Parkinson’s Patients Carrying Distinct Genetic Polymorphisms Less likely to Experience Levodopa–induced Dyskinesia, Study Shows

Parkinson’s patients carrying two types of genetic polymorphisms — a gene that has more than one variant in a given population — in the dopamine transporter gene are less likely to suffer from involuntary muscle movements associated with levodopa therapy, a study shows.

The study, “DAT gene polymorphisms (rs28363170, rs393795) and levodopa-induced dyskinesias in Parkinson’s disease,” was published in Neuroscience Letters.

Levodopa is one of the main therapies used to treat Parkinson’s disease. It works by replacing dopamine, a brain chemical produced by dopaminergic neurons that are destroyed gradually in the course of Parkinson’s.

Although levodopa therapy is often recommended to facilitate Parkinson’s symptoms’ management, the compound can have substantial side effects associated with its long-term use, including wearing-off effect (the medicine wears off before the patient can take the next dose), involuntary muscle movements, also known as levodopa-induced dyskinesia (LID), and changes in behavior (impulsive and compulsive behavior).

LID is one of the most common motor side effects of levodopa therapy — estimated to affect up to 95% of all patients taking levodopa for 15 years — and, at the same time, one of the most disabling.

Previous studies have proposed that Parkinson’s patients who are younger when they experience their first symptoms, have faster disease progression, and take higher doses of levodopa, are more likely to develop LID. However, given patients’ clinical variability to develop LID, these risk factors seem insufficient to explain its incidence, suggesting that genetic factors also may be involved.

Several studies have attempted to identify genetic factors that could increase patients’ susceptibility to LID, but results have been inconsistent so far. One particular gene, called dopamine transporter gene (DAT, also known as SLC6A3), might be an interesting candidate, because different genetic variants have been linked to different effects on dopamine uptake by neurons.

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In fact, in Parkinson’s patients, homozygosity (same two copies of a given gene) for a specific form, or allele, of the DAT gene (called 9R) has been associated with an increased risk to develop the disease, whereas homozygosity for another allele, called 10R, has been associated with Parkinson’s protection.

Alleles are variant forms of the same gene (one copy of the gene inherited from each parent) that arise by mutation and are found at the same place on a given chromosome.

In this study, researchers aimed to determine whether different genetic variants of the DAT gene could be associated with patients’ risk to develop LID.

A total of 181 Italian Parkinson’s patients who had been taking at least 300 mg of levodopa daily for three years or more, were recruited. All patients were screened for two different genetic polymorphisms within the DAT gene: the rs28363170 (9R and 10R alleles) and the rs393795 (A and C alleles).

Data failed to reveal any significant difference in LID prevalence among patients who carried the two DAT genetic polymorphisms.

However, patients who possessed two copies of the 10R allele in the rs28363170 region and also carried the A allele in the rs393795 region, were less likely to develop LID in the course of long-term levodopa therapy, compared to patients who did not have these alleles.

“Despite this interesting result, our finding was obtained in an exploratory manner and thus need to be confirmed and replicated in different ethnic background populations and in larger cohorts of patients,” researchers wrote.

“Nevertheless, we believe that the identification of genomic biomarkers involved in drug response variability represents an important step in PD [Parkinson’s disease] treatment and it could be useful to identify patients more prone to better respond to treatments or to develop frequent and disabling conditions as adverse events like LID,” they concluded.