The L444PGBAmutation is associated with early-onset Parkinson's disease in Mexican Mestizos (original) (raw)
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Frontiers in Genetics
The genetic analysis of early-onset Parkinsonian disorder (EOPD) is part of the clinical diagnostics. Several genes have been implicated in the genetic background of Parkinsonism, which is clinically indistinguishable from idiopathic Parkinson's disease. The identification of patient's genotype could support clinical decision-making process and also track and analyse outcomes in a comprehensive fashion. The aim of our study was to analyse the genetic background of EOPD in a Hungarian cohort and to evaluate the clinical usefulness of different genetic investigations. The age of onset was between 25 and 50 years. To identify genetic alterations, multiplex ligation-dependent probe amplification (n = 142), Sanger sequencing of the most common PD-associated genes (n = 142), and next-generation sequencing (n = 54) of 127 genes which were previously associated to neurodegenerative disorders were carried out. The genetic analysis identified several heterozygous damaging substitutions in PD-associated genes (C19orf12, DNAJC6, DNAJC13, EIF4G1, LRRK2, PRKN, PINK1, PLA2G6, SYNJ1). CNVs in PRKN and SNCA genes were found in five patients. In our cohort, nine previously published genetic risk factors were detected in three genes (GBA, LRRK2, and PINK1). In nine cases, two or three coexisting pathogenic mutations and risk variants were identified. Advances of sequencing technologies make it possible to aid diagnostics of PD by widening the scope of analysis to genes which were previously linked to other neurodegenerative disorders. Our data suggested that rare damaging variants are enriched versus neutral variants, among PD patients in the Hungarian population, which raise the possibility of an oligogenic effect. Heterozygous mutations of multiple recessive genes involved in the same pathway may perturb the molecular process linked to PD pathogenesis. Comprehensive genetic assessment of individual patients can rarely reveal monogenic cause in EOPD, although it may identify the involvement of multiple PD-associated genes in the background of the
Frequency of Known Mutations in Early-Onset Parkinson Disease
Archives of Neurology, 2010
Objective-To assess the frequency and clinical characteristics of carriers of previously identified mutations in six genes associated with early onset Parkinson disease (EOPD) and provide empirical data that can be used to inform genetic counseling.
Glucocerebrosidase mutations in Thai patients with Parkinson's disease
2014
Background: GBA mutations are an important risk factor in developing Parkinson's disease (PD) worldwide. The study aimed to determine the frequency and clinical characteristics of GBA mutations in a Thai PD cohort of 480 patients and 395 control subjects. Methods: Direct sequencing of GBA was performed in all early-onset PD patients (EOPD: n ¼ 108) and 100 PD patients with age at onset over 50 years (AAO > 50y-PD). The study subsequently screened all identified mutations in the remaining AAO > 50y-PD patients and all control subjects. Predictive factors associated with risk of developing PD were analyzed. Comparisons of clinical characteristics of PD patients with and without GBA mutations were also carried out. Results: Heterozygous GBA mutations were identified in 24 patients (5%) and 2 controls (0.5%). Seven identified GBA point mutations comprised p.L444P, p.N386K, p.P428S, IVS2þ1G > A, IVS9þ3G > C, IVS10-9_10GT > AG and c.1309delG, of which five mutations were novel. Multiple logistic regression analysis revealed that GBA mutations were more frequent in EOPD than AAO > 50y-PD groups (OR ¼ 4.64, P < 0.022). Patients with GBA mutations had mean age at onset (43.1 ± 10.2, mean ± standard deviation) earlier than patients without GBA mutations (54.4 ± 13.9, P ¼ 0.002). The patients with GBA mutations also had a more rapid progressive course, in which they were more likely to have higher Hoehn and Yahr staging (OR ¼ 4.20, P ¼ 0.006) and slightly lower means of Schwab-England ADL score [74.1 ± 17.1 vs. 81.0 ± 18.08 (OR ¼ 0.98, 95%CI ¼ 0.96e1.01, P ¼ 0.162)]. Conclusion: GBA mutations are an important risk of PD in the Thai population. Patients having the mutations are likely to have early onset and may exhibit more rapid motor progression.
Neuroscience Letters, 2016
Parkinson's disease (PD) is the second most common neurodegenerative disorder, with cases of either familial or sporadic origin. Several polymorphisms in a number of genes have been proved to have an important role in the development of PD. Particular attention has recently been paid to genes of the glucocerebrosidase (GBA) and the vacuolar protein sortingassociated protein 35 (VPS35). In this study, the three most common mutations (L444P, N370S and R120W) of the GBA gene and the D620N mutation of the VPS35 gene were examined in 124 Hungarian patients diagnosed with sporadic PD (SPD) and 122 control subjects. The frequency of the L444P mutation of the GBA gene proved to be higher in the PD patients (2.4%) than in the controls (0%), although the difference was not statistically significant. All the patients who carried the mutant allele were in the early-onset PD (EOPD) group. However, neither the R120W nor the N370S variant of the GBA gene nor D620N mutation of the VPS35 gene were detected among the PD cases or the controls. Even though these results suggest that the studied mutations are quite rare in SPD patients, the most frequent L444P mutation of the GBA gene may be associated with the development of EOPD in the Hungarian population.
Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease
New England Journal of Medicine, 2009
Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease.