Parkinson's disease in GTP cyclohydrolase 1 mutation carriers

被引：144

作者：

Mencacci, Niccolo E. ^{[1
,2
,3
]}

Isaias, Ioannis U. ^{[4
,5
]}

Reich, Martin M. ^{[4
]}

Ganos, Christos ^{[6
,7
,8
]}

Plagnol, Vincent ^{[9
]}

Polke, James M. ^{[10
]}

Bras, Jose ^{[1
]}

Hersheson, Joshua ^{[1
]}

Stamelou, Maria ^{[6
,11
,12
]}

Pittman, Alan M. ^{[1
,13
]}

Noyce, Alastair J. ^{[1
,13
]}

Mok, Kin Y. ^{[1
]}

Opladen, Thomas ^{[14
]}

Kunstmann, Erdmute ^{[15
]}

Hodecker, Sybille ^{[7
]}

Muenchau, Alexander ^{[8
]}

Volkmann, Jens ^{[5
]}

Samnick, Samuel ^{[16
]}

Sidle, Katie ^{[1
]}

Nanji, Tina ^{[10
]}

Sweeney, Mary G. ^{[10
]}

Houlden, Henry ^{[1
]}

Batla, Amit ^{[6
]}

Zecchinelli, Anna L. ^{[5
]}

Pezzoli, Gianni ^{[5
]}

Marotta, Giorgio ^{[17
]}

Lees, Andrew ^{[13
]}

Alegria, Paulo ^{[18
]}

Krack, Paul ^{[19
,20
]}

Cormier-Dequaire, Florence ^{[21
,22
]}

Lesage, Suzanne ^{[21
]}

Brice, Alexis ^{[13
,21
,23
]}

Heutink, Peter ^{[24
]}

Gasser, Thomas ^{[24
]}

Lubbe, Steven J. ^{[25
]}

Morris, Huw R. ^{[25
]}

Taba, Pille ^{[26
]}

Koks, Sulev ^{[27
]}

Majounie, Elisa ^{[28
]}

Gibbs, Raphael ^{[28
]}

Singleton, Andrew ^{[28
]}

Hardy, John ^{[1
,13
]}

Klebe, Stephan ^{[4
]}

Bhatia, Kailash P. ^{[6
]}

Wood, Nicholas W. ^{[1
]}

机构：

[1] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[2] IRCCS Ist Auxol Italiano, Dept Neurol, I-20149 Milan, Italy

[3] Univ Milan, Neurosci Lab, Dept Pathophysiol & Transplantat, Dino Ferrari Ctr, I-20149 Milan, Italy

[4] Univ Hosp, Dept Neurol, D-97080 Wurzburg, Germany

[5] Ist Clin Perfezionamento, Parkinson Inst, I-20126 Milan, Italy

[6] UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England

[7] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, D-20246 Hamburg, Germany

[8] Med Univ Lubeck, Inst Neurogenet, Dept Paediat & Adult Movement Disorders & Neurops, D-23538 Lubeck, Germany

[9] UCL Genet Inst, London WC1E 6BT, England

[10] Natl Hosp Neurol & Neurosurg, Neurogenet Unit, London WC1N 3BG, England

[11] Univ Athens, Attiko Hosp, Neurol Clin, Athens 12642, Greece

[12] Univ Marburg, Neurol Clin, D-35032 Marburg, Germany

[13] UCL Inst Neurol, Reta Lila Weston Inst Neurol Studies, London WC1N 3BG, England

[14] Univ Childrens Hosp Heidelberg, Div Inborn Errors Metab, D-69120 Heidelberg, Germany

[15] Univ Wurzburg, Inst Human Genet, D-97070 Wurzburg, Germany

[16] Univ Hosp, Dept Nucl Med, D-97080 Wurzburg, Germany

[17] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Nucl Med, I-20122 Milan, Italy

[18] Hosp Beatriz Angelo, Serv Neurol, P-2674514 Loures, Portugal

[19] Univ Grenoble 1, CHU Grenoble, Movement Disorder Unit, F-38043 Grenoble, France

[20] Grenoble Inst Neurosci, INSERM U836, F-38043 Grenoble, France

[21] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975,INSERM,U975,CNRS,UMR 7225, Paris, France

[22] Hop La Pitie Salpetriere, AP HP, Dept Neurol, Ctr Invest Clin CIC 9503, Paris, France

[23] Hop La Pitie Salpetriere, Dept Genet & Cytogenet, F-75013 Paris, France

[24] Univ Tubingen, DZNE Deutsch Zentrum Neurodegenerat Erkrankungen, Hertie Inst Clin Brain Res, German Ctr Neurodegenerat Dis, D-72076 Tubingen, Germany

[25] UCL Inst Neurol, Dept Clin Neurosci, London WC1N 3BG, England

[26] Univ Tartu, Dept Neurol & Neurosurg, EE-50090 Tartu, Estonia

[27] Univ Tartu, Dept Pathophysiol, Ctr Excellence Translat Med, EE-50411 Tartu, Estonia

[28] NIA, Neurogenet Lab, Bethesda, MD 20892 USA

来源：

BRAIN | 2014年 / 137卷

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

GCH1; DOPA-responsive-dystonia; Parkinson's disease; dopamine; exome sequencing; DOPA-RESPONSIVE DYSTONIA; I GENE-MUTATIONS; PHENYLALANINE LOADING TEST; TYROSINE-HYDROXYLASE; AUTOSOMAL-DOMINANT; DIFFERENTIAL-DIAGNOSIS; ONSET DYSTONIA; DEFICIENCY; HYPERPHENYLALANINEMIA; TRANSPORTER;

D O I：

10.1093/brain/awu179

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([I-123]N-omega-fluoropropyl- 2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.

引用

页码：2480 / 2492

页数：13

共 58 条

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