Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
Identifieur interne : 000512 ( PubMed/Corpus ); précédent : 000511; suivant : 000513Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
Auteurs : Niccol E. Mencacci ; Ioannis U. Isaias ; Martin M. Reich ; Christos Ganos ; Vincent Plagnol ; James M. Polke ; Jose Bras ; Joshua Hersheson ; Maria Stamelou ; Alan M. Pittman ; Alastair J. Noyce ; Kin Y. Mok ; Thomas Opladen ; Erdmute Kunstmann ; Sybille Hodecker ; Alexander Münchau ; Jens Volkmann ; Samuel Samnick ; Katie Sidle ; Tina Nanji ; Mary G. Sweeney ; Henry Houlden ; Amit Batla ; Anna L. Zecchinelli ; Gianni Pezzoli ; Giorgio Marotta ; Andrew Lees ; Paulo Alegria ; Paul Krack ; Florence Cormier-Dequaire ; Suzanne Lesage ; Alexis Brice ; Peter Heutink ; Thomas Gasser ; Steven J. Lubbe ; Huw R. Morris ; Pille Taba ; Sulev Koks ; Elisa Majounie ; J. Raphael Gibbs ; Andrew Singleton ; John Hardy ; Stephan Klebe ; Kailash P. Bhatia ; Nicholas W. WoodSource :
- Brain : a journal of neurology [ 1460-2156 ] ; 2014.
English descriptors
- KwdEn :
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Databases, Genetic, Europe (epidemiology), Female, GTP Cyclohydrolase (genetics), Genetic Variation, Heterozygote, Humans, Male, Middle Aged, Mutation (genetics), Parkinson Disease (diagnosis), Parkinson Disease (epidemiology), Parkinson Disease (genetics), Pedigree, Risk, United States (epidemiology), Young Adult.
- MESH :
- chemical , genetics : GTP Cyclohydrolase.
- geographic , epidemiology : Europe, United States.
- diagnosis : Parkinson Disease.
- epidemiology : Parkinson Disease.
- genetics : Mutation, Parkinson Disease.
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Databases, Genetic, Female, Genetic Variation, Heterozygote, Humans, Male, Middle Aged, Pedigree, Risk, Young Adult.
Abstract
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 ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(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.
DOI: 10.1093/brain/awu179
PubMed: 24993959
Links to Exploration step
pubmed:24993959Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.</title><author><name sortKey="Mencacci, Niccol E" sort="Mencacci, Niccol E" uniqKey="Mencacci N" first="Niccol E" last="Mencacci">Niccol E. Mencacci</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK2 IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience - Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano, 20149 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Isaias, Ioannis U" sort="Isaias, Ioannis U" uniqKey="Isaias I" first="Ioannis U" last="Isaias">Ioannis U. Isaias</name><affiliation><nlm:affiliation>3 Department of Neurology, University Hospital, 97080 Würzburg, Germany4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Reich, Martin M" sort="Reich, Martin M" uniqKey="Reich M" first="Martin M" last="Reich">Martin M. Reich</name><affiliation><nlm:affiliation>3 Department of Neurology, University Hospital, 97080 Würzburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Ganos, Christos" sort="Ganos, Christos" uniqKey="Ganos C" first="Christos" last="Ganos">Christos Ganos</name><affiliation><nlm:affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK6 Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany7 Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Plagnol, Vincent" sort="Plagnol, Vincent" uniqKey="Plagnol V" first="Vincent" last="Plagnol">Vincent Plagnol</name><affiliation><nlm:affiliation>8 UCL Genetics Institute, London WC1E 6BT, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Polke, James M" sort="Polke, James M" uniqKey="Polke J" first="James M" last="Polke">James M. Polke</name><affiliation><nlm:affiliation>9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Bras, Jose" sort="Bras, Jose" uniqKey="Bras J" first="Jose" last="Bras">Jose Bras</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Hersheson, Joshua" sort="Hersheson, Joshua" uniqKey="Hersheson J" first="Joshua" last="Hersheson">Joshua Hersheson</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Stamelou, Maria" sort="Stamelou, Maria" uniqKey="Stamelou M" first="Maria" last="Stamelou">Maria Stamelou</name><affiliation><nlm:affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK10 Neurology Clinic, Attiko Hospital, University of Athens, 126 42 Haidari, Athens, Greece11 Neurology Clinic, Philipps University, 35032 Marburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Pittman, Alan