Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset

Abstract

Objective: To characterize sequence variation within the glucocerebrosidase (GBA) gene in a select subset of our sample of patients with familial Parkinson disease (PD) and then to test in our full sample whether these sequence variants increased the risk for PD and were associated with an earlier onset of disease. Methods:We performed a comprehensive study of all GBA exons in one patient with PD from each of 96 PD families, selected based on the family-specific lod scores at the GBA locus. Identified GBA variants were subsequently screened in all 1325 PD cases from 566 multiplex PD families and in 359 controls.Results: Nine different GBA variants, five previously reported, were identified in 21 of the 96 PD cases sequenced. Screening for these variants in the full sample identified 161 variant carriers (12.2%) in 99 different PD families. An unbiased estimate of the frequency of the five previously reported GBA variants in the familial PD sample was 12.6% and in the control sample was 5.3% (odds ratio 2.6; 95% confidence interval 1.5-4.4). Presence of a GBA variant was associated with an earlier age at onset (p ϭ 0.0001). On average, those patients carrying a GBA variant had onset with PD 6.04 years earlier than those without a GBA variant. Conclusions:This study suggests that GBA is a susceptibility gene for familial Parkinson disease (PD) and patients with GBA variants have an earlier age at onset than patients with PD without GBA variants. Neurology

CNS expression of glucocerebrosidase corrects α-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy

“…In addition, GBA1-null mutations (84GG or IVS2+1) are associated with the highest risk for synucleinopathies, whereas a putative folding mutation N370S having the highest residual activity presents the lowest risk (38). Hence, the data suggest that mutations in GBA1 are sufficient to initiate aberrant α-syn folding but decrease in glucocerebrosidase activity (regardless of mutations) seems to accelerate misprocessing, and thereby increase the susceptibility and cause earlier onset of PD-like changes (8,39).…”

The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease

“…Founder mutations in GBA can be detected in 1 out of 16 Ashkenazi Jews, and were shown to be important risk factors for Parkinson disease (PD) in this population 2,3 and in many other populations worldwide. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Three other lysosomal storage diseases that are caused by founder mutations can be found in the AJ population: Tay-Sachs disease 19 (carrier frequency of 1:27 20 ), Niemann-Pick disease type A 21 (1:115 20 ), and mucolipidosis type IV 22 (1:89 20 ). These 3 autosomal recessive diseases are caused by mutations in genes encoding lysosomal enzymes, 23 and their deficiency results in cellular accumulation of the enzymes' substrates.…”

Glucocerebrosidase Mutations in Parkinson Disease

“…However, in one study, even though depression scores were higher in GBA mutation PD patients than in GBA mutation negative patients, the difference in scoring above the cut-off was not significant [62]; other studies did not find any significant differences in mood disorders [10,13,54], and a longitudinal study did not show differences in depression neither at baseline nor during the follow-up [51].…”

“…In the routine clinical environment, GBA linked PD is virtually indistinguishable from idiopathic PD, with a marginally earlier age of onset and slightly higher prevalence of cognitive effects the only suggestive features in this setting [13,14]. There are more subtle features associated with GBA PD, which may be elicited in research settings and are discussed in the clinical section of this review.…”

“…However, significant differences in cognitive function between PD patients with and without GBA mutations were not confirmed in some studies [13,62,71,72]. It has been reported that there is significantly higher frequency of usage of acetylcholine esterase inhibitors for dementia in GBA PD compared with idiopathic PD [73], and one study found significant differences in selfreported cognitive impairment [74].…”