To describe a patient with intellectual disability and early-onset parkinsonism carrying a pathogenic de novo PPP2R5D variant.

PPP2R5D encodes a regulatory subunit of protein phosphatase involved in dopaminergic neurotransmission. De novo variants are linked to neurodevelopmental delay, autism spectrum disorder, dysmorphic features, speech impairment, seizures, and levodopa-responsive parkinsonism.

Informed consent was obtained from the legal guardian. Medical records and brain imaging were reviewed. Trio-based whole-exome sequencing (WES) was performed.

The patient is a 33-year-old Middle Eastern male with intellectual disability and autism. Despite mildly delayed motor milestones, he achieved independent ambulation and maintained good motor function. At age 30, he developed progressive parkinsonism and became mostly wheelchair-bound.
WES revealed a de novo missense variant, p.D251A, in PPP2R5D. Absent in gnomAD v4.1, it is classified as pathogenic per ACMG criteria (PP3, PM2, PM5, PM1, PP2, PP5, PS2). Given prior reports of levodopa responsiveness, we initiated carbidopa/levodopa 25/100 mg, titrated to two tablets three times daily. His parkinsonism markedly improved, restoring independent ambulation. DaTscan confirmed dopaminergic deficiency (Figure 1).
WES also identified compound heterozygous FBXO7 variants: c.788-4_788-2delinsG (pathogenic) and p.G245V (VUS), another gene linked to levodopa-responsive parkinsonism

We report a 33-year-old male with intellectual disability and levodopa-responsive early-onset parkinsonism harboring a de novo PPP2R5D variant. Five pathogenic variants in 15 patients have been linked to parkinsonism (Table 1), all showing favorable levodopa response. The p.D251A variant was previously reported in individuals with intellectual disability but no parkinsonism. Co-occurring PPP2R5D and FBXO7 variants may suggest a synergistic contribution to the patient’s levodopa-responsive parkinsonism.

This case highlights the value of genetic testing in guiding treatment for neurodevelopmental presentations with overlapping movement disorders. We plan to expand our analysis by identifying PPP2R5D variant carriers in the Global Parkinson’s Genetic Program (GP2), which includes genome sequencing data from over 20,000 individuals.