Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in Parkinson's disease.

David Devos, Stéphanie Lejeune, Florence Cormier-Dequaire, Khadija Tahiri, Fanny Charbonnier-Beaupel, Nathalie Rouaix, Alain Duhamel, Bernard Sablonnière, Anne-Marie Bonnet, Cecilia Bonnet, Noel Zahr, Jean Costentin, Marie Vidailhet, Jean-Christophe Corvol

Journal: Parkinsonism & related disorders 2014;20(2):170-5

PMID: 24216088

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

In Parkinson's disease (PD), the response to L-dopa is highly variable and unpredictable. The major pathway for dopamine synthesis from L-dopa is decarboxylation by aromatic L-amino acid decarboxylase (AAAD, encoded by the DDC gene).

OBJECTIVE

To determine the motor response to L-dopa in PD patients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDC(T/C)) and rs3837091 AGAG del (DDC(AGAG/-))).

METHODS

Thirty-three Caucasian PD patients underwent an acute l-dopa challenge together with the peripheral AAAD inhibitor benserazide and were genotyped for rs921451 and rs3837091. The primary efficacy criterion was the motor response to L-dopa, as estimated by the area under the curve for the change in the Unified Parkinson's Disease Rating Scale part III (UPDRS) score relative to baseline (AUCΔUPDRS) in the 4 h following L-dopa administration. Secondary endpoints were pharmacokinetic parameters for plasma levels of L-dopa and dopamine. Investigators and patients were blinded to genotypes data throughout the study.

RESULTS

When adjusted for the L-dopa dose, the AUCΔUPDRS was significantly lower in DDC(CC/CT) patients (n = 14) than in DDC(TT) patients (n = 19) and significantly lower in DDC(-/- or AGAG/-) patients (n = 8) than in DDC(AGAG/AGAG) patients (n = 25). There were no significant intergroup differences in plasma pharmacokinetic parameters for L-dopa and dopamine.

DISCUSSION

The rs921451 and rs3837091 polymorphisms of the DDC gene promoter influence the motor response to L-dopa but do not significantly change peripheral pharmacokinetic parameters for L-dopa and dopamine. Our results suggest that DDC may be a genetic modifier of the l-dopa response in Parkinson's disease.

Address: INSERM (French National Institute of Medical Research and Health), APHP (Assistance Publique Hopitaux de Paris), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France; Lille Nord de France University, Department of Medical Pharmacology, Lille University Medical Center, Faculty of Medicine of Lille 2, EA 4610, France. Electronic address: [email protected].; INSERM (French National Institute of Medical Research and Health), APHP (Assistance Publique Hopitaux de Paris), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France; INSERM, UMRS_975 unit, UPMC (Pierre and Marie Curie University), CNRS UMR7525 CR-ICM, Paris, France.; INSERM, UMRS_975 unit, UPMC (Pierre and Marie Curie University), CNRS UMR7525 CR-ICM, Paris, France.; INSERM, UMRS_975 unit, UPMC (Pierre and Marie Curie University), CNRS UMR7525 CR-ICM, Paris, France; APHP (Assistance Publique Hopitaux de Paris), Pitié-Salpêtrière Hospital, Department of Pharmacy, France; APHP, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France.; Lille Nord de France University, Department of Molecular Biology, Lille University Medical Center, France.; APHP, Pitié-Salpêtrière Hospital, Department of Neurology, France.; INSERM (French National Institute of Medical Research and Health), APHP (Assistance Publique Hopitaux de Paris), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France.; APHP, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France.; University of Rouen, Neuropharmacology Laboratory, Rouen, France.; INSERM (French National Institute of Medical Research and Health), APHP (Assistance Publique Hopitaux de Paris), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France; INSERM, UMRS_975 unit, UPMC (Pierre and Marie Curie University), CNRS UMR7525 CR-ICM, Paris, France; APHP, Pitié-Salpêtrière Hospital, Department of Neurology, France.

DOI: 10.1016/j.parkreldis.2013.10.017

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MeSH Terms: Aged, Antiparkinson Agents, Area Under Curve, Cross-Over Studies, Dopa Decarboxylase, Double-Blind Method, Drug Resistance, Female, Genetic Predisposition to Disease, Genotype, Humans, Levodopa, Male, Middle Aged, Parkinson Disease, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, ROC Curve