<i>RHOBTB2</i> Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood.

Abstract

To explore the phenotypic spectrum of <i>RHOBTB2</i>-related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals. Individuals with <i>RHOBTB2</i>-related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review. Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of <i>RHOBTB2</i>, confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in <i>ATP1A3</i>, these events were reported later only in <i>RHOBTB2</i> mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients. Although heterozygous <i>RHOBTB2</i> mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. <i>RHOBTB2</i> testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for <i>ATPA1A3</i> mutations.