. 2021 Mar 16;96(11):e1539-e1550.

doi: 10.1212/WNL.0000000000011543. Epub 2021 Jan 27.

RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood

Sara Zagaglia¹, Dora Steel¹, S Krithika¹, Laura Hernandez-Hernandez¹, Helena Martins Custodio¹, Kathleen M Gorman¹, Aikaterini Vezyroglou¹, Rikke S Møller¹, Mary D King¹, Trine Bjørg Hammer¹, Robert Spaull¹, Walid Fazeli¹, Tobias Bartolomaeus¹, Diane Doummar¹, Boris Keren¹, Cyril Mignot¹, Nathalie Bednarek¹, J Helen Cross¹, Andrew A Mallick¹, Alba Sanchis-Juan¹, Anna Basu¹, F Lucy Raymond¹, Bryan J Lynch¹, Anirban Majumdar¹, Hannah Stamberger¹, Sarah Weckhuysen¹, Sanjay M Sisodiya², Manju A Kurian²

Affiliations

¹ From 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.
² From 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. manju.kurian@ucl.ac.uk s.sisodiya@ucl.ac.uk.

PMID: 33504645
PMCID: PMC8032376
DOI: 10.1212/WNL.0000000000011543

RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood

Sara Zagaglia et al. Neurology. 2021.

. 2021 Mar 16;96(11):e1539-e1550.

doi: 10.1212/WNL.0000000000011543. Epub 2021 Jan 27.

Authors

Affiliations

¹ From 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.
² From 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. manju.kurian@ucl.ac.uk s.sisodiya@ucl.ac.uk.

PMID: 33504645
PMCID: PMC8032376
DOI: 10.1212/WNL.0000000000011543

Abstract

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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Figures

**Figure 1. Pathogenic Mutations Within the *RHOBTB2* Gene**
Note that the longest transcript, NM_001160036.1, does not include exons 4 and 5. UTR = untranslated region.

**Figure 2. Patient 2, 1 Year of Age, Demonstrating an Episode of Patchy Erythema and Pallor During a Bath**

See this image and copyright information in PMC

References

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RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood

Affiliations

RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases