Zagaglia, S;
Steel, D;
Krithika, S;
Hernandez-Hernandez, L;
Custodio, HM;
Gorman, KM;
Vezyroglou, A;
... Kurian, MA; + view all
(2021)
RHOBTB2 mutations expand the phenotypic spectrum of alternating hemiplegia of childhood.
Neurology
, 96
(11)
e1539-e1550.
10.1212/WNL.0000000000011543.
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Abstract
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.
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