TRPM3-Related Neurodevelopmental Disorder

Clinical characteristics: TRPM3-related neurodevelopmental disorder (TRPM3-NDD) is characterized by congenital hypotonia, developmental delay affecting motor and speech/language skills, mild-to-severe intellectual disability, seizures, ophthalmologic manifestations including strabismus, nystagmus, and refractive errors, and musculoskeletal manifestations (e.g., talipes equinovarus, hip dysplasia, scoliosis). Reported seizure types include febrile, absence, generalized tonic-clonic, infantile spasms, and atonic drops. Cerebellar atrophy may be seen on brain MRI.

Diagnosis/testing: The diagnosis of TRPM3-NDD is established in a proband with a heterozygous pathogenic variant in TRPM3 identified by molecular genetic testing.

Management: Treatment of manifestations: Developmental and educational support; physical medicine and therapies for ataxia as needed; anti-seizure medications for epilepsy as needed; standard treatments for ophthalmologic manifestations, musculoskeletal manifestations, and hearing impairment; social work support and care coordination as needed.

Surveillance: Monitor developmental progress, educational needs, changes in neurologic manifestations, growth, feeding, behavioral issues, and family needs at each visit; ophthalmologic and hearing evaluation annually.

Genetic counseling: TRPM3-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Vertical transmission of a TRPM3 pathogenic variant from an affected father to an affected son has been reported in one family to date. Each child of an individual with TRPM3-NDD has a 50% chance of inheriting the pathogenic variant. Once the TRPM3 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.