Genetic study of early-onset Parkinson's disease in the Malaysian population

Tay, Yi Wen; Tan, Ai Huey; Lim, Jia Lun; Lohmann, Katja; Ibrahim, Khairul Azmi; Aziz, Zariah Abdul; Chin, Yen Theng; Mawardi, Ahmad Shahir; Lim, Thien Thien; Looi, Irene; Chia, Yuen Kang; Ooi, Joshua Chin Ern; Cheah, Wee Kooi; Closas, Alfand Marl F. Dy; Lit, Lei Cheng; Hor, Jia Wei; Toh, Tzi Shin; Muthusamy, Karthikeyan; Bauer, Péter; Skrahin, Volha; Rolfs, Arndt; Klein, Christine; Ahmad‐Annuar, Azlina; Lim, Shen‐Yang

doi:10.1016/j.parkreldis.2023.105399

Cited by 12 publications

(5 citation statements)

References 27 publications

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“…Regarding other Asian populations, a study assessing the genetic landscape of PD in Malaysia showed comparable outcomes, as 11 out of 161 young onset PD patients (6.8%) harbored PRKN mutations. PRKN exon 7 deletion appeared to be common among Malay patients [64]. In a Vietnamese early-onset PD population (N = 83), among 24 pathogenic/likely pathogenic mutations found in this study group, the second most common altered alleles were detected in PRKN (second to LRRK2), corresponding to 29%.…”

Section: Prkn (Parkin)mentioning

confidence: 62%

The Landscape of Monogenic Parkinson’s Disease in Populations of Non-European Ancestry: A Narrative Review

Koros,

Bougea,

Simitsi

et al. 2023

Genes

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Introduction: There has been a bias in the existing literature on Parkinson’s disease (PD) genetics as most studies involved patients of European ancestry, mostly in Europe and North America. Our target was to review published research data on the genetic profile of PD patients of non-European or mixed ancestry. Methods: We reviewed articles published during the 2000–2023 period, focusing on the genetic status of PD patients of non-European origin (Indian, East and Central Asian, Latin American, sub-Saharan African and Pacific islands). Results: There were substantial differences regarding monogenic PD forms between patients of European and non-European ancestry. The G2019S Leucine Rich Repeat Kinase 2 (LRRK2) mutation was rather scarce in non-European populations. In contrast, East Asian patients carried different mutations like p.I2020T, which is common in Japan. Parkin (PRKN) variants had a global distribution, being common in early-onset PD in Indians, in East Asians, and in early-onset Mexicans. Furthermore, they were occasionally present in Black African PD patients. PTEN-induced kinase 1 (PINK1) and PD protein 7 (DJ-1) variants were described in Indian, East Asian and Pacific Islands populations. Glucocerebrosidase gene variants (GBA1), which represent an important predisposing factor for PD, were found in East and Southeast Asian and Indian populations. Different GBA1 variants have been reported in Black African populations and Latin Americans. Conclusions: Existing data reveal a pronounced heterogeneity in the genetic background of PD. A number of common variants in populations of European ancestry appeared to be absent or scarce in patients of diverse ethnic backgrounds. Large-scale studies that include genetic screening in African, Asian or Latin American populations are underway. The outcomes of such efforts will facilitate further clinical studies and will possibly contribute to the identification of either new pathogenic mutations in already described genes or novel PD-related genes.

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Section: Prkn (Parkin)mentioning

confidence: 62%

The Landscape of Monogenic Parkinson’s Disease in Populations of Non-European Ancestry: A Narrative Review

Koros,

Bougea,

Simitsi

et al. 2023

Genes

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“…1 ). Recently, for example, in a study of Malaysian early-onset PD (EOPD), the rate of “solved” monogenic cases (i.e., where the cause of PD is attributed to pathogenic variant[s] in a single gene) increased from 21.7% overall to 48.5% when considering only the subgroup of EOPD patients with a positive family history [ 16 ]. Conversely, while it has been argued that the lack of a positive family history in the majority of PD patients points to environmental causation, many such individuals have, in fact, been shown to harbor a pathogenic genetic variant (e.g., 53.4% of the pathogenic variant-positive Malaysian EOPD patients had no history of PD in either the immediate or extended family [ 16 ]).…”

Section: Evidence For An Important Genetic Role In Pdmentioning

confidence: 99%

“…2 ) [ 47–50 ]. It is worth noting here that in China and India (by far the two most populous countries in the world, being home to ∼2.9 billion people, and also with extensive diasporas globally [ 16 ]), the vast majority of PD patients with family pedigrees compatible with autosomal dominant inheritance remain “unsolved” (e.g., 95% of the 242 probands studied by Zhao et al [ 37 ], and 100% of 44 probands in the study by Punia et al which tested specifically for pathogenic LRRK2 variants [ 51 ]), suggesting that additional genetic determinants of PD remain to be discovered in these large populations [ 52, 53 ].…”

