Glucocerebrosidase gene mutation is a risk factor for early onset of Parkinson disease among Taiwanese

Abstract

Background: Mutations in the glucocerebrosidase (GBA) gene have recently been identified as contributing to the development of Parkinson disease (PD) in Ashkenazi Jews. Methods: To investigate whether this finding can be confirmed in a Taiwanese population, we conducted a case control study in a cohort of 518 PD patients and 339 controls for the three common GBA mutations in Taiwan, L444P, RecNciI and R120W, using PCR restriction enzyme assay and DNA sequencing. Results: Heterozygous GBA mutations were detected in 16 PD patients (3.1%) and four controls (1.2%). Although this difference was not statistically significant (p = 0.0703), the average age at disease onset of the 16 PD patients (50.6 (12.3) years) was significantly younger than that of the total patient group (63.8 (10.5) years; p = 0.0007) and the noncarrier patient group (64.2 (10.2) years; p = 0.0005). After stratification by age, the frequency of mutation carriers was significantly higher for the early onset PD (EOPD, age at onset

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

“…11 A large study of both Jewish and non-Jewish samples found an association between GBA mutations and PD in the Jewish group only. 15 Chinese patients with PD from Singapore demonstrated a significant association with GBA, 21 whereas a similar study of Chinese patients from Taiwan did not. 20 A survey of Italian patients with PD for the N370S and L444P mutations found a significant association of these variants with PD, 22 while a Norwegian sample showed comparable frequencies of these two mutations in patients with PD and controls.…”

“…23 In some studies, patients with PD harboring GBA variants had earlier age at disease onset. 12,15,19,21 Whether the discrepant results regarding the association of GBA with disease and age at onset result from true ethnic differences in GBA variant frequencies or from differences in the scope of the studies (i.e., only screening for certain variants as opposed to sequencing the entire coding region) remains to be determined.…”

“…The remaining five variants had been previously reported in patients with PD and GD, as well as controls. 8,[10][11][12][13][14][15]17,[19][20][21] An unbiased estimate (using resampling techniques as described in Methods) of the frequency of the five previously reported GBA variants in the subset of the familial PD sample that met our strictest diagnostic criteria of verified PD was 12.6% and in the control sample was 5.3% (table 3). The mean age at onset of the patients with PD harboring a GBA variant was 56.8 years (median: 58, range: 30 -79).…”

“…[10][11][12][13][14][15][16][17][18][19][20][21][22][23] The goals of this study were to characterize sequence variation within GBA in a select subset of our large sample of patients with familial PD and then to test in the entire sample whether these sequence variants increased the risk for PD or were associated with an earlier onset of disease.…”

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.…”