GBA variants in REM sleep behavior disorder: A multicenter study.
Lynne Krohn1, Jennifer A Ruskey1, Uladzislau Rudakou1
1From the Department of Human Genetics (L.K., U.R., G.A.R., Z.G.-O.), Montreal Neurological Institute (L.K., J.A.R., U.R., E.L., F.A., R.B.P., G.A.R., Z.G.-O.), and Department of Neurology and Neurosurgery (J.A.R., F.A., R.B.P., G.A.R., Z.G.-O.), McGill University, Montréal; Oxford Parkinson's Disease Centre (M.T.M.H.) and Nuffield Department of Clinical Neurosciences (M.T.M.H.), University of Oxford, UK; Sleep Disorders Unit (I.A.), Pitié Salpêtrière Hospital, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière and Sorbonne Universities, Paris; National Reference Center for Narcolepsy, Sleep Unit (Y.D.), Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, France; Sleep Disorders Unit, Department of Neurology (B.H., A.S.), Medical University of Innsbruck, Austria; Department of Clinical Neurophysiology and Sleep Center (C.C.M.), University Lille North of France, CHU Lille; Sleep Disorder Unit (B.A.), Carémeau Hospital, University Hospital of Nîmes, France; Department of Biomedical and Neuromotor Sciences (DIBINEM) (G.P., E.A.), Alma Mater Studiorum, University of Bologna; IRCCS (G.P., E.A.), Istituto delle Scienze Neurologiche, Bologna; Department of Neurological Sciences (L.F.-S.), Università Vita-Salute San Raffaele, Milan, Italy; Department of Neurology with Institute of Translational Neurology (A.H.), University of Muenster, Germany; Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN; UC Gardner Neuroscience Institute and Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Cincinnati, OH; Sleep and Neurology Unit (V.C.D.C.), Beau Soleil Clinic, Montpellier; EuroMov (V.C.D.C.), University of Montpellier, France; Paracelsus-Elena-Klinik (B.M., F.S.-D., C.T.), Kassel; Department of Neurology (B.M., C.T.), University Medical Centre Goettingen; Department of Neurology (F.S.-D., W.O.), Philipps University, Marburg, Germany; Department of Neurology and Centre of Clinical Neuroscience (K.S., D.K.), Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic; Department of Medical Sciences and Public Health, Sleep Disorder Research Center (M.F., M.P.), University of Cagliari, Italy; Laboratory for Sleep Disorders (F.D., M.V.) and Department of Neurology (F.D., M.V.), St. Dimpna Regional Hospital, Geel, Belgium; Department of Medicine (DAME) (M.T., M.V.), University of Udine, Italy; Department of Clinical and Movement Neurosciences (M.T.), UCL Queen Square Institute of Neurology, London, UK; Clinical Neurology Unit (G.L.G., M.V.), Department of Neurosciences, University Hospital of Udine; DMIF (G.L.G.), University of Udine, Italy; Centre d'Études Avancées en Médecine du Sommeil (J.-F.G., A.D., J.Y.M., R.B.P.), Hôpital du Sacré-Cœur de Montréal; and Departments of Psychology (J.-F.G.), Neurosciences (A.D.), and Psychiatry (J.Y.M.), Université du Québec à Montréal, Canada.
Glucocerebrosidase (GBA) variants significantly increase the risk of isolated REM sleep behavior disorder (iRBD). These variants may also accelerate conversion to neurodegeneration, suggesting potential screening opportunities.
Area of Science:
- Genetics
- Neurology
- Sleep Medicine
Background:
- Isolated REM sleep behavior disorder (iRBD) is a prodromal sign of synucleinopathies.
- Glucocerebrosidase (GBA) gene variants are implicated in neurodegenerative diseases.
Purpose of the Study:
- To investigate the association between GBA variants and the risk of iRBD.
- To examine the impact of GBA variants on age at onset and conversion to overt neurodegeneration.
Main Methods:
- Full sequencing of the GBA gene in 4,147 individuals (1,061 iRBD patients, 3,086 controls).
- Analysis of GBA variant effects on iRBD risk, age at onset, and conversion rates.
Main Results:
- GBA variants were more frequent in iRBD patients (9.5%) than controls (4.1%), showing a 2.45-fold increased risk.
- Severe GBA variants were associated with an earlier age at onset (52.8 years) and a higher conversion rate to neurodegeneration (52.5% vs. 35.6%).
- Mild variants also increased iRBD risk (OR 3.69), with a trend for faster conversion in severe variant carriers, though these findings require larger sample validation.
Conclusions:
- GBA variants are strongly linked to increased iRBD risk and potentially accelerated neurodegeneration.
- Screening healthy GBA variant carriers for RBD could identify individuals at high risk for future synucleinopathies.
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