PI4KA-Related Disorder

Clinical characteristics: PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects). Age of onset is typically antenatal or in early childhood; individuals can present with any combination of these features. Rare individuals present with later-onset hereditary spastic paraplegia. Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria.

Diagnosis/testing: The diagnosis of PI4KA-related disorder is established in a proband with characteristic features and biallelic PI4KA pathogenic variants identified by molecular genetic testing.

Management: Treatment: Individualized care by a multidisciplinary team; physical therapy, occupational therapy, mobility aids, and medical management as needed for limb spasticity and motor issues; speech-language therapy for speech impairment and/or dysphagia; communication aids as needed; educational support for intellectual disability; anti-seizure medication as needed for seizures; gastrostomy as needed for feeding issues; treatments for multiple intestinal atresia and inflammatory bowel disease per surgeon and gastroenterologist; treatment of immunodeficiency per immunologist; standard treatment for hearing and vision issues.

Surveillance: Neurologic, developmental, and gastrointestinal assessments annually or as needed; consider complete blood count and inflammatory markers annually or as indicated by symptomatology; endoscopy as needed; monitor for increased susceptibility to infection; annual audiology and ophthalmology evaluations throughout childhood.

Genetic counseling: PI4KA-related disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PI4KA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the PI4KA pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.