M" sort="Pittman, Alan M" uniqKey="Pittman A" first="Alan M" last="Pittman">Alan M. Pittman</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Noyce, Alastair J" sort="Noyce, Alastair J" uniqKey="Noyce A" first="Alastair J" last="Noyce">Alastair J. Noyce</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Mok, Kin Y" sort="Mok, Kin Y" uniqKey="Mok K" first="Kin Y" last="Mok">Kin Y. Mok</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Opladen, Thomas" sort="Opladen, Thomas" uniqKey="Opladen T" first="Thomas" last="Opladen">Thomas Opladen</name><affiliation><nlm:affiliation>13 Division of Inborn Errors of Metabolism, University Children's Hospital Heidelberg, 69120 Heidelberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Kunstmann, Erdmute" sort="Kunstmann, Erdmute" uniqKey="Kunstmann E" first="Erdmute" last="Kunstmann">Erdmute Kunstmann</name><affiliation><nlm:affiliation>14 Institut of Human Genetics, Julius-Maximilian-University, 97070 Würzburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Hodecker, Sybille" sort="Hodecker, Sybille" uniqKey="Hodecker S" first="Sybille" last="Hodecker">Sybille Hodecker</name><affiliation><nlm:affiliation>6 Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Munchau, Alexander" sort="Munchau, Alexander" uniqKey="Munchau A" first="Alexander" last="Münchau">Alexander Münchau</name><affiliation><nlm:affiliation>7 Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Volkmann, Jens" sort="Volkmann, Jens" uniqKey="Volkmann J" first="Jens" last="Volkmann">Jens Volkmann</name><affiliation><nlm:affiliation>4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Samnick, Samuel" sort="Samnick, Samuel" uniqKey="Samnick S" first="Samuel" last="Samnick">Samuel Samnick</name><affiliation><nlm:affiliation>15 Department of Nuclear Medicine, University Hospital, 97080 Würzburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Sidle, Katie" sort="Sidle, Katie" uniqKey="Sidle K" first="Katie" last="Sidle">Katie Sidle</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Nanji, Tina" sort="Nanji, Tina" uniqKey="Nanji T" first="Tina" last="Nanji">Tina Nanji</name><affiliation><nlm:affiliation>9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Sweeney, Mary G" sort="Sweeney, Mary G" uniqKey="Sweeney M" first="Mary G" last="Sweeney">Mary G. Sweeney</name><affiliation><nlm:affiliation>9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Houlden, Henry" sort="Houlden, Henry" uniqKey="Houlden H" first="Henry" last="Houlden">Henry Houlden</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Batla, Amit" sort="Batla, Amit" uniqKey="Batla A" first="Amit" last="Batla">Amit Batla</name><affiliation><nlm:affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Zecchinelli, Anna L" sort="Zecchinelli, Anna L" uniqKey="Zecchinelli A" first="Anna L" last="Zecchinelli">Anna L. Zecchinelli</name><affiliation><nlm:affiliation>4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Pezzoli, Gianni" sort="Pezzoli, Gianni" uniqKey="Pezzoli G" first="Gianni" last="Pezzoli">Gianni Pezzoli</name><affiliation><nlm:affiliation>4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Marotta, Giorgio" sort="Marotta, Giorgio" uniqKey="Marotta G" first="Giorgio" last="Marotta">Giorgio Marotta</name><affiliation><nlm:affiliation>16 Department of Nuclear Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Lees, Andrew" sort="Lees, Andrew" uniqKey="Lees A" first="Andrew" last="Lees">Andrew Lees</name><affiliation><nlm:affiliation>12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Alegria, Paulo" sort="Alegria, Paulo" uniqKey="Alegria P" first="Paulo" last="Alegria">Paulo Alegria</name><affiliation><nlm:affiliation>17 Serviço de Neurologia, Hospital Beatriz Ângelo, 2674-514 Loures, Portugal.</nlm:affiliation></affiliation></author><author><name sortKey="Krack, Paul" sort="Krack, Paul" uniqKey="Krack P" first="Paul" last="Krack">Paul Krack</name><affiliation><nlm:affiliation>18 Movement Disorder Unit, CHU Grenoble, Joseph Fourier University, and INSERM U836, Grenoble Institute Neuroscience, F-38043 Grenoble, France.