Mutations in the GCH1 Gene Are Associated with Parkinson Disease (S17.001)
2014-04-08

OBJECTIVE: To systematically explore the relationship between GCH1 mutations and Parkinson disease. BACKGROUND: GTP cyclohydrolase-1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Heterozygous loss-of-function mutations in GCH1 are the most common cause of dopa-responsive dystonia, a metabolic disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. DESIGN/METHODS: We describe clinical, genetic and nigrostriatal dopaminergic imaging findings ([123I]FP-CIT SPECT) of four unrelated pedigrees in which pathogenic GCH1 mutations were identified in patients with classic dopa-responsive dystonia and in family members with adult-onset parkinsonism. The frequency of GCH1 coding or splice-mutation mutations was evaluated in the exome-sequencing data of 1337 Parkinson disease cases without a family of history of dystonia and 5209 ethnicity-matched controls. RESULTS: Dopamine-transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson disease-like nigrostriatal dopaminergic denervation. In the exome sequencing data we identified 11 different heterozygous GCH1 mutations, including four mutations known to cause dopa-responsive dystonia (Q110X, V204I, K224R, M230I), six novel mutations (L92I, T112A, A120S, D134G, R198Q, G217V) and one benign variant (P69L). The frequency of pathogenic and novel non-synonymous coding mutations in GCH1 was significantly higher in cases (7/1337=0.52%) than in controls (8/5209=0·15%; p=0·02; odds ratio 3·4, 95% confidence interval=1·2-9·4). All parkinsonian cases identified with GCH1 mutations fully met the UK Parkinson9s Disease Society Brain Bank clinical diagnostic criteria for Parkinson’s disease. CONCLUSIONS: Our results show that GCH1 mutations should be considered as a novel risk factor for PD. GTP cyclohydrolase-1 deficiency 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 disease. Disclosure: Dr. Mencacci has nothing to disclose. Dr. Isaias has nothing to disclose. Dr. Reich has nothing to disclose. Dr. Ganos has nothing to disclose. Dr. Polke has nothing to disclose. Dr. Bras has nothing to disclose. Dr. Hersheson has nothing to disclose. Dr. Pittman has nothing to disclose. Dr. Noyce has nothing to disclose. Dr. Mok has nothing to disclose. Dr. Opladen has nothing to disclose. Dr. Kunstmann has nothing to disclose. Dr. Sidle has nothing to disclose. Dr. Sweeney has nothing to disclose. Dr. Houlden has nothing to disclose. Dr. Sybille has nothing to disclose. Dr. Batla has nothing to disclose. Dr. Munchau has nothing to disclose. Dr. Volkmann has nothing to disclose. Dr. Samnick has nothing to disclose. Dr. Marotta has nothing to disclose. Dr. Zecchinelli has nothing to disclose. Dr. Pezzoli has nothing to disclose. Dr. Lees has received personal compensation for activities with Allon, Genus, Novartis, Teva Neuroscience, Meda, Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline Inc., Ipsen, Lundbeck Research USA Inc., Allergan Inc., Orion, BIAL, Noscira and Roche Diagnostics Corp. Dr. Lees has received research support from the PSP Association, Weston Trust. Dr. Alegria has nothing to disclose. Dr. Krack has nothing to disclose. Dr. Cormier has nothing to disclose. Dr. Lesage has nothing to disclose. Dr. Brice has received personal compensation for activities with the Wolfson Foundation. Dr. Heutink has nothing to disclose. Dr. Gasser has nothing to disclose. Dr. Morris has received personal compensation for activities with AbbVie, UCB Pharma, and Teva Neuroscience. Dr. Lubbe has nothing to disclose. Dr. Majounie has nothing to disclose. Dr. Gibbs has nothing to disclose. Dr. Singleton has nothing to disclose. Dr. Hardy has nothing to disclose. Dr. Klebe has nothing to disclose. Dr. Bhatia has received personal compensation for activities with UCB Pharma, Novartis, and Ipsen as a speaker. Dr. Wood has nothing to disclose. Dr. International Parkinson9s Disease Genomics Consort has nothing to disclose.