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RHOBTB2 mutations expand the phenotypic spectrum of alternating hemiplegia of childhood
journal contribution
posted on 2023-07-26, 15:16 authored by Sara Zagaglia, Dora Steel, S. Krithika, Laura Hernandez-Hernandez, Helena M. Custodio, Kathleen M. Gorman, Aikaterini Vezyroglou, Rikke S. Møller, Mary D. King, Trine B. Hammer, Robert Spaull, Walid Fazeli, Tobias Bartolomaeus, Diane Doummar, Boris Keren, Cyril Mignot, Nathalie Bednarek, J. Helen Cross, Andrew A. Mallick, Alba Sanchis-Juan, Anna Basu, F. Lucy Raymond, Bryan J. Lynch, Anirban Majumdar, Hannah Stamberger, Sarah Weckhuysen, Sanjay M. Sisodiya, Manju A. KurianObjective: To explore the phenotypic spectrum of RHOBTB2-related disorders, and specifically to determine whether patients fulfil criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals.
Methods: Individuals with RHOBTB2-related disorders were identified through a movement disorder clinic at a specialist paediatric centre, with additional cases identified through collaboration with other centres internationally. Clinical data was acquired through retrospective case-note review.
Results: 11 affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, confirmed as de novo in nine cases. All had a complex motor phenotype, including at least two 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 eight experienced hemiplegic episodes. In contrast to classical AHC, commonly caused by mutations in ATP1A3, these events were only reported later in RHOBTB2-mutation-positive patients, from twenty months of age. Seven patients had epilepsy, but of these, four achieved seizure-freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin colour change and gastrointestinal symptoms, each in four patients.
Conclusion: Although heterozygous RHOBTB2 mutations were originally described in early infantile epileptic encephalopathy (EIEE64), our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations.
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NeurologyISSN
1526-632XExternal DOI
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Wolters KluwerLanguage
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2021-02-26Legacy Faculty/School/Department
Faculty of Science & EngineeringNote
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