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Benign Hereditary Chorea

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Chorea

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Abstract

Benign hereditary chorea (BHC) is a rare autosomal dominant condition, characterized by nonprogressive chorea with neither significant intellectual impairment nor caudate atrophy. It was first described almost 50 years ago. Genetic testing is available since the last decade, leading physicians to classify adequately patients and separate them from other similar conditions, mainly Huntington disease and myoclonus-dystonia, which have a different prognosis and treatment. Associated clinical features have become broader every day, and molecular testing confirms accurately the diagnosis. Different grades of affection in the thyroid gland, lung, and brain are associated with mutations on the TITF-1 gene at chromosome 14q. Nowadays, less than 50 families have been reported and reviewed with typical or atypical symptoms. Since BHC is a nonprogressive condition and some patients respond favorably to some drugs, it is important to characterize it correctly in order to offer the best treatment options and give the right prognosis to the affected subject and relatives.

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References

  1. Haerer AF, Currier RD, Jackson JF. Hereditary nonprogressive chorea of early onset. N Engl J Med. 1967;276:1220–4.

    Article  CAS  PubMed  Google Scholar 

  2. Pincus JH, Chutorian A. Familial benign chorea with intention a clinical entity. J Pediatr. 1967;70:724–9.

    Article  CAS  PubMed  Google Scholar 

  3. Burns J, Neuhäuser G, Tomasi L. Benign hereditary non-progressive chorea of early onset. Clinical genetics of the syndrome and report of a new family. Neuropadiatrie. 1976;7:431–8.

    Article  CAS  PubMed  Google Scholar 

  4. Sleigh G, Lindenbaum RH. Benign (non-paroxysmal) familial chorea. Paediatric perspectives. Arch Dis Child. 1981;56:616–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Schrag A, Quinn NP, Bhatia KP, Marsden CD. Benign hereditary chorea—entity or syndrome? Mov Disord. 2000;15:280–8.

    Article  CAS  PubMed  Google Scholar 

  6. De Vries BBA, Arts WFM, Breedveld GJ, Hoogeboom JJM, Niermeijer MF, Heutink P. Benign hereditary chorea of early onset maps to chromosome 14q. Am J Hum Genet. 2000;66:136–42.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Willemsen MA, Breedveld GJ, Wouda M, Otten BJ, Yntema JL, Lammens M, et al. Brain-Thyroid-Lung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Eur J Pediatr. 2005;164:28–30.

    Article  PubMed  Google Scholar 

  8. Asmus F, Devlin A, Munz M, Zimprich A, Gasser T, Chinnery PF. Clinical differentiation of genetically proven benign hereditary chorea and myoclonus-dystonia. Mov Disord. 2007;22:2104–9.

    Article  PubMed  Google Scholar 

  9. Breedveld GJ, Percy AK, MacDonald ME, de Vries BBA, Yapijakis C, Dure LS, et al. Clinical and genetic heterogeneity in benign hereditary chorea. Neurology. 2002;59:579–84.

    Article  CAS  PubMed  Google Scholar 

  10. Salvado M, Boronat-Guerrero S, Hernández-Vara J, Álvarez-Sabin J. Chorea due to TITF1/NKX2-1 mutation: phenotypical description and therapeutic response in a family. Rev Neurol. 2013;56:515–20.

    PubMed  Google Scholar 

  11. Kleiner-Fisman G, Lang AE. Benign hereditary chorea revisited: a journey to understanding. Mov Disord. 2007;22:2297–305.

    Article  PubMed  Google Scholar 

  12. Fernández M, Raskind W, Matsushita M, Wolff J, Lipe H, Bird T. Hereditary benign chorea, clinical and genetic features of a distinct disease. Neurology. 2001;57:106–10.

    Article  PubMed  Google Scholar 

  13. Do Carmo Costa M, Costa C, Silva AP, Evangelista P, Santos L, Ferro A, et al. Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics. 2005;6:209–15.

    Article  Google Scholar 

  14. Carre A, Szinnai G, Castanet M, Sura-Trueba S, Tron E, Broutin-L’Hermite I, et al. Five new TTF1/NKX2.1 mutations in brain lung–thyroid syndrome: rescue by PAX8 synergism in one case. Hum Mol Genet. 2009;18:2266–76.