</nlm:affiliation></affiliation></author><author><name sortKey="Cormier Dequaire, Florence" sort="Cormier Dequaire, Florence" uniqKey="Cormier Dequaire F" first="Florence" last="Cormier-Dequaire">Florence Cormier-Dequaire</name><affiliation><nlm:affiliation>19 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975; Inserm, U975, Cnrs, UMR 7225, Paris, France20 Centre d'Investigation Clinique (CIC-9503), Département de Neurologie, Hôpital Pitié-Salpétriêre, AP-HP, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Lesage, Suzanne" sort="Lesage, Suzanne" uniqKey="Lesage S" first="Suzanne" last="Lesage">Suzanne Lesage</name><affiliation><nlm:affiliation>19 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975; Inserm, U975, Cnrs, UMR 7225, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation><nlm:affiliation>19 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975; Inserm, U975, Cnrs, UMR 7225, Paris, France21 Département de Génétique et Cytogénétique, Pitié-Salpêtrière hospital, 75013 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Heutink, Peter" sort="Heutink, Peter" uniqKey="Heutink P" first="Peter" last="Heutink">Peter Heutink</name><affiliation><nlm:affiliation>22 DZNE-Deutsches Zentrum für Neurodegenerative Erkrankungen (German Centre for Neurodegenerative Diseases), Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation><nlm:affiliation>22 DZNE-Deutsches Zentrum für Neurodegenerative Erkrankungen (German Centre for Neurodegenerative Diseases), Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Lubbe, Steven J" sort="Lubbe, Steven J" uniqKey="Lubbe S" first="Steven J" last="Lubbe">Steven J. Lubbe</name><affiliation><nlm:affiliation>23 Department of Clinical Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Morris, Huw R" sort="Morris, Huw R" uniqKey="Morris H" first="Huw R" last="Morris">Huw R. Morris</name><affiliation><nlm:affiliation>23 Department of Clinical Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Taba, Pille" sort="Taba, Pille" uniqKey="Taba P" first="Pille" last="Taba">Pille Taba</name><affiliation><nlm:affiliation>24 Department of Neurology and Neurosurgery, University of Tartu, 50090 Tartu, Estonia.</nlm:affiliation></affiliation></author><author><name sortKey="Koks, Sulev" sort="Koks, Sulev" uniqKey="Koks S" first="Sulev" last="Koks">Sulev Koks</name><affiliation><nlm:affiliation>25 Department of Pathophysiology, Centre of Excellence for Translational Medicine, University of Tartu, 50411 Tartu, Estonia.</nlm:affiliation></affiliation></author><author><name sortKey="Majounie, Elisa" sort="Majounie, Elisa" uniqKey="Majounie E" first="Elisa" last="Majounie">Elisa Majounie</name><affiliation><nlm:affiliation>26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Raphael Gibbs, J" sort="Raphael Gibbs, J" uniqKey="Raphael Gibbs J" first="J" last="Raphael Gibbs">J. Raphael Gibbs</name><affiliation><nlm:affiliation>26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name><affiliation><nlm:affiliation>26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Klebe, Stephan" sort="Klebe, Stephan" uniqKey="Klebe S" first="Stephan" last="Klebe">Stephan Klebe</name><affiliation><nlm:affiliation>3 Department of Neurology, University Hospital, 97080 Würzburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Bhatia, Kailash P" sort="Bhatia, Kailash P" uniqKey="Bhatia K" first="Kailash P" last="Bhatia">Kailash P. Bhatia</name><affiliation><nlm:affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK n.wood@ucl.ac.uk k.bhatia@ucl.ac.uk.</nlm:affiliation></affiliation></author><author><name sortKey="Wood, Nicholas W" sort="Wood, Nicholas W" uniqKey="Wood N" first="Nicholas W" last="Wood">Nicholas W. Wood</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK n.wood@ucl.ac.uk k.bhatia@ucl.ac.uk.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:24993959</idno><idno type="pmid">24993959</idno><idno type="doi">10.1093/brain/awu179</idno><idno type="wicri:Area/PubMed/Corpus">000512</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000512</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.