Section: Evidence For An Important Genetic Role In Pdmentioning

confidence: 99%

Parkinson’s Disease is Predominantly a Genetic Disease

Lim,

Klein

2024

Journal of Parkinson’s Disease

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The discovery of a pathogenic variant in the alpha-synuclein (SNCA) gene in the Contursi kindred in 1997 indisputably confirmed a genetic cause in a subset of Parkinson’s disease (PD) patients. Currently, pathogenic variants in one of the seven established PD genes or the strongest known risk factor gene, GBA1, are identified in ∼15% of PD patients unselected for age at onset and family history. At first sight, the steep increase in PD prevalence exceeding that of other neurodegenerative diseases may argue against a predominant genetic etiology. Notably, the principal genetic contribution in PD is conferred by pathogenic variants in LRRK2 and GBA1 and, in both cases, characterized by an overall late age of onset and age-related penetrance. In addition, polygenic risk plays a considerable role in PD. However, it is likely that, in the majority of PD patients, a complex interplay of aging, genetic, environmental, and epigenetic factors leads to disease development.5% of PD patients unselected for age at onset and family history. At first sight, the steep increase in PD prevalence exceeding that of other neurodegenerative diseases may argue against a predominant genetic etiology. Notably, the principal genetic contribution in PD is conferred by pathogenic variants in LRRK2 and GBA1 and, in both cases, characterized by an overall late age of onset and age-related penetrance. In addition, polygenic risk plays a considerable role in PD. However, it is likely that, in the majority of PD patients, a complex interplay of aging, genetic, environmental, and epigenetic factors leads to disease development.

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“…Results of testing for monogenic and GBA1-related PD (which prioritized familial and/or EOPD cases) were available for 61 patients: next generation sequencing-based PD gene panel (n=21), 15 multiplex ligation-dependent probe amplification (n=13), 28 and/or whole genome sequencing (n=44, under the Global Parkinson's Genetics Project [GP2]). 17 Twelve (19.7%) were found to have variants in the risk factor GBA1 gene (n=10), 15,29 and in the monogenic LRRK2 (n=1) 30 or PRKN genes (n=1) 28 (Supplementary Table 3). Among the patients with GBA1 variants, only two were able to have their LEDD substantially reduced (by 30% or 50%) post-operatively.…”

Section: Pd Patientsmentioning

confidence: 99%

“…GBA1-variant carriers accounted for two of the patients with dementia (severe in one [PD-1414], with significant cognitive problems starting within a few months post-operatively in her 50s (13 years after PD diagnosis) despite undergoing otherwise uncomplicated DBS (first-pass placements of the cranial electrodes and no peri-operative brain haemorrhage); 27 and moderately severe in the other [PD-0203], occurring within four years post-operatively in his 50s [17 years post-diagnosis]); 15 and one of the patients (PD-2045) having problematic gambling and attempting suicide (described above). A good DBS outcome was obtained in the patient with PARK-PRKN, 28 whereas the benefit was small-tomedium only in the patient with LRRK2 p.R1441C. 30 The "Asian" LRRK2 risk variants p.R1628P and p.G2385R were detected in 10.3% (15/145) and 7.6% (10/132) of patients, respectively.…”

Section: Pd Patientsmentioning

confidence: 99%

Real-World Experience of Deep Brain Stimulation Surgery in a Developing Southeast Asian Country

Dy Closas,

Tan,

Tay

et al. 2023

Preprint

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Background: The availability of deep brain stimulation (DBS), a highly efficacious treatment for several movement disorders, remains low in developing countries, with scarce data available on utilization and outcomes. Objectives: We characterized the DBS cohort and outcomes at a Malaysian quaternary medical centre. Methods: A retrospective chart review was done on DBS-related surgery at the University of Malaya, including clinico-demographic, genetics, and outcomes data focusing on post-operative medication reduction and complications. Results: 149 Parkinson disease (PD) patients underwent DBS targeting the subthalamic nucleus. Six had globus pallidus internus DBS (primarily for dystonia). Only 16.1% of cases were government-funded. Of the 133 PD patients operated in the past decade (2013-2022), 25 (18.8%) had disease duration <5 years. At 6-12 months post-DBS, median levodopa-equivalent daily dosage (LEDD) reduction was 440.5 [418.9] mg/day, corresponding to a reduction of at least 50% and at least 30% in 42.2% and 69.8% of patients, respectively. LEDD reductions were larger in the early-onset and short-duration subgroups. Three patients (1.9% of 155) had symptomatic intracranial hemorrhage, resulting in stroke in two. Pathogenic monogenic or GBA1 variants were detected in 12/61 (19.7%) of patients tested, mostly comprising the GBA1 variant p.L483P (14.8%). Conclusion: This is the largest report on DBS from Southeast Asia. The procedures were effective, and complication rates on par with international norms. Our study found a high frequency of GBA1-PD; and included a substantial number of patients with short-duration PD, who had good outcomes. It also highlights the inequity of access to device-aided therapy.

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Genetic study of early-onset Parkinson's disease in the Malaysian population

Cited by 12 publications

References 27 publications

The Landscape of Monogenic Parkinson’s Disease in Populations of Non-European Ancestry: A Narrative Review

The Landscape of Monogenic Parkinson’s Disease in Populations of Non-European Ancestry: A Narrative Review

Parkinson’s Disease is Predominantly a Genetic Disease

Real-World Experience of Deep Brain Stimulation Surgery in a Developing Southeast Asian Country

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