    Article  CAS  PubMed  Google Scholar 

  15. Gras D, Jonard L, Roze E, Chantot-Bastaraud S, Koht J, Motte J, et al. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF-1/NKX2-1 gene. J Neurol Neurosurg Psychiatry. 2012;83:956–62.

    Article  PubMed  Google Scholar 

  16. Bird TD, Carlson CB, Hall JG. Familial essential (‘benign’) chorea. J Med Genet. 1976;13:357–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Leli DA, Furlow Jr TW, Falgout JC. Benign familial chorea: an association with intellectual impairment. J Neurol Neurosurg Psychiatry. 1984;47:471–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Breedveld GJ, van Dongen JWF, Danesino C, Guala A, Percy AK, Dure LS, et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet. 2002;11:971–9.

    Article  CAS  PubMed  Google Scholar 

  19. Krude H, Schütz B, Bierbermann H, von Moers A, Schnabel D, Neitzel H, et al. Choreoathetosis, hypothyroidism, and pulmonary alterations due to NKX2.1 haploinsufficiency. J Clin Invest. 2002;109:475–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Armstrong MJ, Shah BB, Chen B, Angel MJ, Lang AE. Expanding the phenomenology of benign hereditary chorea: evolution from chorea to myoclonus and dystonia. Mov Disord. 2011;26:2296–7.

    Article  PubMed  Google Scholar 

  21. Asmus F, Horber V, Pohlenz J, Schwabe D, Zimprich A, Munz M, et al. A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology. 2005;64:1952–4.

    Article  CAS  PubMed  Google Scholar 

  22. Asmus F, Langseth A, Doherthy E, Nestor T, Munz M, Gasser T, et al. ‘Jerky” dystonia in children: spectrum of phenotypes and genetic testing. Mov Disord. 2009;24:702–9.

    Article  PubMed  Google Scholar 

  23. Devos D, Vuillaume I, de Becdelievre A, de Martinville B, Dhaenens CM, Cuvellier JC, et al. New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes. Mov Disord. 2006;21:2237–40.

    Article  PubMed  Google Scholar 

  24. Doyle DA, González I, Thomas B, Scavina M. Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1. J Pediatr. 2004;145:190–3.

    Article  CAS  PubMed  Google Scholar 

  25. Ferrara AM, Da Michele G, Salvatore E, Di Maio L, Zampella E, Capuano S, et al. A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid. 2008;18:1005–9.

    Article  CAS  PubMed  Google Scholar 

  26. Ferrara JM, Adam OR, Kirwin SM, Houghton DJ, Shepherd C, Vinette KMB, et al. Brain-lung-thyroid disease: clinical features of a kindred with a novel thyroid transcription factor 1 mutation. J Child Neurol. 2012;27:68–73.

    Article  PubMed  Google Scholar 

  27. Glik A, Vuillaume I, Devos D, Inzelberg R. Psychosis, short-stature in benign hereditary chorea: a novel thyroid transcription factor-1 mutation. Mov Disord. 2008;23:1744–7.

    Article  PubMed  Google Scholar 

  28. Guala A, Falco V, Breedveld G, De Filippi P, Danesino C. Deletion of PAX9 and oligodontia: a third family and review of the literature. Int J Paediatr Dent. 2008;18:441–5.

    Article  PubMed  Google Scholar 

  29. Mahajnah M, Inbar D, Steinmetz A, Heutink P, Breedveld GJ, Straussberg R. Benign hereditary chorea: clinical, neuroimaging, and genetic findings. J Child Neurol. 2007;22:1231–4.

    Article  PubMed  Google Scholar 

  30. Maquet E, Costagliola S, Parma J, Christophe-Hobertus C, Oligny LL, Fournet JC, et al. Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. J Clin Endocrinol Metab. 2009;94:197–203.

    Article  CAS  PubMed  Google Scholar 

  31. Nakamura K, Sekijima Y, Nagamatsu K, Yoshida K, Ikeda S. A novel nonsense mutation in the TITF-1 gene in a Japanese family with benign hereditary chorea. J Neurol Sci. 2012;313:189–92.

