Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
نویسندگان
چکیده
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.
منابع مشابه
LETTER TOTHE EDITOR Reply: Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
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, Universita‘ degli Studi di Milano, 20149 Milan, Italy 3 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, Lond...
متن کاملReply: Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
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, Universita‘ degli Studi di Milano, 20149 Milan, Italy 3 Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, Lond...
متن کاملLETTER TOTHE EDITOR Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
Sir, We read with great interest the study titled ‘Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers’ in the September edition of Brain (Mencacci et al., 2014). The study demonstrates loss-of-function variants in the GCH1 gene are not only a major cause of DOPA-responsive dystonia but are also enriched in relatives with adult-onset parkinsonism. Furthermore, the authors identify, th...
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BACKGROUND Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l-dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. OBJECTIVE To delineate the neurological and psychiatric phenotype in all affected individuals of three extended families. METHODS GTP cyclohydrolase deficie...
متن کاملLETTER TOTHE EDITOR Parkinsonism in GTP cyclohydrolase 1 mutation carriers
Sir, We read with great interest the article by Mencacci and colleagues (2014) reporting a significantly higher frequency of GTP cyclohydrolase 1 (GCH1) variants in patients with Parkinson’s disease compared to controls. Whole-exome sequencing of a large case-control cohort showed that rare GCH1 coding variants are associated with a 7-fold increased risk of Parkinson’s disease. Heterozygous los...
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