</title><author><name sortKey="Mencacci, Niccol E" sort="Mencacci, Niccol E" uniqKey="Mencacci N" first="Niccol E" last="Mencacci">Niccol E. Mencacci</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK2 IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience - Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano, 20149 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Isaias, Ioannis U" sort="Isaias, Ioannis U" uniqKey="Isaias I" first="Ioannis U" last="Isaias">Ioannis U. Isaias</name><affiliation><nlm:affiliation>3 Department of Neurology, University Hospital, 97080 Würzburg, Germany4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Reich, Martin M" sort="Reich, Martin M" uniqKey="Reich M" first="Martin M" last="Reich">Martin M. Reich</name><affiliation><nlm:affiliation>3 Department of Neurology, University Hospital, 97080 Würzburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Ganos, Christos" sort="Ganos, Christos" uniqKey="Ganos C" first="Christos" last="Ganos">Christos Ganos</name><affiliation><nlm:affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK6 Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany7 Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Plagnol, Vincent" sort="Plagnol, Vincent" uniqKey="Plagnol V" first="Vincent" last="Plagnol">Vincent Plagnol</name><affiliation><nlm:affiliation>8 UCL Genetics Institute, London WC1E 6BT, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Polke, James M" sort="Polke, James M" uniqKey="Polke J" first="James M" last="Polke">James M. Polke</name><affiliation><nlm:affiliation>9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Bras, Jose" sort="Bras, Jose" uniqKey="Bras J" first="Jose" last="Bras">Jose Bras</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Hersheson, Joshua" sort="Hersheson, Joshua" uniqKey="Hersheson J" first="Joshua" last="Hersheson">Joshua Hersheson</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Stamelou, Maria" sort="Stamelou, Maria" uniqKey="Stamelou M" first="Maria" last="Stamelou">Maria Stamelou</name><affiliation><nlm:affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK10 Neurology Clinic, Attiko Hospital, University of Athens, 126 42 Haidari, Athens, Greece11 Neurology Clinic, Philipps University, 35032 Marburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Pittman, Alan M" sort="Pittman, Alan M" uniqKey="Pittman A" first="Alan M" last="Pittman">Alan M. Pittman</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Noyce, Alastair J" sort="Noyce, Alastair J" uniqKey="Noyce A" first="Alastair J" last="Noyce">Alastair J. Noyce</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Mok, Kin Y" sort="Mok, Kin Y" uniqKey="Mok K" first="Kin Y" last="Mok">Kin Y. Mok</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Opladen, Thomas" sort="Opladen, Thomas" uniqKey="Opladen T" first="Thomas" last="Opladen">Thomas Opladen</name><affiliation><nlm:affiliation>13 Division of Inborn Errors of Metabolism, University Children's Hospital Heidelberg, 69120 Heidelberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Kunstmann, Erdmute" sort="Kunstmann, Erdmute" uniqKey="Kunstmann E" first="Erdmute" last="Kunstmann">Erdmute Kunstmann</name><affiliation><nlm:affiliation>14 Institut of Human Genetics, Julius-Maximilian-University, 97070 Würzburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Hodecker, Sybille" sort="Hodecker, Sybille" uniqKey="Hodecker S" first="Sybille" last="Hodecker">Sybille Hodecker</name><affiliation><nlm:affiliation>6 Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Munchau, Alexander" sort="Munchau, Alexander" uniqKey="Munchau A" first="Alexander" last="Münchau">Alexander Münchau</name><affiliation><nlm:affiliation>7 Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Volkmann, Jens" sort="Volkmann, Jens" uniqKey="Volkmann J" first="Jens" last="Volkmann">Jens Volkmann</name><affiliation><nlm:affiliation>4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Samnick, Samuel" sort="Samnick, Samuel" uniqKey="Samnick S" first="Samuel" last="Samnick">Samuel Samnick</name><affiliation><nlm:affiliation>15 Department of Nuclear Medicine, University Hospital, 97080 Würzburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Sidle, Katie" sort="Sidle, Katie" uniqKey="Sidle K" first="Katie" last="Sidle">Katie Sidle</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Nanji, Tina" sort="Nanji, Tina" uniqKey="Nanji T" first="Tina" last="Nanji">Tina Nanji</name><affiliation><nlm:affiliation>9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Sweeney, Mary G" sort="Sweeney, Mary G" uniqKey="Sweeney M" first="Mary G" last="Sweeney">Mary G. Sweeney</name><affiliation><nlm:affiliation>9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Houlden, Henry" sort="Houlden, Henry" uniqKey="Houlden H" first="Henry" last="Houlden">Henry Houlden</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Batla, Amit" sort="Batla, Amit" uniqKey="Batla A" first="Amit" last="Batla">Amit Batla</name><affiliation><nlm:affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Zecchinelli, Anna L" sort="Zecchinelli, Anna L" uniqKey="Zecchinelli A" first="Anna L" last="Zecchinelli">Anna L. Zecchinelli</name><affiliation><nlm:affiliation>4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Pezzoli, Gianni" sort="Pezzoli, Gianni" uniqKey="Pezzoli G" first="Gianni" last="Pezzoli">Gianni Pezzoli</name><affiliation><nlm:affiliation>4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Marotta, Giorgio" sort="Marotta, Giorgio" uniqKey="Marotta G" first="Giorgio" last="Marotta">Giorgio Marotta</name><affiliation><nlm:affiliation>16 Department of Nuclear Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.