Parkinson's disease in GTP cyclohydrolase 1 mutation carriers
Standard
Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. / Mencacci, Niccolò E; Isaias, Ioannis U; Reich, Martin M; Ganos, Christos; Plagnol, Vincent; Polke, James M; Bras, Jose; Hersheson, Joshua; Stamelou, Maria; Pittman, Alan M; Noyce, Alastair J; Mok, Kin Y; Opladen, Thomas; Kunstmann, Erdmute; Hodecker, Sybille; Münchau, Alexander; Volkmann, Jens; Samnick, Samuel; Sidle, Katie; Nanji, Tina; Sweeney, Mary G; Houlden, Henry; Batla, Amit; Zecchinelli, Anna L; Pezzoli, Gianni; Marotta, Giorgio; Lees, Andrew; Alegria, Paulo; Krack, Paul; Cormier-Dequaire, Florence; Lesage, Suzanne; Brice, Alexis; Heutink, Peter; Gasser, Thomas; Lubbe, Steven J; Morris, Huw R; Taba, Pille; Koks, Sulev; Majounie, Elisa; Raphael Gibbs, J; Singleton, Andrew; Hardy, John; Klebe, Stephan; Bhatia, Kailash P; Wood, Nicholas W; International PSC Study Group (IPSCSG); UCL-exomes consortium.
In: BRAIN, Vol. 137, No. Pt 9, 01.09.2014, p. 2480-92.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Parkinson's disease in GTP cyclohydrolase 1 mutation carriers
AU - Mencacci, Niccolò E
AU - Isaias, Ioannis U
AU - Reich, Martin M
AU - Ganos, Christos
AU - Plagnol, Vincent
AU - Polke, James M
AU - Bras, Jose
AU - Hersheson, Joshua
AU - Stamelou, Maria
AU - Pittman, Alan M
AU - Noyce, Alastair J
AU - Mok, Kin Y
AU - Opladen, Thomas
AU - Kunstmann, Erdmute
AU - Hodecker, Sybille
AU - Münchau, Alexander
AU - Volkmann, Jens
AU - Samnick, Samuel
AU - Sidle, Katie
AU - Nanji, Tina
AU - Sweeney, Mary G
AU - Houlden, Henry
AU - Batla, Amit
AU - Zecchinelli, Anna L
AU - Pezzoli, Gianni
AU - Marotta, Giorgio
AU - Lees, Andrew
AU - Alegria, Paulo
AU - Krack, Paul
AU - Cormier-Dequaire, Florence
AU - Lesage, Suzanne
AU - Brice, Alexis
AU - Heutink, Peter
AU - Gasser, Thomas
AU - Lubbe, Steven J
AU - Morris, Huw R
AU - Taba, Pille
AU - Koks, Sulev
AU - Majounie, Elisa
AU - Raphael Gibbs, J
AU - Singleton, Andrew
AU - Hardy, John
AU - Klebe, Stephan
AU - Bhatia, Kailash P
AU - Wood, Nicholas W
AU - International PSC Study Group (IPSCSG)
AU - UCL-exomes consortium
N1 - © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Child
KW - Databases, Genetic
KW - Europe
KW - Female
KW - GTP Cyclohydrolase
KW - Genetic Variation
KW - Heterozygote
KW - Humans
KW - Male
KW - Middle Aged
KW - Mutation
KW - Parkinson Disease
KW - Pedigree
KW - Risk
KW - United States
KW - Young Adult
U2 - 10.1093/brain/awu179
DO - 10.1093/brain/awu179
M3 - SCORING: Journal article
C2 - 24993959
VL - 137
SP - 2480
EP - 2492
JO - BRAIN
JF - BRAIN
SN - 0006-8950
IS - Pt 9
ER -