Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The Huntington's disease-like syndromes: what to consider in patients with a negative Huntington's disease gene test

Abstract

Huntington's disease (HD), which is caused by a triplet-repeat expansion in the IT15 gene (also known as huntingtin or HD), accounts for about 90% of cases of chorea of genetic etiology. In recent years, several other distinct genetic disorders have been identified that can present with a clinical picture indistinguishable from that of HD. These disorders are termed Huntington's disease-like (HDL) syndromes. So far, four such conditions have been recognized, namely disorders attributable to mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), and the gene encoding the TATA box-binding protein (HDL4/SCA17), and a recessively inherited HD phenocopy in a single family (HDL3), the genetic basis of which is currently poorly understood. These disorders, however, account for only a small proportion of cases with the HD phenotype but a negative genetic test for HD, and the list of HDL genes and conditions is set to grow. In this article, we review the most important HD phenocopy disorders identified to date and discuss the clinical clues that guide further investigation. We will concentrate on the four so-called HDL syndromes mentioned above, as well as other genetic disorders such as dentatorubral–pallidoluysian atrophy, neuroferritinopathy, pantothenate-kinase-associated neurodegeneration and chorea–acanthocytosis.

Key Points

  • Huntington's disease (HD) caused by mutation of the IT15 gene is the most important genetic cause of chorea

  • A diagnosis of HD should be considered in patients presenting with the classic triad of symptoms, comprising adult-onset personality changes, generalized chorea and cognitive decline

  • The syndrome of chorea in combination with other neurological and neuropsychiatric features seen in HD is known to be genetically heterogeneous; phenocopies are termed Huntington's disease-like (HDL) syndromes

  • Mutations underlying HDL syndromes have been identified in the prion gene (HDL1), the junctophilin 3 gene (HDL2) and the gene encoding the TATA box-binding protein (HDL4/SCA17)

  • One family with a recessively inherited HD phenocopy (HDL3) of poorly-understood genetic etiology has also been reported

  • HDL syndromes account for only a small proportion of cases with the HD phenotype, but should be considered in patients who test negative for the classic HD gene mutation

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. The 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

    Article  Google Scholar 

  2. Simpson SA and Johnston AW (1989) The prevalence and patterns of care of Huntington's chorea in Grampian. Br J Psychiatry 155: 799–804

    Article  CAS  PubMed  Google Scholar 

  3. Harper PS (1992) The epidemiology of Huntington's disease. Hum Genet 89: 365–376

    Article  CAS  PubMed  Google Scholar 

  4. Stevanin G et al. (2002) CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients. Neurology 58: 965–967

    Article  CAS  PubMed  Google Scholar 

  5. Bauer P et al. (2004) Trinucleotide repeat expansion in SCA17/TBP in white patients with Huntington's disease-like phenotype. J Med Genet 41: 230–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kambouris M et al. (2000) Localization of the gene for a novel autosomal recessive neurodegenerative Huntington-like disorder to 4p15.3. Am J Hum Genet 66: 445–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Xiang F et al. (1998) A Huntington disease-like neurodegenerative disorder maps to chromosome 20p. Am J Hum Genet 63: 1431–1438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Margolis RL et al. (2001) A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion. Ann Neurol 50: 373–380

    Article  CAS  PubMed  Google Scholar 

  9. Lewis V et al. (2003) Novel prion protein insert mutation associated with prolonged neurodegenerative illness. Neurology 60: 1620–1624

    Article  CAS  PubMed  Google Scholar 

  10. Moore RC et al. (2001) Huntington disease phenocopy is a familial prion disease. Am J Hum Genet 69: 1385–1388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Laplanche JL et al. (1999) Prominent psychiatric features and early onset in an inherited prion disease with a new insertional mutation in the prion protein gene. Brain 122: 2375–2386

