title: Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.
abstract: Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.
authors: 1 MRC Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK 2 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors: Fatima
authors: F
authors: Jaffer
authors: 3 NIHR UCLH Biomedical Research Centre Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK 4 Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK.
authors: Andreja
authors: A
authors: Avbersek
authors: 5 A.I.S.EA Onlus, Via Sernovella, 37 - Verderio Superiore, 23878 Lecco, Italy.
authors: Rosaria
authors: R
authors: Vavassori
authors: 6 Paediatric Neurology Department, Hospital Sant Joan de Déu, P° de Sant Joan de Déu, 2 08950 Esplugues de Llobregat, Barcelona University, Barcelona, Spain.
authors: Carmen
authors: C
authors: Fons
authors: 6 Paediatric Neurology Department, Hospital Sant Joan de Déu, P° de Sant Joan de Déu, 2 08950 Esplugues de Llobregat, Barcelona University, Barcelona, Spain.
authors: Jaume
authors: J
authors: Campistol
authors: 7 Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, Istituto Giannina Gaslini, Largo Gaslini 5, 26148, University of Genoa, Genoa, Italy.
authors: Michela
authors: M
authors: Stagnaro
authors: 7 Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, Istituto Giannina Gaslini, Largo Gaslini 5, 26148, University of Genoa, Genoa, Italy.
authors: Elisa
authors: E
authors: De Grandis
authors: 7 Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, Istituto Giannina Gaslini, Largo Gaslini 5, 26148, University of Genoa, Genoa, Italy.
authors: Edvige
authors: E
authors: Veneselli
authors: 8 University Medical Center Göttingen, Georg August University, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Georg August University, Robert Koch Strasse 40, 37099 Göttingen, Germany.
authors: Hendrik
authors: H
authors: Rosewich
authors: 9 Child Neurology Unit IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy.
authors: Melania
authors: M
authors: Gianotta
authors: 10 Clinical Neurophysiology Unit, IRCCS "E. Medea", Via Don L. Monza 20, 23842 Bosisio Parini (LC), Italy.
authors: Claudio
authors: C
authors: Zucca
authors: 11 Department of Pediatric Neuroscience, IRCCS Foundation Neurological Institute C. Besta, Via Celoria 11, 20133 Milano, Italy.
authors: Francesca
authors: F
authors: Ragona
authors: 11 Department of Pediatric Neuroscience, IRCCS Foundation Neurological Institute C. Besta, Via Celoria 11, 20133 Milano, Italy.
authors: Tiziana
authors: T
authors: Granata
authors: 11 Department of Pediatric Neuroscience, IRCCS Foundation Neurological Institute C. Besta, Via Celoria 11, 20133 Milano, Italy.
authors: Nardo
authors: N
authors: Nardocci
authors: 12 Division of Paediatric Neurology, Duke University, T0913J Children Health Centre, Duke University Medical Centre, Durham, USA.
authors: Mohamed
authors: M
authors: Mikati
authors: 12 Division of Paediatric Neurology, Duke University, T0913J Children Health Centre, Duke University Medical Centre, Durham, USA.
authors: Ashley R
authors: AR
authors: Helseth
authors: 13 Division of Neurology, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8.
authors: Cyrus
authors: C
authors: Boelman
authors: 13 Division of Neurology, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8.
authors: Berge A
authors: BA
authors: Minassian
authors: 14 Inherited Cardiovascular Diseases Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, and Institute of Cardiovascular Science, University College London, London, WC1N 3JH, UK.
authors: Sophia
authors: S
authors: Johns
authors: 15 Florey Institute of Neurosciences and Mental Health, and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
authors: Sarah I
authors: SI
authors: Garry
authors: 15 Florey Institute of Neurosciences and Mental Health, and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
authors: Ingrid E
authors: IE
authors: Scheffer
authors: 16 Centre de reference epilepsies rares et Sclérose tubéreuse de Bourneville (site Parisien adolescents-adultes), Hôpital Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital 75651 Paris cedex 13, France.
authors: Isabelle
authors: I
authors: Gourfinkel-An
authors: 17 Neuropediatric Department Centro Hospitalar do Porto, Rua da Boavista, 8274050-111, Porto, Portugal.
authors: Ines
authors: I
authors: Carrilho
authors: 18 Clinical Neurosciences, Developmental Neuroscience Programme, UCL Institute of Child Health, & Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
authors: Sarah E
authors: SE
authors: Aylett
authors: 1 MRC Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors: Matthew
authors: M
authors: Parton
authors: 1 MRC Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors: Michael G
authors: MG
authors: Hanna
authors: 2 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors: Henry
authors: H
authors: Houlden
authors: 18 Clinical Neurosciences, Developmental Neuroscience Programme, UCL Institute of Child Health, & Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
authors: Brian
authors: B
authors: Neville
authors: 19 Molecular Neurosciences, Developmental Neurosciences Programme, UCL Institute of Child Health and Department of Neurology, Great Ormond Street Hospital, London, London, WC1N 3JH, UK.
authors: Manju A
authors: MA
authors: Kurian
authors: 3 NIHR UCLH Biomedical Research Centre Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK 4 Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK.
authors: Jan
authors: J
authors: Novy
authors: 3 NIHR UCLH Biomedical Research Centre Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK 4 Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK.
authors: Josemir W
authors: JW
authors: Sander
authors: 20 Department of Cardiac Electrophysiology, The Heart Hospital, Institute of Cardiovascular Science, University College London, 16-18 Westmoreland St, London W1G 8PH, UK.
authors: Pier D
authors: PD
authors: Lambiase
authors: 21 Cardiac and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
authors: Elijah R
authors: ER
authors: Behr
authors: 22 European Network for Research on Alternating Hemiplegia, ENRAH, Brussels, Belgium.
authors: Tsveta
authors: T
authors: Schyns
authors: 23 Epilepsy, Sleep and Paediatric Neurophysiology Department (ESEFNP), University Hospitals of Lyon (HCL), and DYCOG team, Lyon Neuroscience Research Centre (CRNL), INSERM U1028; CNRS UMR 5292, Lyon, France.
authors: Alexis
authors: A
authors: Arzimanoglou
authors: 18 Clinical Neurosciences, Developmental Neuroscience Programme, UCL Institute of Child Health, & Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK 24 Young Epilepsy, St. Piers Lane, Lingfield, Surrey RH7 6PW, UK.
authors: J Helen
authors: JH
authors: Cross
authors: 14 Inherited Cardiovascular Diseases Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, and Institute of Cardiovascular Science, University College London, London, WC1N 3JH, UK.
authors: Juan P
authors: JP
authors: Kaski
authors: 3 NIHR UCLH Biomedical Research Centre Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK 4 Epilepsy Society, Chalfont-St-Peter, Bucks, SL9 0RJ, UK s.sisodiya@ucl.ac.uk.
authors: Sanjay M
authors: SM
authors: Sisodiya
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001342:Autonomic Nervous System Diseases / Q000209:etiology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004562:Electrocardiography; D005260:Female; D006331:Heart Diseases / Q000175:diagnosis / Q000209:etiology*; D006339:Heart Rate / Q000235:genetics; D006352:Heart Ventricles / Q000503:physiopathology; D006429:Hemiplegia / Q000150:complications* / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007391:International Cooperation; D008297:Male; D009154:Mutation / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics; D055815:Young Adult
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ATP1A3; Na+/K+-ATPase; SUDEP; alternating hemiplegia of childhood; electrocardiogram