Objective: To evaluate the genotype and phenotype of early-onset Parkinson´s Disease (EOPD) in the Nepalese population.

Background: A significant proportion of early-onset PD (EOPD) can be attributed to a monogenic cause or involves the risk gene GBA1.¹ However, these have never been studied in Nepalese PD patients.

Method: We prospectively recruited all the EOPD patients ≤ 50 years presenting to Department of Neurology, Tribhuvan University Teaching Hospital from April 2022 to January 2023. 10mL of blood sample was collected and DNA was extracted in the research laboratory of the Department of Biochemistry. DNA samples were sent for whole genome sequencing, via the Global Parkinson´s Genetics Program(GP2). Single nucleotide variations (SNVs) in 74 PD- and neurodegeneration-linked genes were analyzed.

Results: A total of 40 subjects ( 27 index EOPD patients and 13 unaffected family members) were enrolled. The mean age of PD patients was 42.0±8.9 years ranging from 25-50 years and male-female ratio of 16:11. A remarkably high frequency of the pathogenic GBA1 p.Leu 483 Arg (L483R) variant was identified in 11 PD patients (40.7%). This variant is classified as “severe” in the GBA1 browser.² Variants of uncertain significance (VUS) were identified in several PD- and neurodegeneration-linked genes including LRRK2, VPS35, MAPT, and DCTN1. Three of the clinically unaffected relatives were also found to harbour GBA1 L483R. The mean age of onset of GBA1 variant carriers was 40.1±7.3 years, with disease duration of 3.9±1.9 years. Their mean ON-medication MDS- unified Parkinson’s disease rating scale (MDS-UPDRS) part 3, Montreal Cognitive Assessment (MoCA) and Hoehn and Yahr (H&Y) scores were 22.3±10.2, 25.0±3.7 and 2.5±0.5 respectively. Structural variant and repeat expansion analyses are in progress.

Conclusion: We found a remarkably higher prevalence of GBA1-PD among a pilot cohort of Nepalese EOPD patients, even compared to other Asian cohorts.^3,4 The patients’ cognitive functions appear to match their education level, with the caveat that most of them were still only a short duration into their disease. Further analysis of cognitive and motor functions is needed to obtain a better understanding of genotype-phenotype correlations in patients with GBA1 variants in our cohort.

Table 1: Clinical characteristics of GBA1 L483R

References: 1. Lim SY, Tan AH, Ahmad-Annuar A, Okubadejo NU, Lohmann K, Morris HR, Toh TS, Tay YW, Lange LM, Bandres-Ciga S, Mata I, Foo JN, Sammler E, Ooi JCE, Noyce AJ, Bahr N, Luo W, Ojha R, Singleton AB, Blauwendraat C, Klein C. Uncovering the genetic basis of Parkinson’s disease globally: from discoveries to the clinic. Lancet Neurol. 2024 Dec;23(12):1267-1280. doi: 10.1016/S1474-4422(24)00378-8. Epub 2024 Oct 21. PMID: 39447588.
2. Parlar SC, Grenn FP, Kim JJ, Baluwendraat C, Gan-Or Z. Classification of GBA1 Variants in Parkinson’s Disease: The GBA1-PD Browser. Mov Disord. 2023 Mar;38(3):489-495. doi: 10.1002/mds.29314. Epub 2023 Jan 4. PMID: 36598340; PMCID: PMC10033371.
3. Lim JL, Lohmann K, Tan AH, Tay YW, Ibrahim KA, Abdul Aziz Z, Mawardi AS, Puvanarajah SD, Lim TT, Looi I, Ooi JC. Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson’s disease: mutational spectrum and clinical features. Journal of Neural Transmission. 2022 Jan 1:1-2.
4. Rossi M, Schaake S, Usnich T, Boehm J, Steffen N, Schell N, Krüger C, Gül-Demirkale T, Bahr N, Kleinz T, Madoev H, Laabs BH, Gan-Or Z, Alcalay RN, Lohmann K, Klein C. Classification and Genotype-Phenotype Relationships of GBA1 Variants: MDSGene Systematic Review. Mov Disord. 2025 Feb 10. doi: 10.1002/mds.30141. Epub ahead of print. PMID: 39927608.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/prevalence-and-characteristics-of-glucocerebrosidase-genetic-variants-in-nepalese-early-onset-parkinsons-disease-patients/