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 (DDCT/G) and rs3837091 AGAG del (DDCAGAG/-)). 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 (AUC(Delta UPDRS)) 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 AUC(Delta UPDRS) was significantly lower in DDCCC/CT patients (n = 14) than in DDCIT patients (n = 19) and significantly lower in DDC-/- (or) (AGAG/-) patients (n = 8) than in DDCAGAG/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. (C) 2013 Elsevier Ltd. All rights reserved.