    Article  PubMed  Google Scholar 

  12. Caughey B and Baron GS (2006) Prions and their partners in crime. Nature 443: 803–810

    Article  CAS  PubMed  Google Scholar 

  13. Gambetti P et al. (2003) Hereditary Creutzfeldt–Jakob disease and fatal familial insomnia. Clin Lab Med 23: 43–64

    Article  PubMed  Google Scholar 

  14. Stevanin G et al. (2003) Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes. Brain 126: 1599–1603

    Article  PubMed  Google Scholar 

  15. Costa MC et al. (2006) Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype. J Hum Genet 51: 645–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Keckarevic M et al. (2005) Yugoslav HD phenocopies analyzed on the presence of mutations in PrP, ferritin, and Jp-3 genes. Int J Neurosci 115: 299–301

    Article  CAS  PubMed  Google Scholar 

  17. Margolis RL et al. (2005) Huntington's disease like-2: review and update. Acta Neurol Taiwan 14: 1–8

    PubMed  Google Scholar 

  18. Bauer I et al. (2002) Trinucleotide repeat expansions in the junctophilin-3 gene are not found in Caucasian patients with a Huntington's disease-like phenotype. Ann Neurol 51: 662

    Article  PubMed  Google Scholar 

  19. Krause A et al. (2005) HDL2 mutations are an important cause of Huntington's disease in patients with African ancestry [abstract #A17]. J Neurol Neurosurg Psychiatr 76 (Suppl 4): S007

    Google Scholar 

  20. Margolis RL et al. (2004) Huntington's disease-like 2 (HDL2) in North America and Japan. Ann Neurol 56: 670–674

    Article  CAS  PubMed  Google Scholar 

  21. Teive HAG et al. (2007) Huntington's disease-like 2: the first case report in Latin America in a patient without African ethnic origin. Mov Disord 22 (Suppl 16): S26

    Google Scholar 

  22. Greenstein PE et al. (2007) Huntington's disease like-2 neuropathology. Mov Disord [doi: 10.1002/mds.21417]

    Article  PubMed  Google Scholar 

  23. Walker RH et al. (2002) Autosomal dominant chorea–acanthocytosis with polyglutamine-containing neuronal inclusions. Neurology 58: 1031–1037

    Article  CAS  PubMed  Google Scholar 

  24. Walker RH et al. (2003) Huntington's disease-like 2 can present as chorea–acanthocytosis. Neurology 61: 1002–1004

    Article  CAS  PubMed  Google Scholar 

  25. Walker RH et al. (2007) Neurologic phenotypes associated with acanthocytosis. Neurology 68: 92–98

    Article  CAS  PubMed  Google Scholar 

  26. Holmes SE et al. (2001) A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat Genet 29: 377–378

    Article  CAS  PubMed  Google Scholar 

  27. Rudnicki DD et al. (2007) Huntington's disease-like 2 is associated with CUG repeat-containing RNA foci. Ann Neurol 61: 272–282

    Article  CAS  PubMed  Google Scholar 

  28. Al-Tahan AY et al. (1999) A novel autosomal recessive 'Huntington's disease-like' neurodegenerative disorder in a Saudi family. Saudi Med J 20: 85–89

    CAS  PubMed  Google Scholar 

  29. Lesperance MM and Burmeister M (2000) Interpretation of linkage data for a Huntington-like disorder mapping to 4p15.3. Am J Hum Genet 67: 262–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nakamura K et al. (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10: 1441–1448

    Article  CAS  PubMed  Google Scholar 

  31. Zuhlke C et al. (2003) Phenotypical variability of expanded alleles in the TATA-binding protein gene: reduced penetrance in SCA17? J Neurol 250: 161–163

    Article  CAS  PubMed  Google Scholar 

  32. Maltecca F et al. (2003) Intergenerational instability and marked anticipation in SCA-17. Neurology 61: 1441–1443

    Article  CAS  PubMed  Google Scholar 

  33. Craig K et al. (2005) Minimum prevalence of spinocerebellar ataxia 17 in the north east of England. J Neurol Sci 239: 105–109

    Article  CAS  PubMed  Google Scholar 

  34. Koide R et al. (1999) A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet 8: 2047–2053

    Article  CAS  PubMed  Google Scholar 

  35. Schneider SA et al. (2006) Phenotypic homogeneity of the Huntington disease-like presentation in a SCA17 family. Neurology 67: 1701–1703

