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01-01-2013 | Original Communication

Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation

Authors: Takashi Konishi, Satoshi Kono, Masaya Fujimoto, Tatsuhiro Terada, Kozo Matsushita, Yasuomi Ouchi, Hiroaki Miyajima

Published in: Journal of Neurology | Issue 1/2013

Abstract

Mutations in the NKX2.1 gene, which is essential for the development, differentiation and organization of the basal ganglia, cause benign hereditary chorea (BHC) characterized by childhood-onset non-progressive chorea. We herein report the clinical features of six patients from a single family with a novel intronic mutation and present the dopaminergic neuronal imaging by using positron emission tomography (PET) imaging to assess the integrity of the striatal dopaminergic system using [¹¹C]-CFT for the presynaptic dopamine transporter function and [¹¹C]-raclopride for the postsynaptic D2 receptor function. The patients showed mild generalized chorea without either congenital hypothyroidism or a history of pulmonary infection and some of the patients had goiter. Genetic analyses of NKX2.1 gene showed a novel heterozygous c.464-9C>A mutation that created a new acceptor splice site resulting in the production of an aberrant transcript with a 7-bp insertion identical to a intronic sequence of genomic DNA. Oral levodopa failed to improve the involuntary movement, while haloperidol, a dopamine D2 receptor blocking agent, exacerbated the choric movement in a single patient. The dopaminergic PET studies in the two patients revealed decreased raclopride binding in the striatum, while the CFT binding was not altered. The impairment of D2 receptor function in the basal ganglia may result in exacerbation of the chorea induced by haloperidol. The molecular brain imaging and therapeutic response may help elucidate the pathophysiological mechanism of the motor control in the BHC-associated NKX2.1 mutation.

Aizman O, Brismar H, Uhlen P, Zettergren E, Levey AI, Forssberg H, Greengard P, Aperia A (2000) Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons. Nat Neurosci 3:226–230PubMedCrossRef

Antonini A, Leenders KL, Eidelberg D (1998) [11C]raclopride-PET studies of the Huntington’s disease rate of progression: relevance of the trinucleotide repeat length. Ann Neurol 43:253–255PubMedCrossRef

Antonini A, Leenders KL, Spiegel R, Meier D, Vontobel P, Weigell-Weber M, Sanchez-Pernaute R, de Yebenez JG, Boesiger P, Weindl A, Maguire RP (1996) Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain 119:2085–2095PubMedCrossRef

Asmus F, Horber V, Pohlenz J, Schwabe D, Zimprich A, Munz M, Schoning M, Gasser T (2005) A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology 64:1952–1954PubMedCrossRef

Breedveld GJ (2002) Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 11:971–979PubMedCrossRef

Buratti E, Chivers M, Kralovicova J, Romano M, Baralle M, Krainer AR, Vorechovsky I (2007) Aberrant 5′ splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. Nucleic Acids Res 35:4250–4263PubMedCrossRef

Carre A, Szinnai G, Castanet M, Sura-Trueba S, Tron E, Broutin-L’Hermite I, Barat P, Goizet C, Lacombe D, Moutard ML, Raybaud C, Raynaud-Ravni C, Romana S, Ythier H, Leger J, Polak M (2009) Five new TTF1/NKX2.1 mutations in brain–lung–thyroid syndrome: rescue by PAX8 synergism in one case. Hum Mol Genet 18:2266–2276PubMedCrossRef

Costa MC, Costa C, Silva AP, Evangelista P, Santos L, Ferro A, Sequeiros J, Maciel P (2005) Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics 6:209–215PubMedCrossRef

Davis RL, Homer VM, George PM, Brennan SO (2009) A deep intronic mutation in FGB creates a consensus exonic splicing enhancer motif that results in afibrinogenemia caused by aberrant mRNA splicing, which can be corrected in vitro with antisense oligonucleotide treatment. Hum Mutat 30:221–227PubMedCrossRef

10.

Deng YP, Albin RL, Penney JB, Young AB, Anderson KD, Reiner A (2004) Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study. J Chem Neuroanat 27:143–164PubMedCrossRef

11.