</nlm:affiliation></affiliation></author><author><name sortKey="Lees, Andrew" sort="Lees, Andrew" uniqKey="Lees A" first="Andrew" last="Lees">Andrew Lees</name><affiliation><nlm:affiliation>12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Alegria, Paulo" sort="Alegria, Paulo" uniqKey="Alegria P" first="Paulo" last="Alegria">Paulo Alegria</name><affiliation><nlm:affiliation>17 Serviço de Neurologia, Hospital Beatriz Ângelo, 2674-514 Loures, Portugal.</nlm:affiliation></affiliation></author><author><name sortKey="Krack, Paul" sort="Krack, Paul" uniqKey="Krack P" first="Paul" last="Krack">Paul Krack</name><affiliation><nlm:affiliation>18 Movement Disorder Unit, CHU Grenoble, Joseph Fourier University, and INSERM U836, Grenoble Institute Neuroscience, F-38043 Grenoble, France.</nlm:affiliation></affiliation></author><author><name sortKey="Cormier Dequaire, Florence" sort="Cormier Dequaire, Florence" uniqKey="Cormier Dequaire F" first="Florence" last="Cormier-Dequaire">Florence Cormier-Dequaire</name><affiliation><nlm:affiliation>19 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975; Inserm, U975, Cnrs, UMR 7225, Paris, France20 Centre d'Investigation Clinique (CIC-9503), Département de Neurologie, Hôpital Pitié-Salpétriêre, AP-HP, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Lesage, Suzanne" sort="Lesage, Suzanne" uniqKey="Lesage S" first="Suzanne" last="Lesage">Suzanne Lesage</name><affiliation><nlm:affiliation>19 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975; Inserm, U975, Cnrs, UMR 7225, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation><nlm:affiliation>19 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975; Inserm, U975, Cnrs, UMR 7225, Paris, France21 Département de Génétique et Cytogénétique, Pitié-Salpêtrière hospital, 75013 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Heutink, Peter" sort="Heutink, Peter" uniqKey="Heutink P" first="Peter" last="Heutink">Peter Heutink</name><affiliation><nlm:affiliation>22 DZNE-Deutsches Zentrum für Neurodegenerative Erkrankungen (German Centre for Neurodegenerative Diseases), Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation><nlm:affiliation>22 DZNE-Deutsches Zentrum für Neurodegenerative Erkrankungen (German Centre for Neurodegenerative Diseases), Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Lubbe, Steven J" sort="Lubbe, Steven J" uniqKey="Lubbe S" first="Steven J" last="Lubbe">Steven J. Lubbe</name><affiliation><nlm:affiliation>23 Department of Clinical Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Morris, Huw R" sort="Morris, Huw R" uniqKey="Morris H" first="Huw R" last="Morris">Huw R. Morris</name><affiliation><nlm:affiliation>23 Department of Clinical Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Taba, Pille" sort="Taba, Pille" uniqKey="Taba P" first="Pille" last="Taba">Pille Taba</name><affiliation><nlm:affiliation>24 Department of Neurology and Neurosurgery, University of Tartu, 50090 Tartu, Estonia.</nlm:affiliation></affiliation></author><author><name sortKey="Koks, Sulev" sort="Koks, Sulev" uniqKey="Koks S" first="Sulev" last="Koks">Sulev Koks</name><affiliation><nlm:affiliation>25 Department of Pathophysiology, Centre of Excellence for Translational Medicine, University of Tartu, 50411 Tartu, Estonia.</nlm:affiliation></affiliation></author><author><name sortKey="Majounie, Elisa" sort="Majounie, Elisa" uniqKey="Majounie E" first="Elisa" last="Majounie">Elisa Majounie</name><affiliation><nlm:affiliation>26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Raphael Gibbs, J" sort="Raphael Gibbs, J" uniqKey="Raphael Gibbs J" first="J" last="Raphael Gibbs">J. Raphael Gibbs</name><affiliation><nlm:affiliation>26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name><affiliation><nlm:affiliation>26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Klebe, Stephan" sort="Klebe, Stephan" uniqKey="Klebe S" first="Stephan" last="Klebe">Stephan Klebe</name><affiliation><nlm:affiliation>3 Department of Neurology, University Hospital, 97080 Würzburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Bhatia, Kailash P" sort="Bhatia, Kailash P" uniqKey="Bhatia K" first="Kailash P" last="Bhatia">Kailash P. Bhatia</name><affiliation><nlm:affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK n.wood@ucl.ac.uk k.bhatia@ucl.ac.uk.