PPP2R5D-Related Neurodevelopmental Disorder

Clinical characteristics: PPP2R5D-related neurodevelopmental disorder (PPP2R5D-NDD) is characterized by mild-to-profound neurodevelopmental delay, pronounced hypotonia, and macrocephaly. Onset of independent walking varies widely, and ataxia and movement disorders, including early-onset parkinsonism, are reported. Almost all individuals have speech impairment, with a wide range of abilities. Autism spectrum disorder is also reported in some individuals. Seizures and ophthalmologic abnormalities are reported in fewer than half of individuals. Gastrointestinal and skeletal manifestations are reported. Endocrine, cardiac, and genitourinary issues are each reported in a few individuals. To date, more than 100 individuals with PPP2R5D-NDD have been reported.

Diagnosis: The diagnosis of PPP2R5D-NDD is established in a proband by identification of a heterozygous pathogenic variant in PPP2R5D by molecular genetic testing.

Management: Treatment of manifestations: Standard treatment for developmental delays, intellectual disability, neurobehavioral issues, sleep dysregulation, seizures, visual impairment, gastrointestinal and skeletal manifestations, parkinsonism, and endocrine issues. Develop transition plan to adult care; provide family any community resources.

Surveillance: Assess developmental progress and educational needs at each visit; behavior assessment as clinically indicated; ophthalmology evaluations per ophthalmologist or as needed; assess for gastrointestinal and skeletal manifestations at each visit; evaluation with neurology as needed for movement disorder; assess for impairment in fine motor, gross motor, and activities of daily living at each visit; assess for precocious puberty annually throughout early childhood; assess for cryptorchism at each visit in early childhood.

Genetic counseling: PPP2R5D-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, an individual diagnosed with PPP2R5D-NDD has the disorder as the result of a pathogenic variant inherited from an affected, heterozygous parent. Each child of an individual with PPP2R5D-NDD has a 50% chance of inheriting the pathogenic variant. Once the PPP2R5D pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.