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Parkinson's disease in GTP cyclohydrolase 1 mutation carriers

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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, Jahrgang 137, Nr. Pt 9, 01.09.2014, S. 2480-92.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Mencacci, NE, Isaias, IU, Reich, MM, Ganos, C, Plagnol, V, Polke, JM, Bras, J, Hersheson, J, Stamelou, M, Pittman, AM, Noyce, AJ, Mok, KY, Opladen, T, Kunstmann, E, Hodecker, S, Münchau, A, Volkmann, J, Samnick, S, Sidle, K, Nanji, T, Sweeney, MG, Houlden, H, Batla, A, Zecchinelli, AL, Pezzoli, G, Marotta, G, Lees, A, Alegria, P, Krack, P, Cormier-Dequaire, F, Lesage, S, Brice, A, Heutink, P, Gasser, T, Lubbe, SJ, Morris, HR, Taba, P, Koks, S, Majounie, E, Raphael Gibbs, J, Singleton, A, Hardy, J, Klebe, S, Bhatia, KP, Wood, NW, International PSC Study Group (IPSCSG) & UCL-exomes consortium 2014, 'Parkinson's disease in GTP cyclohydrolase 1 mutation carriers', BRAIN, Jg. 137, Nr. Pt 9, S. 2480-92. https://doi.org/10.1093/brain/awu179

APA

Mencacci, N. E., Isaias, I. U., Reich, M. M., Ganos, C., Plagnol, V., Polke, J. M., Bras, J., Hersheson, J., Stamelou, M., Pittman, A. M., Noyce, A. J., Mok, K. Y., Opladen, T., Kunstmann, E., Hodecker, S., Münchau, A., Volkmann, J., Samnick, S., Sidle, K., ... UCL-exomes consortium (2014). Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. BRAIN, 137(Pt 9), 2480-92. https://doi.org/10.1093/brain/awu179

Vancouver

Mencacci NE, Isaias IU, Reich MM, Ganos C, Plagnol V, Polke JM et al. Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. BRAIN. 2014 Sep 1;137(Pt 9):2480-92. https://doi.org/10.1093/brain/awu179

Bibtex

@article{4e14a07ef3a64ecebf9258c7d8925b73,
title = "Parkinson's disease in GTP cyclohydrolase 1 mutation carriers",
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.",
keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Child, Databases, Genetic, Europe, Female, GTP Cyclohydrolase, Genetic Variation, Heterozygote, Humans, Male, Middle Aged, Mutation, Parkinson Disease, Pedigree, Risk, United States, Young Adult",
author = "Mencacci, {Niccol{\`o} E} and Isaias, {Ioannis U} and Reich, {Martin M} and Christos Ganos and Vincent Plagnol and Polke, {James M} and Jose Bras and Joshua Hersheson and Maria Stamelou and Pittman, {Alan M} and Noyce, {Alastair J} and Mok, {Kin Y} and Thomas Opladen and Erdmute Kunstmann and Sybille Hodecker and Alexander M{\"u}nchau and Jens Volkmann and Samuel Samnick and Katie Sidle and Tina Nanji and Sweeney, {Mary G} and Henry Houlden and Amit Batla and Zecchinelli, {Anna L} and Gianni Pezzoli and Giorgio Marotta and Andrew Lees and Paulo Alegria and Paul Krack and Florence Cormier-Dequaire and Suzanne Lesage and Alexis Brice and Peter Heutink and Thomas Gasser and Lubbe, {Steven J} and Morris, {Huw R} and Pille Taba and Sulev Koks and Elisa Majounie and {Raphael Gibbs}, J and Andrew Singleton and John Hardy and Stephan Klebe and Bhatia, {Kailash P} and Wood, {Nicholas W} and {International PSC Study Group (IPSCSG)} and {UCL-exomes consortium}",
note = "{\textcopyright} The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.",
year = "2014",
month = sep,
day = "1",
doi = "10.1093/brain/awu179",
language = "English",
volume = "137",
pages = "2480--92",
journal = "BRAIN",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "Pt 9",

}

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 -