</nlm:affiliation></affiliation></author><author><name sortKey="Wood, Nicholas W" sort="Wood, Nicholas W" uniqKey="Wood N" first="Nicholas W" last="Wood">Nicholas W. Wood</name><affiliation><nlm:affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK n.wood@ucl.ac.uk k.bhatia@ucl.ac.uk.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Brain : a journal of neurology</title><idno type="eISSN">1460-2156</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Aged</term><term>Aged, 80 and over</term><term>Child</term><term>Databases, Genetic</term><term>Europe (epidemiology)</term><term>Female</term><term>GTP Cyclohydrolase (genetics)</term><term>Genetic Variation</term><term>Heterozygote</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Mutation (genetics)</term><term>Parkinson Disease (diagnosis)</term><term>Parkinson Disease (epidemiology)</term><term>Parkinson Disease (genetics)</term><term>Pedigree</term><term>Risk</term><term>United States (epidemiology)</term><term>Young Adult</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>GTP Cyclohydrolase</term></keywords><keywords scheme="MESH" type="geographic" qualifier="epidemiology" xml:lang="en"><term>Europe</term><term>United States</term></keywords><keywords scheme="MESH" qualifier="diagnosis" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="epidemiology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mutation</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Aged</term><term>Aged, 80 and over</term><term>Child</term><term>Databases, Genetic</term><term>Female</term><term>Genetic Variation</term><term>Heterozygote</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Pedigree</term><term>Risk</term><term>Young Adult</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24993959</PMID><DateCreated><Year>2014</Year><Month>08</Month><Day>15</Day></DateCreated><DateCompleted><Year>2014</Year><Month>11</Month><Day>06</Day></DateCompleted><DateRevised><Year>2016</Year><Month>11</Month><Day>22</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1460-2156</ISSN><JournalIssue CitedMedium="Internet"><Volume>137</Volume><Issue>Pt 9</Issue><PubDate><Year>2014</Year><Month>Sep</Month></PubDate></JournalIssue><Title>Brain : a journal of neurology</Title><ISOAbbreviation>Brain</ISOAbbreviation></Journal><ArticleTitle>Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.</ArticleTitle><Pagination><MedlinePgn>2480-92</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1093/brain/awu179</ELocationID><Abstract><AbstractText>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 ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(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.</AbstractText><CopyrightInformation>© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mencacci</LastName><ForeName>Niccolò E</ForeName><Initials>NE</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK2 IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience - Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano, 20149 Milan, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Isaias</LastName><ForeName>Ioannis U</ForeName><Initials>IU</Initials><AffiliationInfo><Affiliation>3 Department of Neurology, University Hospital, 97080 Würzburg, Germany4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Reich</LastName><ForeName>Martin M</ForeName><Initials>MM</Initials><AffiliationInfo><Affiliation>3 Department of Neurology, University Hospital, 97080 Würzburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ganos</LastName><ForeName>Christos</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK6 Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany7 Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Plagnol</LastName><ForeName>Vincent</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>8 UCL Genetics Institute, London WC1E 6BT, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Polke</LastName><ForeName>James