    Article  CAS  PubMed  Google Scholar 

  36. Rolfs A et al. (2003) Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). Ann Neurol 54: 367–375

    Article  PubMed  Google Scholar 

  37. Gunther P et al. (2004) Basal ganglia involvement of a patient with SCA 17—a new form of autosomal dominant spinocerebellar ataxia. J Neurol 251: 896–897

    Article  CAS  PubMed  Google Scholar 

  38. Lasek K et al. (2006) Morphological basis for the spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA17). Brain 129: 2341–2352

    Article  CAS  PubMed  Google Scholar 

  39. Manganelli F et al. (2006) Electrophysiologic characterization in spinocerebellar ataxia 17. Neurology 66: 932–934

    Article  CAS  PubMed  Google Scholar 

  40. Naito H and Oyanagi S (1982) Familial myoclonus epilepsy and choreoathetosis: hereditary dentatorubral–pallidoluysian atrophy. Neurology 32: 798–807

    Article  CAS  PubMed  Google Scholar 

  41. Kanazawa I (1998) Dentatorubral–pallidoluysian atrophy or Naito–Oyanagi disease. Neurogenetics 2: 1–17

    Article  CAS  PubMed  Google Scholar 

  42. Takano T et al. (1996) Assignment of the dentatorubral and pallidoluysian atrophy (DRPLA) gene to 12p13.31 by fluorescence in situ hybridization. Genomics 32: 171–172

    Article  CAS  PubMed  Google Scholar 

  43. Nagafuchi S et al. (1994) Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA). Nat Genet 8: 177–182

    Article  CAS  PubMed  Google Scholar 

  44. Koide R et al. (1994) Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA). Nat Genet 6: 9–13

    Article  CAS  PubMed  Google Scholar 

  45. Aoki M et al. (1994) Maternal anticipation of DRPLA. Hum Mol Genet 3: 1197–1198

    Article  CAS  PubMed  Google Scholar 

  46. Warner TT et al. (1994) DRPLA in Europe. Nat Genet 6: 225

    Article  CAS  PubMed  Google Scholar 

  47. Le Ber I et al. (2003) Prevalence of dentatorubral–pallidoluysian atrophy in a large series of white patients with cerebellar ataxia. Arch Neurol 60: 1097–1099

    Article  PubMed  Google Scholar 

  48. Becher MW et al. (1997) Dentatorubral and pallidoluysian atrophy (DRPLA): clinical and neuropathological findings in genetically confirmed North American and European pedigrees. Mov Disord 12: 519–530

    Article  CAS  PubMed  Google Scholar 

  49. Licht DJ and Lynch DR (2002) Juvenile dentatorubral–pallidoluysian atrophy: new clinical features. Pediatr Neurol 26: 51–54

    Article  PubMed  Google Scholar 

  50. Lee IH et al. (2001) Dentatorubropallidoluysian atrophy in Chinese. Arch Neurol 58: 1905–1908

    Article  CAS  PubMed  Google Scholar 

  51. Martins S et al. (2003) Portuguese families with dentatorubropallidoluysian atrophy (DRPLA) share a common haplotype of Asian origin. Eur J Hum Genet 11: 808–811

    Article  CAS  PubMed  Google Scholar 

  52. Curtis AR et al. (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28: 350–354

    Article  CAS  PubMed  Google Scholar 

  53. Chinnery PF et al. (2003) Neuroferritinopathy in a French family with late onset dominant dystonia. J Med Genet 40: e69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Maciel P et al. (2005) Neuroferritinopathy: missense mutation in FTL causing early-onset bilateral pallidal involvement. Neurology 65: 603–605

    Article  CAS  PubMed  Google Scholar 

  55. Anderson LJ et al. (2001) Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 22: 2171–2179

    Article  CAS  PubMed  Google Scholar 

  56. Chinnery PF et al. (2007) Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation. Brain 130: 110–119

    Article  PubMed  Google Scholar 

  57. Taly AB et al. (2007) Wilson disease: description of 282 patients evaluated over 3 decades. Medicine (Baltimore) 86: 112–121

