PPP2R1A-Related Neurodevelopmental Disorder

Clinical characteristics: PPP2R1A-related neurodevelopmental disorder (NDD) is characterized by: severe, persistent hypotonia; developmental delay with variable intellectual outcomes, typically in the moderate-to-severe intellectual disability range; seizures (more commonly seen in individuals with microcephaly and/or severe intellectual disability); attention-deficit/hyperactivity disorder and other behavioral problems (anxiousness, repetitive movements, self-injurious or destructive behavior, and autism spectrum disorder); feeding and swallowing issues; and dysmorphic features of the head and face. A minority of affected individuals have ear anomalies, hearing loss, ptosis, generalized joint hypermobility, and patent ductus arteriosus. Brain MRI findings are nonspecific but typically include complete or partial agenesis of the corpus callosum. Nonprogressive ventriculomegaly may be seen in a subset of affected individuals and is often associated with specific pathogenic variants in PPP2R1A: c.544C>T (p.Arg182Trp) and c.547C>T (p.Arg183Trp).

Diagnosis/testing: The diagnosis of PPP2R1A-NDD is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in PPP2R1A identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy with consideration of gastrostomy tube placement for persistent feeding issues; standard treatment for epilepsy, developmental delay / intellectual disability, scoliosis, ear anomalies, hearing loss, dental crowding, congenital heart defects, and ptosis.

Surveillance: At each visit: measure growth parameters; evaluate nutritional status and oral intake; assess for new neurologic manifestations such as seizures and changes in muscle tone; monitor developmental progress and educational needs; assess mobility, self-help skills, and need for developmental therapies. At each visit until skeletal maturity: physical exam to assess for scoliosis. Annually or as clinically indicated: dental evaluation, audiology evaluation (through childhood), and behavioral assessment for anxiety, attention, and aggressive or self-injurious behavior.

Genetic counseling: PPP2R1A-related NDD is expressed in an autosomal dominant manner and typically caused by a de novo PPP2R1A pathogenic variant. The risk to other family members is presumed to be low. Once a PPP2R1A pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.