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Published on: August 15, 2019
RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood
Sara Zagaglia1, Dora Steel1, S Krithika1
1From the UCL Queen Square Institute of Neurology (S.Z., S.K., L.H.-H., H.M.C., S.M.S.), London; Chalfont Centre for Epilepsy (S.Z., S.K., H.M.C., S.M.S.), Buckinghamshire; Department of Neurology (D.S., A.V., J.H.C., M.A.K.), Great Ormond Street Hospital; Clinical Neurosciences (A.V., J.H.C.), and Neurogenetics Group (D.S., M.A.K.), Developmental Neurosciences NIHR BRC UCL Great Ormond Street Institute of Child Health, London; School of Life Sciences (S.K.), Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, UK; Department of Neurology and Clinical Neurophysiology (K.M.G., M.D.K., B.J.L.), Children's Health Ireland at Temple Street, Dublin 1; School of Medicine and Medical Sciences (K.M.G., M.D.K.), University College Dublin, Dublin 4, Ireland; Danish Epilepsy Centre (R.S.M., T.B.H.), Dianalund; Department of Regional Health Research (R.S.M.), University of Southern Denmark, Odense; Department of Paediatric Neurology (R.S., A.A.M., A.M.), Bristol Royal Hospital for Children, UK; Pediatric Neurology (W.F.), Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne; Institute of Human Genetics (T.B.), University of Leipzig Medical Center, Germany; Departement de Neuropediatrie (D.D.), Centre de Référence Neurogénetique Mouvements Anormaux, Hôpital Armand Trousseau, and Department of Genetics (B.K., C.M.), La Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris; Centre de Référence Déficiences Intellectuelles de Causes Rares (C.M.); Departement de Pediatrie (N.B.), American Memorial Hospital, CHU Reims; CReSTIC (N.B.), University of Reims Champagne-Ardennes, France; University of Bristol (A.A.M.); Department of Haematology (A.S.-J.) and Cambridge Institute for Medical Research (F.L.R.), University of Cambridge; NIHR BioResource (A.S.-J., F.L.R.), Cambridge University Hospitals NHS Foundation Trust; Paediatric Neurology (A.B.), Great North Childrens Hospital, Newcastle upon Tyne; Population Health Sciences Institute (A.B.), Newcastle University, UK; Applied & Translational Genomics Group (H.S., S.W.), VIB-Center for Molecular Neurology, University of Antwerp; and Department of Neurology (H.S., S.W.), University Hospital Antwerp, Belgium.
Insights
RHOBTB2 gene mutations cause a wide range of symptoms, including movement disorders and features resembling alternating hemiplegia of childhood (AHC). Consider RHOBTB2 testing for AHC-like phenotypes, especially when ATP1A3 mutations are absent.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- RHOBTB2 mutations were initially linked to early infantile epileptic encephalopathy type 64.
- The full phenotypic spectrum of RHOBTB2-related disorders remains incompletely understood.
Purpose of the Study:
- To delineate the phenotypic spectrum of RHOBTB2-related disorders.
- To determine if patients with RHOBTB2 mutations meet the diagnostic criteria for alternating hemiplegia of childhood (AHC).
Main Methods:
- Retrospective case-note review of 11 individuals with RHOBTB2-related disorders.
- Genetic analysis to identify RHOBTB2 variants.
- Clinical data acquisition from a specialist pediatric movement disorder clinic and international collaborations.
Main Results:
- All 11 patients had heterozygous missense variants in RHOBTB2 exon 9 (de novo in 9).
- A complex motor phenotype was universal, with at least two movement disorders (e.g., ataxia, dystonia).
- Ten patients had paroxysmal movement disorders, and eight experienced hemiplegic episodes, resembling AHC but with later onset (from 20 months).
- Seven patients had epilepsy (4 seizure-free), and all had moderate to severe intellectual disability.
- Other features included skin color changes and gastrointestinal symptoms in 4 patients each.
Conclusions:
- RHOBTB2 mutations are associated with a broader clinical phenotype than previously recognized, including complex movement disorders with AHC-like features.
- RHOBTB2 gene testing is recommended for patients presenting with AHC-like phenotypes, particularly those negative for ATP1A3 mutations.
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.
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