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

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• 作者：David Devos ; St茅phanie Lejeune ; Florence Cormier-Dequaire ; Khadija Tahiri ; Fanny Charbonnier-Beaupel ; Nathalie Rouaix ; Alain Duhamel ; Bernard Sablonni猫re ; Anne-Marie Bonnet ; Cecilia Bonnet ; Noel Zahr ; Jean Costentin ; Marie Vidailhet ; Jean-Christophe Corvol
• 关键词：Parkinson's disease ; Dopamine ; l-amino acid decarboxylase ; Genetic ; l-dopa
• 刊名：Parkinsonism and Related Disorders
• 出版年：February, 2014
• 年：2014
• 卷：20
• 期：2
• 页码：170-175
• 全文大小：539 K

文摘

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聽T聽>聽C polymorphism (DDC^T/C) and rs3837091 AGAG del (DDC^{AGAG/鈭?/sup>)).}

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_螖UPDRS) in the 4聽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_螖UPDRS was significantly lower in DDC^CC/CT patients (n聽=聽14) than in DDC^TT patients (n聽=聽19) and significantly lower in DDC^{鈭?鈭?or AGAG/鈭?/sup> patients (n聽=聽8) than in DDCAGAG/AGAG patients (n聽=聽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.