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Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers

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Niccolò 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. Wood
DOI: http://dx.doi.org/10.1093/brain/awu179 2480-2492 First published online: 3 July 2014

Summary

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.

  • GCH1
  • DOPA-responsive-dystonia
  • Parkinson’s disease
  • dopamine
  • exome sequencing
  • Abbreviations
    BH4
    tetrahydrobiopterin
    DAT
    dopamine-transporter
    123I-FP-CIT
    [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane
    SPECT
    single photon computed tomography
  • 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.

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