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, 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

Publikation: Bidrag til tidsskriftArtikelForskningpeer review


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 pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review.

RESULTS: Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, 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 ATP1A3, these events were reported later only in RHOBTB2 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.

CONCLUSION: Although heterozygous RHOBTB2 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. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations.

Sider (fra-til)e1539-e1550
Udgave nummer11
Tidlig onlinedato27 jan. 2021
StatusUdgivet - 16 mar. 2021


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