Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease

Abstract

Idiopathic Parkinson's disease (IPD) is a progressive neurodegenerative disorder for which no restorative or neuroprotective therapy is available. Interest has recently been directed to association studies on polymorphisms of various genes, mainly those related to dopamine metabolism and transport, and their effect on response to PD, which includes primarily levodopa and dopaminomimetics. Approximately 15-20% of patients with PD do not respond to levodopa, and the majority of those who do respond develop adverse fluctuations in motor response, primarily levodopa-induced dyskinesias. This review summarizes the influence of polymorphisms in various genes on the relative risk of IPD and on levodopa efficacy. It focuses on the importance of well-designed polymorphism studies that include large samples of patients with IPD and tightly matched controls and use identical methodologies. Valid data on such polymorphisms might increase the efficacy of levodopa, decrease its side effects, and reduce the occurrence of levodopa-induced dyskinesias. They might also provide a novel diagnostic tool for PD.

The influence of SLC6A3 and DRD2 polymorphisms on levodopa-therapy in patients with sporadic Parkinson's disease

“…Since the duration and amplitude of dopamine action is determined by a rapid release of extracellular dopamine into presynaptic terminals, studies have suggested that polymorphisms in genes related to degradation and reuptake of dopamine could be involved in the risk of adverse outcomes after long‐term administration of levodopa or other dopaminergic drugs . Although side effects such as dyskinesia and motor fluctuations may severely impair the daily life of patients with PD some of these patients will never develop these effects …”

Clinical Aspects and Management of Levodopa-Induced Dyskinesia

“…PD patients with early disease onset have a high probability to carry mutations for monogenic PD forms, and therefore, early onset and genetic predisposition are two overlapping and possibly interrelated risk factors. Other risk factors associated with increased risk of dyskinesias are female gender [17, 18] and the occurrence of specific polymorphisms for dopamine receptors or dopamine transporters [19–21]. …”

Levodopa-induced dyskinesias and their management

“…PD patients with early disease onset have a high probability to carry mutations for monogenic PD forms and therefore early onset and genetic predisposition are two overlapping and possibly interrelated risk factors. Other risk factors associated with increased risk of dyskinesias are female gender [50,86] and the occurrence of specific polymorphisms for dopamine receptors or dopamine transporters [29,36,68].…”