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, Rikke S Møller, Mary D King Frcpch, Trine Bjørg Hammer, Robert Spaull, Walid Fazeli, Tobias Bartolomaeus, Diane Doummar, Boris Keren, Cyril Mignot, Nathalie Bednarek, J Helen Cross, Andrew A Mallick, Alba Sanchis-JuanAnna Basu, F Lucy Raymond, Bryan J Lynch, Anirban Majumdar, Hannah Stamberger, Sarah Weckhuysen, Sanjay M Sisodiya*, Manju A Kurian*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

15 Citations (Scopus)
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OBJECTIVE: 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.

Original languageEnglish
Article number095539
Pages (from-to)e1539-e1550
Number of pages12
Issue number11
Early online date27 Jan 2021
Publication statusPublished - 16 Mar 2021

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Publisher Copyright:
© 2021 American Academy of Neurology.


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