The following is a summary of “Molecular and Phenotypic Characterization of the RORB-Related Disorder,” published in the December 2023 issue of Neurology by Gokce-Samar et al.

Intellectual disability (ID) and seizures in epilepsy patients have been linked to mutations in the related orphan receptor B (RORB) gene. Still, detailed studies on causative variants in this population are scarce.

Researchers started a retrospective study to decipher the epileptic manifestations associated with RORB pathogenic variants and solidify their causative role.

They collaborated internationally, examining seizure characteristics, EEG data, and genotypes with heterozygous variants in RORB. Ex vivo cortical electroporation was performed in mouse embryos for 5 selected variants, two truncating and three missense for insights into disease mechanisms. Expression and quantified changes were assessed in axonal morphology.

The results showed 35 patients (17 male, median age 10 years, range 2.5–23 years) with 32 RORB heterozygous variants: 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures occurred in 31/35 (89%) patients, with a median onset age of 3 years (4 months–12 years). Absence seizures occurred in 25 patients (81%). Among 28 patients, 19 had “pure” absences or myoclonic absences, while 9 paired them with other seizure types. One patient presented with absences associated with photosensitive occipital seizures. Three patients had tonic-clonic seizures sans absences. Variable-degree ID was noted in 85% of patients. Cultured neuron expression studies showed shorter axons for the 5 tested variants, both truncating and missense, signifying impaired protein function.

Investigators concluded that the absence of seizures & mild-moderate ID dominate RORB disorder, while lab tests confirm variant impact weaker protein function.

Source: neurology.org/doi/10.1212/WNL.0000000000207945