Journal article
Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
Brain, Vol.137(9), pp.2480-2492
2014
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 ([123I]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.
Details
- Title
- Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
- Authors/Creators
- N.E. Mencacci (Author/Creator) - IRCCS Istituto Auxologico ItalianoI.U. Isaias (Author/Creator) - Universitätsklinikum WürzburgM.M. Reich (Author/Creator) - Universitätsklinikum WürzburgC. Ganos (Author/Creator) - University of LübeckV. Plagnol (Author/Creator) - Genetics Institute, Inc.J.M. Polke (Author/Creator) - National Hospital for Neurology and NeurosurgeryJ. Bras (Author/Creator) - UCL Institute of NeurologyJ. Hersheson (Author/Creator) - UCL Institute of NeurologyM. Stamelou (Author/Creator) - University General Hospital AttikonA.M. Pittman (Author/Creator) - UCL Institute of NeurologyA.J. Noyce (Author/Creator) - UCL Institute of NeurologyK.Y. Mok (Author/Creator) - UCL Institute of NeurologyT. Opladen (Author/Creator) - University Hospital HeidelbergE. Kunstmann (Author/Creator) - University of WürzburgS. Hodecker (Author/Creator) - 6 Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, GermanyA. Münchau (Author/Creator) - University of LübeckJ. Volkmann (Author/Creator) - Istituti Clinici di PerfezionamentoS. Samnick (Author/Creator) - Universitätsklinikum WürzburgK. Sidle (Author/Creator) - UCL Institute of NeurologyT. Nanji (Author/Creator) - National Hospital for Neurology and NeurosurgeryM.G. Sweeney (Author/Creator) - National Hospital for Neurology and NeurosurgeryH. Houlden (Author/Creator) - UCL Institute of NeurologyA. Batla (Author/Creator) - UCL Institute of NeurologyA.L. Zecchinelli (Author/Creator) - Istituti Clinici di PerfezionamentoG. Pezzoli (Author/Creator) - Istituti Clinici di PerfezionamentoG. Marotta (Author/Creator) - Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoA. Lees (Author/Creator) - UCL Institute of NeurologyP. Alegria (Author/Creator) - Hospital Beatriz ÂngeloP. Krack (Author/Creator) - Université Joseph FourierF. Cormier-Dequaire (Author/Creator) - Institut du CerveauS. Lesage (Author/Creator) - Institut du CerveauA. Brice (Author/Creator) - Institut du CerveauP. Heutink (Author/Creator) - German Center for Neurodegenerative DiseasesT. Gasser (Author/Creator) - German Center for Neurodegenerative DiseasesS.J. Lubbe (Author/Creator) - UCL Institute of NeurologyH.R. Morris (Author/Creator) - UCL Institute of NeurologyP. Taba (Author/Creator) - University of TartuS. Kõks (Author/Creator) - University of TartuE. Majounie (Author/Creator) - National Institute on AgingJ. Raphael Gibbs (Author/Creator)A. Singleton (Author/Creator) - National Institute on AgingJ. Hardy (Author/Creator) - UCL Institute of NeurologyS. Klebe (Author/Creator) - Universitätsklinikum WürzburgK.P. Bhatia (Author/Creator) - UCL Institute of NeurologyN.W. Wood (Author/Creator) - UCL Institute of Neurology
- Publication Details
- Brain, Vol.137(9), pp.2480-2492
- Publisher
- Oxford University Press
- Identifiers
- 991005540642607891
- Copyright
- © 2014 Oxford University Press
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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