    Article  CAS  PubMed  Google Scholar 

  32. Nettore IC, Mirra P, Ferrara AM, Sibilio A, Pagliara V, Kay SC, et al. Identification and functional characterization of a novel mutation in the NKX2-1 gene: comparison with the data in the literature. Thyroid. 2013;23:675–82.

    Article  CAS  PubMed  Google Scholar 

  33. Ngan ESW, Lang BHH, Liu T, Shum CK, So MT, Lau DK, et al. A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma. J Natl Cancer Inst. 2009;101:162–75.

    Article  CAS  PubMed  Google Scholar 

  34. Pohlenz J, Dumitrescu A, Zundeol D, Martiné U, Schönberger W, Koo E, et al. Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J Clin Invest. 2002;109:469–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Provenzano C, Veneziano L, Appleton R, Frontali M, Civitareale D. Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea. J Neurol Sci. 2008;264:56–62.

    Article  CAS  PubMed  Google Scholar 

  36. Salvatore E, Di Maio L, Filla A, Ferrara AM, Rinaldi C, Saccà F, et al. Benign hereditary chorea: clinical and neuroimaging features in an Italian family. Mov Disord. 2010;25:1491–6.

    Article  PubMed  Google Scholar 

  37. Sempere AP, Aparicio S, Mola S, Pérez-Tur J. Benign hereditary chorea: clinical features and long-term follow-up in a Spanish family. Parkinsonism Relat Disord. 2013;19:394–6.

    Article  PubMed  Google Scholar 

  38. Teissier R, Guillot L, Carré A, Morandini M, Stuckens C, Ythier H, et al. Multiplex ligation-dependent probe amplification improves the detection rate of NKX2.1 mutations in patients affected by brain-lung-thyroid syndrome. Horm Res Paediatr. 2012;77:146–51.

    Article  CAS  PubMed  Google Scholar 

  39. Van den Akker WMR, Brox A, Puelles L, Durston AJ, Medina L. Comparative functional analysis provides evidence for a crucial role for the homeobox gene Nkx2.1/Titf-1 in forebrain evolution. J Comp Neurol. 2008;506:211–23.

    Article  PubMed  Google Scholar 

  40. Ghaffari M, Zeng X, Whitsett JA, Yan C. Nuclear localization domain of thyroid transcription factor-1 in respiratory epithelial cells. Biochem J. 1997;328:757–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Kawano H, Horie M, Honma S, Kawamura K, Takeuchi K, Kimura S. Aberrant trajectory of ascending dopaminergic pathway in mice lacking Nkx2.1. Exp Neurol. 2003;182:103–12.

    Article  CAS  PubMed  Google Scholar 

  42. Sussel L, Marin O, Kimura S, Rubenstein JL. Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development. 1999;126:3359–70.

    CAS  PubMed  Google Scholar 

  43. Konishi T, Kono S, Fujimoto M, Terada T, Matsushita K, Ouchi Y, et al. Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation. J Neurol. 2013;260:207–13.

    Article  PubMed  Google Scholar 

  44. Suchowersky O, Hayden MR, Martin WRW, Stoessl AJ, Hildebrand AM, Pate BD. Cerebral metabolism of glucose in benign hereditary chorea. Mov Disord. 1986;1:33–44.

    Article  CAS  PubMed  Google Scholar 

  45. Maccabelli G, Pichiecchio A, Guala A, Ponzio M, Palesi F, Maranzana Rt D, et al. Advanced magnetic resonance imaging in benign hereditary chorea: study of two familial cases. Mov Disord. 2010;25:2670–4.

    Article  PubMed  Google Scholar 

  46. Kleiner-Fisman G, Calingasan NY, Putt M, Chen J, Beal MF, Lang AE. Alterations of striatal neurons in benign hereditary chorea. Mov Disord. 2005;20:1353–7.

    Article  PubMed  Google Scholar 

  47. Kleiner-Fisman G, Rogaeva E, Halliday W, Houle S, Kawarai T, Sato C, et al. Benign hereditary chorea: clinical, genetic and pathological findings. Ann Neurol. 2003;54:244–7.

    Article  CAS  PubMed  Google Scholar 

  48. Cantara S, Capuano S, Formichi C, Pisu M, Capezzone M, Pacini F. Lack of germline A339V mutation in thyroid transcription factor-1 (TITF-1/NKX2.1) gene in familial papillary thyroid cancer. Thyroid Res. 2010;3:1–4.

