RHOBTB2-Associated Neurological Phenotypes and Underlying Mechanisms: Alternating Hemiplegia of Childhood Beyond ATP1A3

Alternating hemiplegia of childhood (AHC) represents a severe and complex pediatric neurodevelopmental disorder, predominantly characterized by the occurrence of paroxysmal episodes of transient unilateral or bilateral paresis prior to 18 months of age. It belongs to a group of ultra-rare neurological disorders with a prevalence from 1:100,000 to 1:1,000,000. Even though the majority of AHC patients harbor pathogenic variants in the ATP1A3 gene, recent studies have pinpointed to other causative genes in ATP1A3-negative patients, including RHOBTB2. In this review, we report the case of a patient with a severe phenotype of AHC associated with developmental delay, aphasia and epilepsy, caused by a pathogenic de novo variant in the RHOBTB2 gene. Furthermore, we contribute a literature review on ATP1A3-negative AHC with a special focus on RHOBTB2-related AHC phenotypes, along with an overview of the pathophysiological mechanism of variants affecting residues in the BTB domain of the RHOBTB2 protein. The results of our study indicate that RHOBTB2-related AHC might have a more severe clinical presentation compared to ATP1A3-related AHC. Variants in the RHOBTB2 gene should be considered as disease-causing in patients with early-onset seizures, delayed psychomotor development and alternating hemiplegia of childhood.