Devos D, Vuillaume I, de Becdelievre A, de Martinville B, Dhaenens CM, Cuvellier JC, Cuisset JM, Vallee L, Lemaitre MP, Bourteel H, Hachulla E, Wallaert B, Destee A, Defebvre L, Sablonniere B (2006) New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes. Mov Disord 21:2237–2240PubMedCrossRef

12.

Devriendt K, Vanhole C, Matthijs G, de Zegher F (1998) Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N Engl J Med 338:1317–1318PubMedCrossRef

13.

Doyle DA, Gonzalez I, Thomas B, Scavina M (2004) Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1. J Pediatr 145:190–193PubMedCrossRef

14.

Ferrara AM, De Michele G, Salvatore E, Di Maio L, Zampella E, Capuano S, Del Prete G, Rossi G, Fenzi G, Filla A, Macchia PE (2008) A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid 18:1005–1009PubMedCrossRef

15.

Ferrara JM, Adam OR, Kirwin SM, Houghton DJ, Shepherd C, Vinette KM, Litvan I (2012) Brain–lung–thyroid disease: clinical features of a kindred with a novel thyroid transcription factor 1 mutation. J Child Neurol 27:68–73PubMedCrossRef

16.

Fons C, Rizzu P, Garcia-Cazorla A, Martorell L, Ormazabal A, Artuch R, Campistol J, Fernandez-Alvarez E (2012) TITF-1 gene mutation in a case of sporadic non-progressive chorea. Response to levodopa treatment. Brain Dev 34:255–257PubMedCrossRef

17.

Glass M, Dragunow M, Faull RL (2000) The pattern of neurodegeneration in Huntington’s disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington’s disease. Neuroscience 97:505–519PubMedCrossRef

18.

Glik A, Vuillaume I, Devos D, Inzelberg R (2008) Psychosis, short stature in benign hereditary chorea: a novel thyroid transcription factor-1 mutation. Mov Disord 23:1744–1747PubMedCrossRef

19.

Guillot L, Carre A, Szinnai G, Castanet M, Tron E, Jaubert F, Broutin I, Counil F, Feldmann D, Clement A, Polak M, Epaud R (2010) NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “brain–lung–thyroid syndrome”. Hum Mutat 31:E1146–E1162PubMedCrossRef

20.

Iwatani N, Mabe H, Devriendt K, Kodama M, Miike T (2000) Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure. J Pediatr 137:272–276PubMedCrossRef

21.

Kapur S, Zipursky R, Roy P, Jones C, Remington G, Reed K, Houle S (1997) The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study. Psychopharmacology 131:148–152PubMedCrossRef

22.

Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH, Ward JM, Gonzalez FJ (1996) The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev 10:60–69PubMedCrossRef

23.

Kleiner-Fisman G, Calingasan NY, Putt M, Chen J, Beal MF, Lang AE (2005) Alterations of striatal neurons in benign hereditary chorea. Mov Disord 20:1353–1357PubMedCrossRef

24.

Kleiner-Fisman G, Rogaeva E, Halliday W, Houle S, Kawarai T, Sato C, Medeiros H, St George-Hyslop PH, Lang AE (2003) Benign hereditary chorea: clinical, genetic, and pathological findings. Ann Neurol 54:244–247PubMedCrossRef

25.

Kono S, Ouchi Y, Terada T, Ida H, Suzuki M, Miyajima H (2010) Functional brain imaging in glucocerebrosidase mutation carriers with and without parkinsonism. Mov Disord 25:1823–1829PubMedCrossRef

26.

Krude H, Schutz B, Biebermann H, von Moers A, Schnabel D, Neitzel H, Tonnies H, Weise D, Lafferty A, Schwarz S, DeFelice M, von Deimling A, van Landeghem F, DiLauro R, Gruters A (2002) Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest 109:475–480PubMed

27.

Maquet E, Costagliola S, Parma J, Christophe-Hobertus C, Oligny LL, Fournet JC, Robitaille Y, Vuissoz JM, Payot A, Laberge S, Vassart G, Van Vliet G, Deladoey J (2009) 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 94:197–203PubMedCrossRef

28.

