Objective: To examine the prevalence of genetic causes in young-onset Parkinson’s disease (YOPD) patients with levodopa-induced dyskinesia (LID) in Thailand using a next-generation sequencing (NGS) study. The clinical characteristics of those with genetic abnormalities were also explored.

Background: Substantial numbers of YOPD patients have underlying genetic abnormalities. Mutation of GBA has been reported as an important genetic factor in Thailand, associated with rapid motor progression. Genetic studies of YOPD in Thailand were performed traditionally by Sanger sequencing. With the advent of NGS, we are able to study genetics architecture in Thai YOPD.

Method: NGS studies, using the Truseq Neurodegeneration Panel (Illumina, Inc.), were carried out in YOPD patients with a history of LID diagnosed. Demographic data and clinical characteristics were recorded and analysed. Analyses of factors associated with pathogenic variants were also performed.

Results: Pathogenic variants were identified in eight (16.7%) of the 48 patients enrolled. These were 5 (10.4%) heterozygous GBA mutations (c.1448T>C in 3 patients and c.115+1G>A in 2 patients), 2 (4.2%) homozygous PINK1 mutations (p.R492Ter) and 1 (2.1%) PRKN mutation (homozygous exon 7 deletion). Mean age at onset of motor symptoms was not significantly different between patients with or without GBA mutation (37.2±7.9 vs 41.2±8.2 years, respectively). The onset of LID was earlier in patients with GBA mutation compared to those without (34.8±23.4 vs 105.9±57.9 months after the onset of motor symptom, respectively, p=0.001). LID onset within the first 30 months of disease was also found to be independently associated with GBA mutation (odds ratio [95% confidence interval] = 26.4 [2.3-301.4], p=0.008) and with the detection of any pathogenic variants in this cohort (odds ratio [95% confidence interval] = 15.3 [1.5-156.0], p=0.022).

Conclusion: In our study, the NGS technique had a diagnostic yield of 16.7% to identify pathogenic variants in YOPD with LID patients. These included the mutations of GBA, PINK1 and PRKN, with the pathogenic variants of GBA appearing to be more common than the others. The earlier onset of LID was associated with, and may also be predictive of GBA mutation in this population.

References: 1. Pulkes T, Choubtum L, Chitphuk S, Thakkinstian A, Pongpakdee S, Kulkantrakorn K, Hanchaiphiboolkul S, Tiamkao S, Boonkongchuen P.Glucocerebrosidase mutations in Thai patients with Parkinson’s disease. Parkinsonism Relat Disord. 2014 Sep;20(9):986-91. 2. O’Regan G, deSouza RM, Balestrino R, Schapira AH. Glucocerebrosidase Mutations in Parkinson Disease. J Parkinsons Dis. 2017;7(3):411-422.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/is-early-onset-of-levodopa-induced-dyskinesia-a-predictor-of-gba-mutation-a-next-generation-sequencing-study-of-young-onset-parkinsons-disease-patients-in-thailand/