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      Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers

      research-article
      1 , 2 , 3 , 4 , 3 , 5 , 6 , 7 , 8 , 9 , 1 , 1 , 5 , 10 , 11 , 1 , 12 , 1 , 12 , 1 , 13 , 14 , 6 , 7 , 4 , 15 , 1 , 9 , 9 , 1 , 5 , 4 , 4 , 16 , 12 , 17 , 18 , 19 , 20 , 19 , 19 , 21 , 22 , 22 , 23 , 23 , 24 , 25 , 26 , 26 , 26 , 1 , 12 , 3 , 5 , , 1 ,
      Brain
      Oxford University Press
      GCH1, DOPA-responsive-dystonia, Parkinson’s disease, dopamine, exome sequencing

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          Abstract

          Mutations in the gene encoding the dopamine-synthetic enzyme GTP cyclohydrolase-1 ( GCH1) cause DOPA-responsive dystonia (DRD). Mencacci et al. demonstrate that GCH1 variants are associated with an increased risk of Parkinson's disease in both DRD pedigrees and in patients with Parkinson's disease but without a family history of DRD.

          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.

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          Most cited references57

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          ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

          High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a ‘variants reduction’ protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/ .
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            Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.

            Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.
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              Parkinson's disease.

              Parkinson's disease is a common progressive bradykinetic disorder that can be accurately diagnosed. It is characterised by the presence of severe pars-compacta nigral-cell loss, and accumulation of aggregated alpha-synuclein in specific brain stem, spinal cord, and cortical regions. The main known risk factor is age. Susceptibility genes including alpha-synuclein, leucine rich repeat kinase 2 (LRRK-2), and glucocerebrosidase (GBA) have shown that genetic predisposition is another important causal factor. Dopamine replacement therapy considerably reduces motor handicap, and effective treatment of associated depression, pain, constipation, and nocturnal difficulties can improve quality of life. Embryonic stem cells and gene therapy are promising research therapeutic approaches.
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                Author and article information

                Journal
                Brain
                Brain
                brainj
                brain
                Brain
                Oxford University Press
                0006-8950
                1460-2156
                September 2014
                02 July 2014
                02 July 2014
                : 137
                : 9
                : 2480-2492
                Affiliations
                1 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK
                2 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
                3 Department of Neurology, University Hospital, 97080 Würzburg, Germany
                4 Parkinson Institute, Istituti Clinici di Perfezionamento, 20126 Milan, Italy
                5 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK
                6 Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
                7 Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany
                8 UCL Genetics Institute, London WC1E 6BT, UK
                9 Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK
                10 Neurology Clinic, Attiko Hospital, University of Athens, 126 42 Haidari, Athens, Greece
                11 Neurology Clinic, Philipps University, 35032 Marburg, Germany
                12 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London WC1N 3BG, UK
                13 Division of Inborn Errors of Metabolism, University Children’s Hospital Heidelberg, 69120 Heidelberg, Germany
                14 Institut of Human Genetics, Julius-Maximilian-University, 97070 Würzburg, Germany
                15 Department of Nuclear Medicine, University Hospital, 97080 Würzburg, Germany
                16 Department of Nuclear Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy
                17 Serviço de Neurologia, Hospital Beatriz Ângelo, 2674-514 Loures, Portugal
                18 Movement Disorder Unit, CHU Grenoble, Joseph Fourier University, and INSERM U836, Grenoble Institute Neuroscience, F-38043 Grenoble, France
                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
                20 Centre d'Investigation Clinique (CIC-9503), Département de Neurologie, Hôpital Pitié-Salpétriêre, AP-HP, Paris, France
                21 Département de Génétique et Cytogénétique, Pitié-Salpêtrière hospital, 75013 Paris, France
                22 DZNE–Deutsches Zentrum für Neurodegenerative Erkrankungen (German Centre for Neurodegenerative Diseases), Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
                23 Department of Clinical Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK
                24 Department of Neurology and Neurosurgery, University of Tartu, 50090 Tartu, Estonia
                25 Department of Pathophysiology, Centre of Excellence for Translational Medicine, University of Tartu, 50411 Tartu, Estonia
                26 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA
                Author notes
                Correspondence to: Professor Nicholas W. Wood, Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK E-mail: n.wood@ 123456ucl.ac.uk
                Correspondence may also be addressed to: Professor Kailash P. Bhatia, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London WC1N 3BG, UK. E-mail k.bhatia@ 123456ucl.ac.uk

                *These authors contributed equally to this work.

                See doi: [Related article:]10.1093/brain/awu181 for the scientific commentary on this article.

                Article
                awu179
                10.1093/brain/awu179
                4132650
                24993959
                86198a32-49b7-44e8-b534-6438495f57e2
                © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 December 2013
                : 16 May 2014
                : 23 May 2014
                Page count
                Pages: 13
                Categories
                Original Articles

                Neurosciences
                gch1,dopa-responsive-dystonia,parkinson’s disease,dopamine,exome sequencing
                Neurosciences
                gch1, dopa-responsive-dystonia, parkinson’s disease, dopamine, exome sequencing

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