• Login
    JavaScript is disabled for your browser. Some features of this site may not work without it.
    Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. 
    •   QMRO Home
    • Wolfson Institute of Preventive Medicine
    • Centre for Cancer Prevention
    • Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
    •   QMRO Home
    • Wolfson Institute of Preventive Medicine
    • Centre for Cancer Prevention
    • Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
    ‌
    ‌

    Browse

    All of QMROCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects
    ‌
    ‌

    Administrators only

    Login
    ‌
    ‌

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.

    View/Open
    Published version (308.4Kb)
    Volume
    137
    Pagination
    2480 - 2492
    DOI
    10.1093/brain/awu179
    Journal
    Brain
    Issue
    Pt 9
    Metadata
    Show full item record
    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
    Mencacci, NE; Isaias, IU; Reich, MM; Ganos, C; Plagnol, V; Polke, JM; Bras, J; Hersheson, J; Stamelou, M; Pittman, AM
    URI
    http://qmro.qmul.ac.uk/xmlui/handle/123456789/37203
    Collections
    • Centre for Cancer Prevention [935]
    Language
    eng
    Licence information
    Creative Commons Attribution License
    Copyright statements
    The Author (2014).
    Twitter iconFollow QMUL on Twitter
    Twitter iconFollow QM Research
    Online on twitter
    Facebook iconLike us on Facebook
    • Site Map
    • Privacy and cookies
    • Disclaimer
    • Accessibility
    • Contacts
    • Intranet
    • Current students

    Modern Slavery Statement

    Queen Mary University of London
    Mile End Road
    London E1 4NS
    Tel: +44 (0)20 7882 5555

    © Queen Mary University of London.