    Article  Google Scholar 

  49. Kwei KA, Kim YH, Girard L, Kao J, Pacyna-Gengelbach M, Salari K, et al. Genomic profiling identifies TITF1 as a lineage- specific oncogene amplified in lung cancer. Oncogene. 2008;27:3635–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Tang X, Kadara H, Behrens C, Liu DD, Xiao Y, Rice D, et al. Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC: implications in lung cancer pathogenesis and prognosis. Clin Cancer Res. 2011;17:2434–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Kurlan R, Behr J, Shoulson I. Hereditary myoclonus and chorea: the spectrum of hereditary nonprogressive hyperkinetic movement disorders. Mov Disord. 1987;2:301–6.

    Article  CAS  PubMed  Google Scholar 

  52. Nardocci N. Myoclonus-dystonia syndrome. Handb Clin Neurol. 2011;100:563–75.

    Article  PubMed  Google Scholar 

  53. Shimohata T, Hara K, Sanpei K, Nunomura J, Maeda T, Kawachi I, et al. Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3-q23.3. Brain. 2007;130:2302–9.

    Article  PubMed  Google Scholar 

  54. Bordelon YM. Clinical neurogenetics Huntington disease. Neurol Clin. 2013;31:1085–94.

    Article  PubMed  Google Scholar 

  55. MacMillan JC, Morrison PJ, Nervin NC, Shaw DJ, Harper PS, Quarrell OW, et al. Identification of an expanded CAG repeat in the Huntington’s disease gene (IT15) in a family reported to have benign hereditary chorea. J Med Genet. 1993;30:1012–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Britton JW, Uitti RJ, Ahlskog JE, Robinson RG, Kremer B, Hayden MR. Hereditary late-onset chorea without significant dementia: genetic evidence for substantial phenotypic variation in Huntington’s disease. Neurology. 1995;45:443–7.

    Article  CAS  PubMed  Google Scholar 

  57. Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, et al. A worldwide study of the Huntington’s disease mutation, the sensitivity and specificity of measuring CAG repeats. N Engl J Med. 1994;330:1401–6.

    Article  CAS  PubMed  Google Scholar 

  58. Margolis RL, O’Hearn E, Rosenblatt A, Willour V, Holmes SE, Franz ML, et al. A disorder similar to Huntington’s disease is associated with a novel CAG repeat expansion. Ann Neurol. 2001;50:373–80.

    Article  CAS  Google Scholar 

  59. Bardien S, Abrahams F, Soodyall H, van der Merwe L, Greenberg J, Brink T, et al. A South African mixed ancestry family with Huntington disease-like 2: clinical and genetic features. Mov Disord. 2007;22:2083–9.

    Article  PubMed  Google Scholar 

  60. Walker RH, Jung HH, Danek A. Neuroacanthocytosis. Handb Clin Neurol. 2011;100:141–51.

    Article  PubMed  Google Scholar 

  61. Schneider SA, Bhatia KP. Huntington’s disease look-alikes. Handb Clin Neurol. 2011;100:101–12.

    Article  PubMed  Google Scholar 

  62. Wardle M, Morris HR, Robertson NP. Clinical and genetic characteristics of non-Asian dentatorubral-pallidoluysian atrophy: a systematic review. Mov Disord. 2009;24:1636–40.

    Article  PubMed  Google Scholar 

  63. Rajput A. Dentatorubral pallidoluysian atrophy. Handb Clin Neurol. 2011;100:153–9.

    Article  PubMed  Google Scholar 

  64. Tsuji S. Dentatorubral-pallidoluysian atrophy. Handb Clin Neurol. 2012;103:587–94.

    Article  PubMed  Google Scholar 

  65. Van Gaalen J, Giunti P, van de Warrenburg BP. Movement disorders in spinocerebellar ataxias. Mov Disord. 2011;26:792–800.

    Article  PubMed  Google Scholar 

  66. Nutting PA, Cole BR, Schimke RN. Benign, recessively choreo-athetosis of early onset. J Med Genet. 1969;6:408–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Ichiba M, Nakamura M, Kusumoto A, Mizuno E, Kurano Y, Matsuda M, et al. Clinical and molecular genetic assessment of a chorea-acanthocytosis pedigree. J Neurol Sci. 2007;263:124–32.

