GBA variants in REM sleep behavior disorder: a multicenter study

Abstract

Objective: To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration. Methods: A total of 4,147 individuals were included: 1,061 iRBD patients and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk for iRBD, age at onset (AAO) and conversion rates. Results: GBA variants were found in 9.5% of iRBD patients compared to 4.1% in controls (odds ratio [OR]=2.45, 95% CI=1.87-3.22, p=1x10-10). The estimated OR for mild p.N370S variant carriers was 3.69, 95% CI=1.90-7.14, p=3.5x10-5, while for severe variant carriers it was 17.55, 95% CI=2.11-145.9, p=0.0015. Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or non-carriers (p=0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% in non-carriers (p=0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be taken with caution. Conclusions: GBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

Occurrence of Amyotrophic Lateral Sclerosis in Type 1 Gaucher Disease

“…This likely had a minimal effect on our results because mutations in the excluded exons in Europeans are rare. 17 Identification of complex alleles was also limited with our genotyping methods.…”

Comprehensive Analysis of Familial Parkinsonism Genes in Rapid‐Eye‐Movement Sleep Behavior Disorder

“…[8][9][10] The genetic background of iRBD has been only recently studied, with studies showing that there is no full genetic overlap between the genetic background of iRBD and that of PD or DLB. GBA mutations are associated with risk of iRBD, PD, and DLB, [11][12][13][14][15] but pathogenic LRRK2 mutations seem to be involved only in PD and not in iRBD and DLB. 7,16,17 MAPT and APOE variants are important risk factors of PD and DLB, respectively, 18,19 but both genes are not associated with iRBD.…”

“…22 Within the TMEM175 locus, there are two independent risk factors of PD, but only one of them, the coding polymorphism p.M393T, has been associated with iRBD. 23 Here, because GBA and SNCA have been studied previously, 12,22 we aimed at thoroughly examining the roles of PRKN, PINK1, PARK7 (DJ-1), VPS13C, ATP13A2, FBXO7, PLA2G6, LRRK2, GCH1, and VPS35 in iRBD.…”

“…Here, because GBA and SNCA have been studied previously, 12,22 we aimed at thoroughly examining the roles of PRKN , PINK1 , PARK7 ( DJ‐1 ), VPS13C , ATP13A2 , FBXO7 , PLA2G6 , LRRK2 , GCH1 , and VPS35 in iRBD.…”

SMPD1 variants do not have a major role in REM sleep behavior disorder

“…In order to examine the genetic basis of iRBD and its conversion, recent studies have examined whether PD- or DLB-associated genes are also associated with iRBD and whether they affect its conversion. It was demonstrated that while some genes such as GBA (Krohn et al, 2019b), TMEM175 (Krohn et al, 2019a) and SNCA (Krohn et al, 2019c) are associated with iRBD, other PD and DLB genes such as LRRK2 (Ouled Amar Bencheikh et al, 2018), APOE (Gan-Or et al, 2017) and MAPT (Li et al, 2018) are not. However, the association between SMPD1 and iRBD has not been investigated.…”