Genetic variants affect progression in Parkinson disease

By Will Boggs MD

NEW YORK (Reuters Health) - Mutations and polymorphisms in the GBA gene are associated with motor and cognitive progression in Parkinson disease (PD), according to results from the PD Cognitive Genetics Consortium.

"GBA-related PD is a more aggressive form of the disease characterized by faster decline in motor and cognitive function, and affects nearly one in ten PD patients," Dr. Cyrus P. Zabetian from Veterans Affairs Puget Sound Health Care System, Seattle, Washington told Reuters Health by email.

Loss-of-function mutations in the glucocerebrosidase gene (GBA) cause Gaucher disease, and heterozygous GBA mutation carriers have a substantially increased risk for developing PD. Some studies have reported an association between GBA mutations and more rapid progression of PD motor symptoms. Whether the GBA E326K polymorphism, which conveys a modest risk for PD, is also associated with more rapid progression of PD has been unknown.

Dr. Zabetian and colleagues examined the association of GBA mutations and E326K with progression of motor symptoms and cognitive decline in a study of 733 participants from seven sites in the PD Cognitive Genetics Consortium.

Motor symptoms, as measured by the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III, with scores ranging from 0 to 56), worsened by 3.0 points per year for mutation carriers, 3.8 for E326K carriers, 3.4 for carriers of any GBA variant, and only 2.0 for noncarriers, according to the August 29th JAMA Neurology online report.

After adjustment for other covariates, motor progression was significantly greater in carriers of a GBA mutation, E326K, or any GBA variant compared with noncarriers.

A higher proportion of GBA E326K carriers (10/21, 47.6%) - but not mutation carriers - progressed to mild cognitive impairment (MCI) and dementia, compared with noncarriers.

"The GBA E326K polymorphism is thought to have subtle functional effects on glucocerebrosidase enzyme activity in comparison to the more pronounced effects of GBA mutations," Dr. Zabetian said. "Therefore, it was surprising that the association of E326K with progression of motor and cognitive symptoms was similar to or greater than that observed for mutations."

"The mechanisms through which GBA influences PD pathogenesis remain unclear, but growing evidence suggests that the increased risk for PD in GBA carriers is due to decreased glucocerebrosidase function rather than a toxic gain of function," the researchers note.

"Our findings indicate that motor and cognitive deficits progress more rapidly in GBA-related PD," Dr. Zabetian said. "Therefore, patients with this form of the disease have even more to gain from disease-modifying therapies."

"One intriguing possibility for finding such a treatment using a precision medicine approach comes from the wealth of research that has been conducted in Gaucher disease," he said. "The results from our study provide further impetus for investigating these drugs in GBA-related PD."

Dr. Daniel Grinberg from the University of Barcelona, Spain, who recently reviewed the involvement of Gaucher disease mutations in PD, told Reuters Health by email, "The most interesting findings are the confirmation, in a study significantly more powerful than previous ones, of the association of GBA mutations with symptoms and progression of PD and, in particular, the effect of the E326K polymorphism. The latter is surprising because it is not a mutation responsible for Gaucher disease."

"Knowing the molecular bases of diseases is useful both for diagnosis and therapeutic approaches," he said. "In this case, sequencing the GBA gene could help to better characterize PD patients. Additionally, possible therapeutic approaches for PD could be developed based on Gaucher disease therapies."

"More basic research is needed," Dr. Grinberg concluded. "We need to understand the mechanisms through which the altered GBA proteins are affecting PD features to improve treatments for the disease."

Dr. Andrea Carmine Belin from Karolinska Institutet, Solna, Sweden recently reported a strong association between GBA mutations and PD in Sweden. She told Reuters Health, "These findings support the hypothesis on GBA involvement and PD and could show that the E326K variant has an effect on more rapid motor as well as cognitive progression. These findings improve our understanding of pathologic mechanisms underlying the disease."

"Together with LRRK2 and SNCA, genetic variants in GBA constitute the most common known genetic risk factors for sporadic PD today," Dr. Belin said. "This is the largest study of its kind, and they unlike other studies adjusted for concurrent dopamine replacement therapy (DRT) which strongly influences the UPDRS III score used in this study."

"GBA is clearly the most interesting disease-modifying gene in the PD field right now," she added. "Identification of genes that modify the rate of motor and/or cognitive decline can provide targets for development of novel therapies that impact disease onset or slow progression."

SOURCE: http://bit.ly/2bCJaBb

JAMA Neurol 2016.

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