Moya CM, Perez de Nanclares G, Castano L, Potau N, Bilbao JR, Carrascosa A, Bargada M, Coya R, Martul P, Vicens-Calvet E, Santisteban P (2006) Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress. J Clin Endocrinol Metab 91:1832–1841PubMedCrossRef

29.

Nagasaki K, Narumi S, Asami T, Kikuchi T, Hasegawa T, Uchiyama M (2008) Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin. Endocr J 55:875–878PubMedCrossRef

30.

Nakamura K, Sekijima Y, Nagamatsu K, Yoshida K, Ikeda S (2012) A novel nonsense mutation in the TITF-1 gene in a Japanese family with benign hereditary chorea. J Neurol Sci 313:189–192PubMedCrossRef

31.

Narumi S, Muroya K, Asakura Y, Adachi M, Hasegawa T (2010) Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a population-based cohort of Japanese patients. J Clin Endocrinol Metab 95:1981–1985PubMedCrossRef

32.

Ouchi Y, Nobezawa S, Okada H, Yoshikawa E, Futatsubashi M, Kaneko M (1998) Altered glucose metabolism in the hippocampal head in memory impairment. Neurology 51:136–142PubMedCrossRef

33.

Pleasure SJ, Anderson S, Hevner R, Bagri A, Marin O, Lowenstein DH, Rubenstein JL (2000) Cell migration from the ganglionic eminences is required for the development of hippocampal GABAergic interneurons. Neuron 28:727–740PubMedCrossRef

34.

Pohlenz J (2002) Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J Clin Invest 109:469–473PubMed

35.

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

36.

Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB (1988) Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci USA 85:5733–5737PubMedCrossRef

37.

Rincon A, Aguado C, Desviat LR, Sanchez-Alcudia R, Ugarte M, Perez B (2007) Propionic and methylmalonic acidemia: antisense therapeutics for intronic variations causing aberrantly spliced messenger RNA. Am J Hum Genet 81:1262–1270PubMedCrossRef

38.

Roca X, Olson AJ, Rao AR, Enerly E, Kristensen VN, Borresen-Dale AL, Andresen BS, Krainer AR, Sachidanandam R (2008) Features of 5′-splice-site efficiency derived from disease-causing mutations and comparative genomics. Genome Res 18:77–87PubMedCrossRef

39.

Salvatore E, Di Maio L, Filla A, Ferrara AM, Rinaldi C, Sacca F, Peluso S, Macchia PE, Pappata S, De Michele G (2010) Benign hereditary chorea: clinical and neuroimaging features in an Italian family. Mov Disord 25:1491–1496PubMedCrossRef

40.

Sussel L, Marin O, Kimura S, Rubenstein JL (1999) 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 126:3359–3370PubMed

41.

Takuma N, Sheng HZ, Furuta Y, Ward JM, Sharma K, Hogan BL, Pfaff SL, Westphal H, Kimura S, Mahon KA (1998) Formation of Rathke’s pouch requires dual induction from the diencephalon. Development 125:4835–4840PubMed

42.

Uematsu M, Haginoya K, Kikuchi A, Nakayama T, Kakisaka Y, Numata Y, Kobayashi T, Hino-Fukuyo N, Fujiwara I, Kure S (2012) Hypoperfusion in caudate nuclei in patients with brain–lung–thyroid syndrome. J Neurol Sci 315:77–81PubMedCrossRef

43.

van Oostrom JC, Maguire RP, Verschuuren-Bemelmans CC, Veenma-van der Duin L, Pruim J, Roos RA, Leenders KL (2005) Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease. Neurology 65:941–943PubMedCrossRef

44.

Willemsen MA, Breedveld GJ, Wouda S, Otten BJ, Yntema JL, Lammens M, de Vries BB (2005) 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 164:28–30PubMedCrossRef

Title: Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation
Authors: Takashi Konishi
Satoshi Kono
Masaya Fujimoto
Tatsuhiro Terada
Kozo Matsushita
Yasuomi Ouchi
Hiroaki Miyajima
Publication date: 01-01-2013
Publisher: Springer-Verlag
Published in: Journal of Neurology / Issue 1/2013
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-012-6618-z

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Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation

Abstract

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Abstract

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