title: Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
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.
authors.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.
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authors.initials: NE
authors.lastname: Mencacci
authors.affiliation: 3 Department of Neurology, University Hospital, 97080 Würzburg, Germany4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.
authors.forename: Ioannis U
authors.initials: IU
authors.lastname: Isaias
authors.affiliation: 3 Department of Neurology, University Hospital, 97080 Würzburg, Germany.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Reich
authors.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.
authors.forename: Christos
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authors.lastname: Ganos
authors.affiliation: 8 UCL Genetics Institute, London WC1E 6BT, UK.
authors.forename: Vincent
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authors.affiliation: 9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
authors.forename: James M
authors.initials: JM
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authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Jose
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authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Joshua
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authors.lastname: Hersheson
authors.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.
authors.forename: Maria
authors.initials: M
authors.lastname: Stamelou
authors.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.
authors.forename: Alan M
authors.initials: AM
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authors.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.
authors.forename: Alastair J
authors.initials: AJ
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authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
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authors.affiliation: 13 Division of Inborn Errors of Metabolism, University Children's Hospital Heidelberg, 69120 Heidelberg, Germany.
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authors.affiliation: 14 Institut of Human Genetics, Julius-Maximilian-University, 97070 Würzburg, Germany.
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authors.affiliation: 6 Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.
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authors.affiliation: 7 Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.
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authors.affiliation: 4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.
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authors.affiliation: 15 Department of Nuclear Medicine, University Hospital, 97080 Würzburg, Germany.
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authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
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authors.affiliation: 9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
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authors.affiliation: 9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
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authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
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authors.affiliation: 5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK.
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authors.affiliation: 4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.
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authors.affiliation: 4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy.
authors.forename: Gianni
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authors.affiliation: 16 Department of Nuclear Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
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authors.affiliation: 12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK.
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authors.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.
authors.forename: Florence
authors.initials: F
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authors.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.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.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.
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authors.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.
authors.forename: Peter
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authors.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.
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authors.affiliation: 23 Department of Clinical Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
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authors.affiliation: 23 Department of Clinical Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
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authors.initials: HR
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authors.affiliation: 24 Department of Neurology and Neurosurgery, University of Tartu, 50090 Tartu, Estonia.
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authors.affiliation: 25 Department of Pathophysiology, Centre of Excellence for Translational Medicine, University of Tartu, 50411 Tartu, Estonia.
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authors.affiliation: 26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
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authors.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.
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authors.forename: Stephan
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authors.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.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK n.wood@ucl.ac.uk k.bhatia@ucl.ac.uk.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D030541:Databases, Genetic; D005060:Europe / Q000453:epidemiology; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D012306:Risk; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D006136:GTP Cyclohydrolase
keywords: DOPA-responsive-dystonia; GCH1; Parkinson’s disease; dopamine; exome sequencing