    Article  CAS  PubMed  Google Scholar 

  68. Jung HH, Danek A, Walker RH. Neuroacanthocytosis syndromes. Orphanet J Rare Dis. 2011;6:68–77.

    Article  PubMed Central  PubMed  Google Scholar 

  69. Sokolov E, Schneider SA, Bain PG. Chorea-acanthocytosis. Pract Neurol. 2012;12:40–3.

    Article  PubMed  Google Scholar 

  70. Verhagen MMM, Abdo WF, Willemsen MAAP, Hogervorst FB, Smeets DF, Hiel JA, et al. Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology. 2009;73:430–7.

    Article  CAS  PubMed  Google Scholar 

  71. Charlesworth G, Mohire MD, Schneider SA, Stamelou M, Wood NW, Bhatia KP. Ataxia telangiectasia presenting as dopa-responsive cervical dystonia. Neurology. 2013;81:1148–51.

    Article  PubMed Central  PubMed  Google Scholar 

  72. Nissenkorn A, Hassin-Baer S, Lerman SF, Levi YB, Tzadok M, Ben-Zeev B. Movement disorder in ataxia telangiectasia: treatment with amantadine sulphate. J Child Neurol. 2013;28:155–60.

    Article  PubMed  Google Scholar 

  73. Klein C, Wenning GK, Quinn NP, Marsden CD. Ataxia without telangiectasia masquerading as benign hereditary chorea. Mov Disord. 1996;11:217–20.

    Article  CAS  PubMed  Google Scholar 

  74. Wilson DC, Phillips MJ, Cox DW, Roberts EA. Severe hepatic Wilson’s disease in preschool-aged children. J Pediatr. 2000;137:719–22.

    Article  CAS  PubMed  Google Scholar 

  75. Czlonkowska A, Rodo M, Gromadzka G. Late onset Wilson’s disease: therapeutic implications. Mov Disord. 2008;23:896–8.

    Article  PubMed  Google Scholar 

  76. Mihaylova V, Todorov T, Helev H, Kotsev I, Angelova L, Kosseva O, et al. Neurological symptoms, genotype-phenotype correlations and ethnic-specific differences in Bulgarian patients with Wilson disease. Neurologist. 2012;18:184–9.

    Article  PubMed  Google Scholar 

  77. Seo JK. Diagnosis of Wilson disease in young children: molecular genetic testing and a paradigm shift from the laboratory diagnosis. Pediatr Gastroenterol Hepatol Nutr. 2012;15:197–209.

    Article  PubMed Central  PubMed  Google Scholar 

  78. Pavone P, Parano E, Rizzo R, Trifiletti RR. Topical review: autoimmune neuropsychiatric disorders associated with streptococcal infection: Sydenham chorea, PANDAS, and PANDAS variants. J Child Neurol. 2006;21:727–36.

    Article  PubMed  Google Scholar 

  79. Cardoso F. Sydenham’s chorea. Handb Clin Neurol. 2011;100:221–9.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Movement Disorders and Neurodegenerative Diseases Unit, Hospital Civil de Guadalajara “Fray Antonio Alcalde”, Guadalajara, Mexico

    Carlos Zúñiga-Ramírez

  2. Department of Neurology, Instituto Mexicano del Seguro Social, Guadalajara, Mexico

    Héctor Alberto González-Usigli

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  1. Carlos Zúñiga-Ramírez
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  2. Héctor Alberto González-Usigli
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Correspondence to Carlos Zúñiga-Ramírez .

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Editors and Affiliations

  1. Parkinson Disease and Movement Disorders Program and Neurology Department, Hospital de Clínicas, José de San Martín, Buenos Aires, Argentina

    Federico E. Micheli

  2. Parkinson's Disease and Movement Disorders Program, Henry Ford West Bloomfield Hospital, West Bloomfield, Michigan, USA

    Peter A. LeWitt

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Zúñiga-Ramírez, C., González-Usigli, H.A. (2014). Benign Hereditary Chorea. In: Micheli, F., LeWitt, P. (eds) Chorea. Springer, London. https://doi.org/10.1007/978-1-4471-6455-5_2

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