Abstract
Identification of individual risk factors for motor complications in Parkinson's disease (PD) can help to guide personalised medical treatment, particularly since treatment options are still limited. To determine whether common functional gene polymorphisms in the dopamine metabolism predict the onset of motor complications in PD, we performed a retrospective, observer-blinded follow-up study of 30 PD patients who underwent genotyping of dopa-decarboxylase (DDC; rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT; rs4680), and dopamine transporter (DAT; variable number tandem repeat) polymorphisms. Onset of wearing-off and dyskinesias was determined by blinded clinical assessments. Predictive values of genotypes for motor complications were evaluated using Cox proportional hazard models. During a median follow-up time of 11.6 years, 23 (77%) of 30 PD patients developed wearing-off, 16 (53%) dyskinesias, and 23 (77%) any motor complication. The MAOB (rs1799836) polymorphism predicted development of dyskinesias with MAOBCC/(C)/CT genotypes (resulting in low/intermediate brain enzyme activity) being associated with lower hazard ratios (unadjusted HR [95% CI]: 0.264 [0.089–0.787]; p=0.012; adjusted HR [95% CI]: 0.142 [0.039–0.520]; p=0.003) than MAOBTT/(T) genotypes (resulting in high brain enzyme activity). DDC (rs921451), COMT (rs4680), and DAT (VNTR) polymorphisms were not predictive of motor complications. Together, the MAOB (rs1799836) polymorphism predicts the development of dyskinesias in PD patients. Our results need confirmation in larger cohorts. If confirmed, individual assessment of this polymorphism might be helpful for early risk stratification and could comprise a step towards patient-tailored therapeutic strategies to prevent or delay motor complications in the course of PD.
Highlights
Parkinson’s disease (PD) is associated with motor complications, such as wearing-off and levodopa-induced dyskinesia (LID), which affect about 50% of patients after 5 years of treatment. eir pathophysiology involves presynaptic mechanisms [1] and postsynaptic factors downstream to the nigrostriatal dopaminergic input into the striatum [2]
Some investigations into genetic variants of the dopamine receptor D2 (DRD2) gene reported an association with dyskinesia [5,6,7,8], whereas others did not identify an association between DRD2 genotypes and the risk for dyskinesia [9,10,11,12,13,14]
Using quantitative 18F-fluorodopa PET imaging, we have recently shown that the monoamine oxidase B gene intron 13 polymorphism (MAOB; rs1799836) predicts dopamine turnover in de novo PD with the MAOBCC/(C)/CT genotypes leading to lower dopamine turnover [15], which in turn has been associated with a decreased risk for motor complications [16]
Summary
Parkinson’s disease (PD) is associated with motor complications, such as wearing-off and levodopa-induced dyskinesia (LID), which affect about 50% of patients after 5 years of treatment. eir pathophysiology involves presynaptic mechanisms [1] and postsynaptic factors downstream to the nigrostriatal dopaminergic input into the striatum [2]. Parkinson’s disease (PD) is associated with motor complications, such as wearing-off and levodopa-induced dyskinesia (LID), which affect about 50% of patients after 5 years of treatment.
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