RHOBTB2 mutations expand the phenotypic spectrum of alternating hemiplegia of childhood

Zagaglia, Sara and Steel, Dora and Krithika, S. and Hernandez-Hernandez, Laura and Custodio, Helena M. and Gorman, Kathleen M. and Vezyroglou, Aikaterini and Møller, Rikke S. and King, Mary D. and Hammer, Trine B. and Spaull, Robert and Fazeli, Walid and Bartolomaeus, Tobias and Doummar, Diane and Keren, Boris and Mignot, Cyril and Bednarek, Nathalie and Cross, J. Helen and Mallick, Andrew A. and Sanchis-Juan, Alba and Basu, Anna and Raymond, F. Lucy and Lynch, Bryan J. and Majumdar, Anirban and Stamberger, Hannah and Weckhuysen, Sarah and Sisodiya, Sanjay M. and Kurian, Manju A. (2021) RHOBTB2 mutations expand the phenotypic spectrum of alternating hemiplegia of childhood. Neurology. ISSN 1526-632X

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Official URL: https://doi.org/10.1212/WNL.0000000000011543


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.

Item Type: Journal Article
Additional Information: AVAILABLE AT: https://eprint.ncl.ac.uk/268391
Keywords: Developmental disorders, Dystonia
Faculty: Faculty of Science & Engineering
Depositing User: Lisa Blanshard
Date Deposited: 26 Feb 2021 10:07
Last Modified: 09 Sep 2021 16:04
URI: https://arro.anglia.ac.uk/id/eprint/706367

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