RHOBTB2 mutations expand the phenotypic spectrum of alternating hemiplegia of childhood

Sara Zagaglia, Dora Steel, S Krithika, Laura Hernandez-Hernandez, Helena Martins Custodio, Kathleen M Gorman, Aikaterini Vezyroglou,  View ORCID Profile Rikke S Møller, Mary D King FRCPCH, Trine Bjørg Hammer,  View ORCID Profile 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 FRCPCH, Hannah Stamberger, Sarah Weckhuysen, Sanjay M Sisodiya, Manju A Kurian

First published January 27, 2021, DOI: https://doi.org/10.1212/WNL.0000000000011543

This is a paid access journal via © 2021 American Academy of Neurology – Abstract summary attached below:


Objective: To explore the phenotypic spectrum of RHOBTB2-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.

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 a 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 an 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.

Received May 5, 2020.

Accepted in final form December 9, 2020.

© 2021 American Academy of Neurology

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‘AHC and ATP1A3 Natural History Study’ Q&A session with Dr. Katerina Vezyroglou‘AHC and ATP1A3 Natural History Study’ Q&A session with Dr. Katerina Vezyroglou

Thank you to everyone who joined in this helpful Question & Answer session in November of last year with Dr. Katerina Vezyroglou on her research work. As promised, we have included the link to the recorded zoom session for those of you who were unable to attend the event.    We hope you find this helpful and as in the session,  Dr. Vezyrouglou is very happy to hear from anyone who would like to ask  any more questions. All questions are welcome.    As discussed in the zoom chat, this project also feeds into the OBSERV AHC natural history study involving many international centers.  

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