M</ForeName><Initials>JM</Initials><AffiliationInfo><Affiliation>9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bras</LastName><ForeName>Jose</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hersheson</LastName><ForeName>Joshua</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stamelou</LastName><ForeName>Maria</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK10 Neurology Clinic, Attiko Hospital, University of Athens, 126 42 Haidari, Athens, Greece11 Neurology Clinic, Philipps University, 35032 Marburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pittman</LastName><ForeName>Alan M</ForeName><Initials>AM</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Noyce</LastName><ForeName>Alastair J</ForeName><Initials>AJ</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mok</LastName><ForeName>Kin Y</ForeName><Initials>KY</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Opladen</LastName><ForeName>Thomas</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>13 Division of Inborn Errors of Metabolism, University Children's Hospital Heidelberg, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kunstmann</LastName><ForeName>Erdmute</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>14 Institut of Human Genetics, Julius-Maximilian-University, 97070 Würzburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hodecker</LastName><ForeName>Sybille</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>6 Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Münchau</LastName><ForeName>Alexander</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>7 Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Volkmann</LastName><ForeName>Jens</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Samnick</LastName><ForeName>Samuel</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>15 Department of Nuclear Medicine, University Hospital, 97080 Würzburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sidle</LastName><ForeName>Katie</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nanji</LastName><ForeName>Tina</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sweeney</LastName><ForeName>Mary G</ForeName><Initials>MG</Initials><AffiliationInfo><Affiliation>9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Houlden</LastName><ForeName>Henry</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Batla</LastName><ForeName>Amit</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zecchinelli</LastName><ForeName>Anna L</ForeName><Initials>AL</Initials><AffiliationInfo><Affiliation>4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pezzoli</LastName><ForeName>Gianni</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marotta</LastName><ForeName>Giorgio</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>16 Department of Nuclear Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lees</LastName><ForeName>Andrew</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Alegria</LastName><ForeName>Paulo</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>17 Serviço de Neurologia, Hospital Beatriz Ângelo, 2674-514 Loures, Portugal.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Krack</LastName><ForeName>Paul</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>18 Movement Disorder Unit, CHU Grenoble, Joseph Fourier University, and INSERM U836, Grenoble Institute Neuroscience, F-38043 Grenoble, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cormier-Dequaire</LastName><ForeName>Florence</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>19 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975; Inserm, U975, Cnrs, UMR 7225, Paris, France20 Centre d'Investigation Clinique (CIC-9503), Département de Neurologie, Hôpital Pitié-Salpétriêre, AP-HP, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lesage</LastName><ForeName>Suzanne</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>19 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975; Inserm, U975, Cnrs, UMR 7225, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brice</LastName><ForeName>Alexis</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>19 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975; Inserm, U975, Cnrs, UMR 7225, Paris, France21 Département de Génétique et Cytogénétique, Pitié-Salpêtrière hospital, 75013 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Heutink</LastName><ForeName>Peter</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>22 