Adult-onset PPP2R5D -related dystonia–Parkinsonism: A systematic review

PPP2R5D -related neurodevelopmental disorder (Jordan syndrome) is a rare genetic condition characterized by developmental delay, intellectual disability, and macrocephaly. More recently, a small number of patients with PPP2R5D variants have been reported to develop dystonia-parkinsonism during adolescence or adulthood, suggesting an expanded phenotypic spectrum of the disorder. However, the clinical characteristics, genotype–phenotype correlations, neuroimaging findings, and treatment outcomes associated with this presentation remain poorly understood. We conducted a systematic review in accordance with the Preferred Reporting Items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines to characterize PPP2R5D -associated dystonia-parkinsonism. PubMed, Embase, and Directory of Open Access Journals (DOAJ) were searched through March 2025. After screening 149 records, five studies comprising seven genetically confirmed patients met the inclusion criteria. Risk of bias was assessed using Joanna Briggs Institute appraisal tools, and data were synthesized descriptively following the synthesis without meta-analysis (SWiM) framework. Across the included cases, parkinsonism was the predominant clinical manifestation, characterized by bradykinesia, rest tremor, rigidity, gait impairment, and postural instability. Dystonia was present in several patients and was accompanied by developmental delay, intellectual disability, and macrocephaly, reflecting the underlying neurodevelopmental disorder. The recurrent c.598G>A (p.Glu200Lys) variant was identified in five patients, while most pathogenic variants were located in exons 5 and 7. Six patients demonstrated clinical improvement with levodopa and/or dopamine agonist therapy, although three developed impulse control disorders or other behavioral adverse effects. Dopaminergic imaging, when performed, revealed evidence of nigrostriatal dysfunction, whereas conventional brain magnetic resonance imaging was largely unremarkable. All reported variants occurred de novo, and no familial clustering was observed. Collectively, the available evidence suggests that PPP2R5D -associated dystonia-parkinsonism represents a rare but increasingly recognized phenotype characterized by developmental abnormalities and levodopa-responsive parkinsonism. The recurrent p.Glu200Lys variant may represent a potential mutational hotspot, although larger studies are required to confirm genotype–phenotype associations. Early recognition through genetic testing may facilitate accurate diagnosis, guide therapeutic decisions, and enable monitoring for neuropsychiatric complications related to dopaminergic therapy.