease. ILAR J 48:356–73

    Article  CAS  PubMed  Google Scholar 

  77. Squitieri F, Frati L, Ciarmiello A, Lastoria S, Quarrell O (2006) Juvenile Huntington’s disease: does a dosage-effect pathogenic mechanism differ from the classical adult disease? Mech Ageing Dev 127:208–12. doi:10.1016/j.mad.2005.09.012

    Article  PubMed  Google Scholar 

  78. Ranen NG, Stine OC, Abbott MH, Sherr M, Codori AM, Franz ML, Chao NI, Chung AS et al (1995) Anticipation and instability of IT-15 (CAG) n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet 57:593–602

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC (1999) Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington’s disease. Neurology 52:392–4

    Article  CAS  PubMed  Google Scholar 

  80. Sathasivam K, Amaechi I, Mangiarini L, Bates G (1997) Identification of an HD patient with a (CAG) 180 repeat expansion and the propagation of highly expanded CAG repeats in lambda phage. Hum Genet 99:692–5

    Article  CAS  PubMed  Google Scholar 

  81. Seneca S, Fagnart D, Keymolen K, Lissens W, Hasaerts D, Debulpaep S, Desprechins B, Liebaers I et al (2004) Early onset Huntington disease: a neuronal degeneration syndrome. Eur J Pediatr 163:717–21. doi:10.1007/s00431-004-1537-3

    Article  PubMed  Google Scholar 

  82. Telenius H, Kremer HP, Theilmann J, Andrew SE, Almqvist E, Anvret M, Greenberg C, Greenberg J et al (1993) Molecular analysis of juvenile Huntington disease: the major influence on (CAG) n repeat length is the sex of the affected parent. Hum Mol Genet 2:1535–40

    Article  CAS  PubMed  Google Scholar 

  83. Nance MA, Myers RH (2001) Juvenile onset Huntington’s disease—clinical and research perspectives. Ment Retard Dev Disabil Res Rev 7:153–7. doi:10.1002/mrdd.1022

    Article  CAS  PubMed  Google Scholar 

  84. Telenius H, Kremer B, Goldberg YP, Theilmann J, Andrew SE, Zeisler J, Adam S, Greenberg C et al (1994) Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nat Genet 6:409–14. doi:10.1038/ng0494-409

    Article  CAS  PubMed  Google Scholar 

  85. Kremer B, Almqvist E, Theilmann J, Spence N, Telenius H, Goldberg YP, Hayden MR (1995) Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes. Am J Hum Genet 57:343–50

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Squitieri F, Berardelli A, Nargi E, Castellotti B, Mariotti C, Cannella M, Lavitrano ML, de Grazia U et al (2000) Atypical movement disorders in the early stages of Huntington’s disease: clinical and genetic analysis. Clin Genet 58:50–6

    Article  CAS  PubMed  Google Scholar 

  87. Dong Y, Sun YM, Liu ZJ, Ni W, Shi SS, Wu ZY (2013) Chinese patients with Huntington’s disease initially presenting with spinocerebellar ataxia. Clin Genet 83:380–3. doi:10.1111/j.1399-0004.2012.01927.x

    Article  CAS  PubMed  Google Scholar 

  88. Durr A, Hahn-Barma V, Brice A, Pecheux C, Dode C, Feingold J (1999) Homozygosity in Huntington’s disease. J Med Genet 36:172–3

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Myers RH, Leavitt J, Farrer LA, Jagadeesh J, McFarlane H, Mastromauro CA, Mark RJ, Gusella JF (1989) Homozygote for Huntington disease. Am J Hum Genet 45:615–8

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I et al (1987) Homozygotes for Huntington’s disease. Nature 326:194–7. doi:10.1038/326194a0

    Article  CAS  PubMed  Google Scholar 

  91. Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B et al (1994) A worldwide study of the Huntington’s disease mutation: the sensitivity and specificity of measuring CAG repeats. N Engl J Med 330:1401–6. doi:10.1056/NEJM199405193302001

    Article  CAS  PubMed  Google Scholar 

  92. Alonso ME, Yescas P, Rasmussen A, Ochoa A, Macias R, Ruiz I, Suastegui R (2002) Homozygosity in Huntington’s disease: new ethical dilemma caused by molecular diagnosis. Clin Genet 61:437–42

    Article  CAS  PubMed  Google Scholar 

  93. Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D et al (2003) Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain 126:946–55

    Article  PubMed  Google Scholar 

  94. Gusella JF, MacDonald ME (2000) Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci 1:109–15. doi:10.1038/nrd1077

    Article  CAS  PubMed  Google Scholar 

  95. Lerer I, Merims D, Abeliovich D, Zlotogora J, Gadoth N (1996) Machado-Joseph disease: correlation between the clinical features, the CAG repeat length and homozygosity for the mutation. Eur J Hum Genet 4:3–7

    CAS  PubMed  Google Scholar 

  96. Sato K, Kashihara K, Okada S, Ikeuchi T, Tsuji S, Shomori T, Morimoto K, Hayabara T (1995) Does homozygosity advance the onset of dentatorubral-pallidoluysian atrophy? Neurology 45:1934–6

    Article  CAS  PubMed  Google Scholar 

  97. Sobue G, Doyu M, Nakao N, Shimada N, Mitsuma T, Maruyama H, Kawakami S, Nakamura S (1996) Homozygosity for Machado-Joseph disease gene enhances phenotypic severity. J Neurol Neurosurg Psychiatry 60:354–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Shi SS, Lin Y, Zhao GX, Gan SR, Wu ZY (2012) A Chinese pedigree with an individual homozygous for CAG repeats of Huntington’s disease. Psychiatr Genet 22:53–4. doi:10.1097/YPG.0b013e328347c203

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the grant from the National Natural Science Foundation to Zhi-Ying Wu (81125009, Beijing).

Author information

Authors and Affiliations

  1. Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

    Yi-Min Sun

  2. Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China

    Yan-Bin Zhang & Zhi-Ying Wu

  3. Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China

    Yan-Bin Zhang

Authors
  1. Yi-Min Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan-Bin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhi-Ying Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhi-Ying Wu.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, YM., Zhang, YB. & Wu, ZY. Huntington’s Disease: Relationship Between Phenotype and Genotype. Mol Neurobiol 54, 342–348 (2017). https://doi.org/10.1007/s12035-015-9662-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9662-8

Keywords

Search

Navigation