DZNE-Deutsches Zentrum für Neurodegenerative Erkrankungen (German Centre for Neurodegenerative Diseases), Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gasser</LastName><ForeName>Thomas</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>22 DZNE-Deutsches Zentrum für Neurodegenerative Erkrankungen (German Centre for Neurodegenerative Diseases), Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lubbe</LastName><ForeName>Steven J</ForeName><Initials>SJ</Initials><AffiliationInfo><Affiliation>23 Department of Clinical Neuroscience, UCL Institute of Neurology, London WC1N 3BG, 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National Institute on Aging, Bethesda, MD 20892, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Raphael Gibbs</LastName><ForeName>J</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Singleton</LastName><ForeName>Andrew</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hardy</LastName><ForeName>John</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Klebe</LastName><ForeName>Stephan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>3 Department of Neurology, University Hospital, 97080 Würzburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bhatia</LastName><ForeName>Kailash P</ForeName><Initials>KP</Initials><AffiliationInfo><Affiliation>5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK n.wood@ucl.ac.uk k.bhatia@ucl.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wood</LastName><ForeName>Nicholas W</ForeName><Initials>NW</Initials><AffiliationInfo><Affiliation>1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK n.wood@ucl.ac.uk k.bhatia@ucl.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><CollectiveName>International Parkinson’s Disease Genomics Consortium and UCL-exomes consortium</CollectiveName></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>J-0804</GrantID><Agency>Parkinson's UK</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>WT089698</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>G0400000</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>G-0907</GrantID><Agency>Parkinson's UK</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>MC_G0901330</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>G0701075</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>G0700943</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>MC_G1000735</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>076113</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>MR/L501554/1</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>Z01-ES101986</GrantID><Acronym>ES</Acronym><Agency>NIEHS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>089698</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><Agency>Intramural NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>085475</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>R01NS037167</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>Z01-AG000949-02</GrantID><Acronym>AG</Acronym><Agency>NIA NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>G0802760</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>R01CA141668</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>F-1201</GrantID><Agency>Parkinson's UK</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>G1100643</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>090355</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>MC_PC_09003</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D002363">Case Reports</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D052060">Research Support, N.I.H., Intramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D013486">Research Support, U.S. Gov't, Non-P.H.S.</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>07</Month><Day>02</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Brain</MedlineTA><NlmUniqueID>0372537</NlmUniqueID><ISSNLinking>0006-8950</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>EC 3.5.4.16</RegistryNumber><NameOfSubstance UI="D006136">GTP Cyclohydrolase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>AIM</CitationSubset><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>Parkinsonism Relat Disord. 2013 Dec;19(12):1156-9</RefSource><PMID Version="1">24018121</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Brain. 2000 Jun;123 ( Pt 6):1112-21</RefSource><PMID 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