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

Abstract

BackgroundIn 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). ObjectiveTo determine the motor response to l-dopa in PD patients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDCT/C) and rs3837091 AGAG del (DDCAGAG/−)). MethodsThirty-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. ResultsWhen adjusted for the l-dopa dose, the AUCΔUPDRS was significantly lower in DDCCC/CT patients (n = 14) than in DDCTT 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. DiscussionThe 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.