    Article  Google Scholar 

  58. Rubio JP et al. (1997) Chorea–acanthocytosis: genetic linkage to chromosome 9q21. Am J Hum Genet 61: 899–908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rampoldi L et al. (2001) A conserved sorting-associated protein is mutant in chorea-acanthocytosis. Nat Genet 28: 119–120

    Article  CAS  PubMed  Google Scholar 

  60. Ueno S et al. (2001) The gene encoding a newly discovered protein, chorein, is mutated in chorea–acanthocytosis. Nat Genet 28: 121–122

    Article  CAS  PubMed  Google Scholar 

  61. Hardie RJ (1989) Acanthocytosis and neurological impairment—a review. Q J Med 71: 291–306

    CAS  PubMed  Google Scholar 

  62. Gradstein L et al. (2005) Eye movements in chorea–acanthocytosis. Invest Ophthalmol Vis Sci 46: 1979–1987

    Article  PubMed  Google Scholar 

  63. Schneider SA et al. (2006) Severe tongue protrusion dystonia: clinical syndromes and possible treatment. Neurology 67: 940–943

    Article  CAS  PubMed  Google Scholar 

  64. Henkel K et al. (2006) Head of the caudate nucleus is most vulnerable in chorea-acanthocytosis: a voxel-based morphometry study. Mov Disord 21: 1728–1731

    Article  PubMed  Google Scholar 

  65. Alonso ME et al. (1989) Chorea–acanthocytosis: report of a family and neuropathological study of two cases. Can J Neurol Sci 16: 426–431

    Article  CAS  PubMed  Google Scholar 

  66. Hallervorden J and Spatz H (1922) A peculiar illness of the extrapyramidal system predominantly affecting the globus pallidus and the substantia nigra: a contribution to the relationship between these two nuclei [German]. Z Ges Neurol Psychiatr 79: 254–302

    Article  Google Scholar 

  67. Hayflick SJ (2006) Neurodegeneration with brain iron accumulation: from genes to pathogenesis. Semin Pediatr Neurol 13: 182–185

    Article  PubMed  Google Scholar 

  68. Hayflick SJ et al. (2003) Genetic, clinical, and radiographic delineation of Hallervorden–Spatz syndrome. N Engl J Med 348: 33–40

    Article  CAS  PubMed  Google Scholar 

  69. Grimes DA et al. (2000) Late adult onset chorea with typical pathology of Hallervorden–Spatz syndrome. J Neurol Neurosurg Psychiatry 69: 392–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sethi KD et al. (1988) Hallervorden–Spatz syndrome: clinical and magnetic resonance imaging correlations. Ann Neurol 24: 692–694

    Article  CAS  PubMed  Google Scholar 

  71. Hayflick SJ et al. (2006) Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations. AJNR Am J Neuroradiol 27: 1230–1233

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Morgan NV et al. (2006) PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet 38: 752–754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hortnagel K et al. (2004) Infantile neuroaxonal dystrophy and pantothenate kinase-associated neurodegeneration: locus heterogeneity. Neurology 63: 922–924

    Article  CAS  PubMed  Google Scholar 

  74. Mubaidin A et al. (2003) Karak syndrome: a novel degenerative disorder of the basal ganglia and cerebellum. J Med Genet 40: 543–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ching KH et al. (2002) HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology 58: 1673–1674

    Article  CAS  PubMed  Google Scholar 

  76. Danek A et al. (2001) McLeod neuroacanthocytosis: genotype and phenotype. Ann Neurol 50: 755–764

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

SA Schneider was supported by the Brain Research Trust, UK. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kailash P Bhatia.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schneider, S., Walker, R. & Bhatia, K. The Huntington's disease-like syndromes: what to consider in patients with a negative Huntington's disease gene test. Nat Rev Neurol 3, 517–525 (2007). https://doi.org/10.1038/ncpneuro0606

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneuro0606

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing