Link Observed Between GBA Mutations and REM Sleep Behavior Disorder

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Glucocerebrosidase gene mutation has been found to be strongly associated with REM sleep behavior disorder.
Glucocerebrosidase gene mutation has been found to be strongly associated with REM sleep behavior disorder.

VANCOUVER, British Columbia — Research presented here suggest that mutations in the glucocerebrosidase (GBA) gene, and other genetic markers in the GBA region, are strongly associated with rapid eye movement sleep behavior disorder (RBD).

“This association could be even stronger than the association of GBA mutations with [Parkinson's Disease (PD)],” Ziv Gan-Or, MD, PhD, study researcher from the Montreal Neurological Institute and Hospital told Neurology Advisor. “It could imply that GBA mutations are associated with a subtype of PD, which is, among other things, characterized by RBD.”

The findings were presented at the 68th annual meeting of the American Academy of Neurology (AAN).

According to Dr Gan-Or, mutations in GBA are probably the most important genetic risk factors for PD worldwide and are also a risk factor for other forms of synucleinopathies, such as dementia with Lewy bodies (DLB), and possibly for multiple system atrophy.

“Interestingly, individuals with RBD will most likely develop one of these synucleinopathies within 10 to 12 years on average after the diagnosis of RBD,” he said. “Both GBA mutations and RBD are associated with cognitive decline among PD patients, with other nonmotor symptoms, and with faster progression of the disease. Since RBD can occur many years before the onset of motor symptoms of PD, understanding its genetic background is of major importance. It may allow us to identify individuals who are at risk for RBD and for further development of PD or the other synucleinopathies.”

This led Dr Gan-Or and colleagues to conduct the current study in which they sequenced the GBA gene in individuals with PD (n=525), RBD (n=265), and controls (n=691) of French-Canadian/French origin, and culled data from European controls with GBA sequencing (n=2240). The investigators also screened for RBD in 120 PD patients of Ashkenazi-Jewish ancestry who were previously genotyped for founder GBA mutations, and extracted data from the GBA locus from the genome-wide association study of 522 PD patients, 350 RBD patients, and 897 controls of French-Canadian/French origin.

Researchers reported GBA mutations in 10.2% of RBD patients and 4.6% of PD patients, whereas the rate among in-house controls was 1.3% and published European ancestry controls was 1.8% (P<.001 for all comparisons).

Furthermore, there was a higher rate of positive screening for probable RBD in GBA-mutation associated PD patients vs PD patients without GBA mutations (47% vs 24%; P=.026).

In other analysis, in the GBA locus the greatest indicator in RBD patients (rs2230288; P=1 x 10-5) was stronger than the indicator in PD patients (rs35777901; P=3 x 10-4), when compared with healthy controls.

If these findings are confirmed by future research, Dr Gan-Or said they may suggest that GBA mutation carriers should be screened for RBD as an early sign for the development of a synucleinopathy, and that the association between RBD and the enzymatic activity of GBA should be studied as well, since it is possible that GBA activity is reduced among patients with RBD.

“If this will prove to be true, treatment that is targeting GBA and its pathways could be a promising direction to take,” he said.

Another key message of the study, Dr Gan-Or noted, is the distinction between PD, DLB, and subtypes of PD.

“We know that PD patients with GBA mutations have faster cognitive decline and higher rates of hallucinations,” he said. “This may suggest that the distinction between PD with dementia and DLB, at least for carriers of GBA mutations, is wrong. It is possible that this is the same disease rather than distinct entities, whether the motor symptoms had occurred first or whether dementia developed first.”

Click here for more coverage from the 68th Annual Meeting of the American Academy of Neurology, April 15-21, 2016, in Vancouver, British Columbia, Canada.

Reference

Gan-Or Z, Dupre N, Postuma R, et al. GBA mutations in REM sleep behavior disorder and Parkinson's disease. Presented at: The 68th Annual Meeting of the American Academy of Neurology; April 15-21, 2016; Vancouver, British Columbia, Canada. Abstract S19.007.

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