PPP2R5D-Related Neurodevelopmental Disorder

Clinical characteristics: PPP2R5D-related neurodevelopmental disorder is characterized by mild to severe neurodevelopmental delay. Pronounced hypotonia with delay in gross motor skills is common. Onset of independent walking varies widely and ataxia is reported. All reported individuals have speech impairment, with a wide range of abilities. Autism spectrum disorder is reported in six individuals. Macrocephaly is common. Seizures and ophthalmologic abnormalities are reported in fewer than half of individuals. Additional anomalies include skeletal, endocrine, and cardiac malformations, each reported in a few individuals. To date, 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported.

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

Management: Treatment of manifestations: Standard treatment for seizures, visual impairment, and developmental delays.

Surveillance: Monitor for seizures, vision issues, developmental progress, and educational needs.

Genetic counseling: PPP2R5D-related neurodevelopmental disorder is inherited in an autosomal dominant manner. All probands reported to date with PPP2R5D-related neurodevelopmental disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo PPP2R5D pathogenic variant. Risk to future pregnancies is presumed to be low, as the proband most likely has a de novo PPP2R5D pathogenic variant; however, given the theoretic possibility of parental germline mosaicism, recurrence risk to sibs is estimated at 1%, and thus prenatal and preimplantation genetic testing may be considered.