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Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.

Jaffer, F; Avbersek, A; Vavassori, R; Fons, C; Campistol, J; Stagnaro, M; De Grandis, E; Veneselli, E; Rosewich, H; Gianotta, M; et al. Jaffer, F; Avbersek, A; Vavassori, R; Fons, C; Campistol, J; Stagnaro, M; De Grandis, E; Veneselli, E; Rosewich, H; Gianotta, M; Zucca, C; Ragona, F; Granata, T; Nardocci, N; Mikati, M; Helseth, AR; Boelman, C; Minassian, BA; Johns, S; Garry, SI; Scheffer, IE; Gourfinkel-An, I; Carrilho, I; Aylett, SE; Parton, M; Hanna, MG; Houlden, H; Neville, B; Kurian, MA; Novy, J; Sander, JW; Lambiase, PD; Behr, ER; Schyns, T; Arzimanoglou, A; Cross, JH; Kaski, JP; Sisodiya, SM (2015) Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype. Brain, 138 (Pt 10). pp. 2859-2874. ISSN 1460-2156
SGUL Authors: Behr, Elijah Raphael

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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.

Item Type: Article
Additional Information: © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( 4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: ATP1A3, Na+/K+-ATPase, SUDEP, alternating hemiplegia of childhood, electrocardiogram, Adolescent, Adult, Age Factors, Autonomic Nervous System Diseases, Child, Child, Preschool, Cohort Studies, Electrocardiography, Female, Heart Diseases, Heart Rate, Heart Ventricles, Hemiplegia, Humans, Infant, Infant, Newborn, International Cooperation, Male, Mutation, Sodium-Potassium-Exchanging ATPase, Young Adult, Heart Ventricles, Humans, Autonomic Nervous System Diseases, Hemiplegia, Heart Diseases, Electrocardiography, Cohort Studies, Age Factors, Heart Rate, Mutation, International Cooperation, Adolescent, Adult, Child, Child, Preschool, Infant, Infant, Newborn, Female, Male, Sodium-Potassium-Exchanging ATPase, Young Adult, alternating hemiplegia of childhood, ATP1A3, Na+/K+-ATPase, SUDEP, electrocardiogram, Neurology & Neurosurgery, 11 Medical And Health Sciences, 17 Psychology And Cognitive Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA)
Journal or Publication Title: Brain
ISSN: 1460-2156
Language: eng
12 August 2015Published
Publisher License: Creative Commons: Attribution 4.0
Project IDFunderFunder ID
WT093205MAWellcome Trust
WT104033AIAWellcome Trust
J004758Medical Research Council
PubMed ID: 26297560
Web of Science ID: WOS:000365136200016
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