Objective: To investigate the relationship between genetic subtypes and disease progression in Early-Onset Parkinson’s Disease (EOPD) .

Background: Genetic factors play a critical role in the pathogenesis and progression of EOPD patients (age of onset below 50 years). While previous genotype-phenotype studies have primarily been cross-sectional, a comprehensive analysis of longitudinally disease progression is required.

Method: A total of 841 EOPD patients were consecutively recruited and underwent next-generation sequencing and multiplex ligation-dependent probe amplification (MLPA) for Parkinson’s disease-related genes(Fig 1). Among them, 286 with longitudinal follow-up data were included. A linear mixed-effects model with random slopes and intercepts was employed to estimate individual motor progression rates. Patients were grouped based on progression rate: the fastest 25% were classified as fast subgroup, the slowest 25% as slow subgroup, and the middle 50% as intermediate. Genotype distribution and baseline clinical characteristics were compared across subgroups. Binary logistic regression was used to compare progression rates between EOPD patients with specific variants and genetically undefined EOPD (GU-EOPD). Descriptive analyses were conducted for other pathogenic genotypes.

Results: Parkin was the most common pathogenic gene (19.58%), followed by PLA2G6 (5.24%). Genotype distribution and baseline clinical characteristics exhibited heterogeneity across progression subgroups(Fig 2). After adjusting for confounders, Parkin-PD were less likely to be classified as fast progressors compared to GU-EOPD (odds ratio [OR] = 0.352, 95% confidence interval [CI]: 0.137–0.904). In contrast, PLA2G6-PD patients were more likely to be fast progressors (OR = 8.07, 95% CI: 2.38–27.24)(Table 1). Heterogeneity in motor progression was also observed in patients with SNCA, PINK1, DJ-1, VPS35 and CHCHD2 mutations(Table 2). Motor symptom at baseline was significantly more severe in the fast progression subgroup compared to the intermediate subgroup, and the intermediate subgroup was more severe than the slow progression subgroup(Table 3).

Conclusion: The genotype distribution of EOPD patients varies across different subgroups. Disease progression and clinical features are heterogeneous among patients with different genotypes, suggesting that genotype plays a crucial role in clinical manifestations and progression heterogeneity of EOPD.

Overall genotype distribution in the PD cohort

Genotype distribution of patients with follow-ups

Characteristics of Parkin-PD and PLA2G6-PD

Genotype distribution of different subgroups

Clinical manifestations among subgroups

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-analysis-between-genotypes-and-disease-progression-in-parkinsons-disease/