Genetic Mutations May Affect Parkinson’s Progression

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Certain genetic mutations may help determine the length of survival in Parkinson’s disease patients, according to findings by a team of researchers from four institutes in Paris.

Patients with Parkinson’s who carried a mutation in either the LRRK2 or the PRKN genes were found to live longer than those without the mutations. But a mutation in either of two other genes, SNCA or GBA, was linked to a shorter survival time.

“These are important new insights which could help the development of new drugs targeting these genetic variants to slow down or stop the disease,” Aymeric Lanore, MD, of the Paris Brain Institute at Sorbonne University, who led the study, said in a press release.

Until targeted treatments become available, the findings may help doctors talk with their patients about the likely course of their disease.

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“These findings not only help increase our understanding of what drives the progression of Parkinson’s disease, but they may also enable clinicians to have honest conversations with their patients about expected survival times — just as cancer patients are told their prognosis,” said Lanore, adding, “This can empower patients to make decisions about their care and the time they may have left.”

The findings, “Survival in monogenic forms of Parkinson’s disease: results of a large retrospective study,” were presented at this year’s European Academy of Neurology (EAN) Congress.

Parkinson’s occurs when certain nerve cells in a part of the brain that controls movement start to wither and die. Sometimes, this is caused by a mutation in a gene known to be linked to Parkinson’s. The mutation may occur anew or be passed down in a family from parent to child.

One such gene is LRRK2, which provides instructions for making a protein kinase. Mutations in this gene are one of the most common genetic variants in Parkinson’s and have been linked to a form of late-onset Parkinson’s. One other gene is PRKN, which codes for a protein called parkin; it normally helps cells break down proteins into their building blocks for reuse.

Two other genes, SNCA and GBA, also are known to be associated with Parkinson’s. The SNCA gene provides instructions for making alpha-synuclein, a protein that may clump as toxic aggregates inside nerve cells. Mutations in this gene have been linked to early-onset Parkinson’s. The GBA gene gives instructions to make the enzyme glucocerebrosidase, a protein that breaks down a certain component of the membrane that surrounds cells.

To understand how genetic mutations may shape the way the disease develops, researchers looked at the records of the first hospital visit of 2,037 patients with Parkinson’s. Specifically, they measured survival at a certain point in time in a group of patients carrying a certain mutation versus a control group without that mutation.

Patients who had a mutation in the LRRK2 gene had a longer survival time than control patients. Their “hazard ratio of death” was 0.5, meaning that half as many patients who had the mutation had died at a certain point in time compared with the control group.

Similar findings were obtained for patients with a mutation in the PRKN gene (their hazard ratio of death was 0.42).

But patients with a mutation in either the SNCA or the GBA gene had a shorter survival than control patients, with a hazard ratio of death of 10.20 and 1.36, respectively.

“The results suggest the shorter survival of SNCA and GBA patients may be related to faster motor progression of the disease and earlier development of cognitive impairment,” Lanore said.

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