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


CONCLUSIONS
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.
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: david.devos@chru-lille.fr.
David
D
Devos
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.
Stéphanie
S
Lejeune
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.
Florence
F
Cormier-Dequaire
INSERM, UMRS_975 unit, UPMC (Pierre and Marie Curie University), CNRS UMR7525 CR-ICM, Paris, France.
Khadija
K
Tahiri
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.
Fanny
F
Charbonnier-Beaupel
Lille Nord de France University, Department of Molecular Biology, Lille University Medical Center, France.
Nathalie
N
Rouaix
Lille Nord de France University, Department of Molecular Biology, Lille University Medical Center, France.
Alain
A
Duhamel
Lille Nord de France University, Department of Molecular Biology, Lille University Medical Center, France.
Bernard
B
Sablonnière
APHP, Pitié-Salpêtrière Hospital, Department of Neurology, France.
Anne-Marie
AM
Bonnet
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.
Cecilia
C
Bonnet
APHP, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France.
Noel
N
Zahr
University of Rouen, Neuropharmacology Laboratory, Rouen, France.
Jean
J
Costentin
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.
Marie
M
Vidailhet
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.
Jean-Christophe
JC
Corvol
D000368:Aged; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004296:Dopa Decarboxylase / Q000235:genetics*; D004311:Double-Blind Method; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012372:ROC Curve
D000978:Antiparkinson Agents; D007980:Levodopa; D004296:Dopa Decarboxylase
Dopamine; Genetic; Parkinson's disease; l-amino acid decarboxylase; l-dopa