Objective: To investigate disease progression of PLA2G6-related parkinsonism in a longitudinal study.

Background: There is a paucity of follow-up studies on disease progression in PLA2G6-related parkinsonism.

Method: Genetic analysis was performed by multiplex ligation–dependent probe amplification and target sequencing/whole exome sequencing. The dynamic variants of spinocerebellar ataxia were tested in probands with a family history. Twenty-five patients carrying homozygous or compound heterozygous PLA2G6 mutations (PLA2G6 Group) and 211 genetically undefined (GU) patients with Parkinson’s disease (PD), with age at onset <40 years (GU-EOPD Group) were investigated. Fourteen and 42 patients in the PLA2G6 and GU-EOPD Groups, respectively, underwent at least two follow-up visits (Figure 1). Multivariable Cox proportional hazard regression and linear mixed-effects models were used to evaluate disease progression.

Results: At baseline, patients in the PLA2G6 Group were in younger age at onset, had more severe motor and non-motor symptoms, and had worse cognitive function than those of the GU-EOPD Group (Figure 2). Follow-up study showed a shorter time period from motor onset to the development of falling/tumble, dyskinesia, and an advanced stage of disease (Figure 3). The estimated progression rate (standard error) of the motor score (MDS-UPDRS-III) was 1.73 (0.85) points higher per year in the PLA2G6 Group (p = 0.04). The difference in progression rate of the cognition (MMSE) score between the two groups was 0.44 (0.16) (p = 0.01) (Figure 4). After the start of motor symptoms, most PAL2G6 patients developed cognitive/psychiatric dysfunction within 2.60-3.83 years and some were bedridden within 5.00 years (Figure 5).

Conclusion: Patients with PLA2G6-related parkinsonism showed a more rapid deterioration of motor and non-motor symptoms, and cognitive dysfunction than GU-EOPD patients, which might give clues to the development of its pathology.

Figure 1. Flowchart of the study

Figure 2. Motor and non-motor features

Figure 3. Progression of the symptoms

Figure 4. Progression of MDS-UPDRS-III and MMSE

Figure 5.Clinical trajectories

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MDS Abstracts - https://www.mdsabstracts.org/abstract/disease-progression-in-patients-with-pla2g6-related-parkinsonism-a-longitudinal-study/