Progressive Parkinsonism in PPP2R5D-Related Neurodevelopmental Disorder

Area of Science:

• Neurogenetics
• Neurology
• Developmental Biology

Background:

• PPP2R5D-related neurodevelopmental disorder (Houge-Janssens syndrome type 1) is a rare autosomal dominant condition.
• Key features include macrocephaly, intellectual disability, and epilepsy.
• Progressive parkinsonism is an emerging adult phenotype.

Purpose of the Study:

• To highlight progressive parkinsonism as an adult phenotype of PPP2R5D-related disorder.
• To emphasize the importance of genetic diagnosis for therapeutic intervention.
• To describe a case illustrating this presentation.

Main Methods:

• Case report of a 33-year-old female patient.
• Dopamine transporter imaging to assess nigrostriatal function.
• Whole-genome sequencing to identify pathogenic variants.

Main Results:

• The patient presented with progressive mixed-tremor parkinsonism in early adulthood.
• Dopamine transporter imaging confirmed presynaptic nigrostriatal dysfunction.
• Whole-genome sequencing identified a de novo PPP2R5D p.Glu198Lys variant.

Conclusions:

• The triad of macrocephaly, intellectual disability, and early-onset parkinsonism is specific for PPP2R5D-related disorder.
• Targeted genetic evaluation is recommended for adults with neurodevelopmental disorders and parkinsonism.
• Timely diagnosis facilitates access to emerging disease-modifying therapies in clinical trials.