Progressive Parkinsonism in PPP2R5D-Related Neurodevelopmental Disorder

PPP2R5D-related neurodevelopmental disorder (Houge-Janssens syndrome type 1) is a rare autosomal dominant condition characterized by macrocephaly, intellectual disability, and epilepsy. Progressive parkinsonism is an emerging adult phenotype that neurologists should be aware of since timely genetic diagnosis opens the door to disease-modifying therapies currently in clinical trials. We describe a 33-year-old woman with this condition who developed progressive mixed-tremor parkinsonism in early adulthood. Dopamine transporter imaging confirmed presynaptic nigrostriatal dysfunction. Whole-genome sequencing identified the recurrent de novo pathogenic missense variant PPP2R5D p.Glu198Lys. The clinical triad of macrocephaly, intellectual disability, and early-onset parkinsonism is specific for this condition and should prompt targeted genetic evaluation even in adults with a longstanding diagnosis of a neurodevelopmental disorder.