BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials.

Associazione Italiana per la Sindrome di Emiplegia Alternante Lecco Italy

Biostatistics Department University Hospitals of Lyon and UMR 5558 Lyon France

Center for Human Genome Variation Duke University School of Medicine Durham NC USA

Centre National de la Recherche Scientifique UMR7225 Paris France

Child Neurology Unit Maggiore Hospital Bologna Italy

Department of Child Neurology Armand Trousseau Hospital APHP Paris France

Department of Child Neurology Sant Joan de Déu Hospital Barcelona Spain

Department of Child Neurology University Hospitals Leuven Leuven Belgium

Department of Child Neuropsychiatry G Gaslini Hospital University of Genoa Genoa Italy

Department of Clinical and Experimental Epilepsy University College London Institute of Neurology London UK

Department of Genetics University Hospitals of Lyon and Claude Bernard Lyon 1 University Lyon France

Department of Human Genetics Leiden University Medical Centre Leiden The Netherlands

Department of Medicine Duke University School of Medicine Durham NC USA

Department of Medicine University of Melbourne Austin Health Melbourne Australia

Department of Molecular Genetics Neurogenetics Group VIB Antwerp Belgium

Department of Neurology Charles University 1st Faculty of Medicine and Teaching Hospital Prague Czech Republic

Department of Neurology Leiden University Medical Centre Leiden The Netherlands

Department of Neurology Pitié Salpêtrière Hospital APHP Paris France

Department of Paediatrics University of Melbourne Royal Children's Hospital Melbourne Australia

Division of Pediatric Neurology and Department of Neurobiology Duke University School of Medicine Durham NC USA

DYCOG team Lyon Neuroscience Research Centre INSERM U1028; CNRS UMR 5292 Lyon France

Epilepsy Sleep and Pediatric Neurophysiology Department Lyon France

Institut National de la Santé et de la Recherche Médicale U975 Centre de Recherche de l'Institut du Cerveau et de la Moelle Paris France

Institute of Child Health University College London London UK

Institute of Medical Genetics University Cattolica del Sacro Cuore Policlinics A Gemelli Rome Italy

Lyon Neuroscience Research Center CNRS UMR 5292 INSERM U1028 Lyon France

Zobrazit více v PubMed

Verret S, Steele JC. Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy. Pediatrics. 1971;47:675–80. PubMed

Dittrich J, Havlová M, Nevsímalová S. Paroxysmal hemipareses in childhood. Dev Med Child Neurol. 1979;21:800–7. doi: 10.1111/j.1469-8749.1979.tb01705.x. PubMed DOI

Krägeloh I, Aicardi J. Alternating hemiplegia in infants: report of five cases. Dev Med Child Neurol. 1980;22:784–91. doi: 10.1111/j.1469-8749.1980.tb03746.x. PubMed DOI

Aicardi J, Bourgeois M, Goutières F. Alternating hemiplegia of childhood: clinical findings and diagnostic criteria. In: Andermann F, Aicardi J, Vigevano F, editors. Alternating hemiplegia of childhood. New York: Raven; 1995. pp. 3–18.

Sweney MT, Silver K, Gerard-Blanluet M, Pedespan JM, Renault F, Arzimanoglou A, et al. Alternating hemiplegia of childhood: early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics. 2009;123:e534–41. doi: 10.1542/peds.2008-2027. PubMed DOI

Bourgeois M, Aicardi J, Goutières F. Alternating hemiplegia of childhood. J Pediatr. 1993;122:673–9. doi: 10.1016/S0022-3476(06)80003-X. PubMed DOI

Mikati MA, Kramer U, Zupanc ML, Shanahan RJ. Alternating hemiplegia of childhood: clinical manifestations and long-term outcome. Pediatr Neurol. 2000;23:134–41. doi: 10.1016/S0887-8994(00)00157-0. PubMed DOI

Hoei-Hansen CE, Dali CÍ, Lyngbye TJ, Duno M, Uldall P. Alternating hemiplegia of childhood in Denmark: clinical manifestations and ATP1A3 mutation status. Eur J Paediatr Neurol. 2014;18:50–4. doi: 10.1016/j.ejpn.2013.08.007. PubMed DOI

Panagiotakaki E, Gobbi G, Neville B, Ebinger F, Campistol J, Nevsímalová S, et al. Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults. Brain. 2010;133:3598–610. doi: 10.1093/brain/awq295. PubMed DOI

de Vries B, Stam AH, Beker F, van den Maagdenberg AM, Vanmolkot KR, Laan L, et al. CACNA1A mutation linking hemiplegic migraine and alternating hemiplegia of childhood. Cephalalgia. 2008;28:887–91. doi: 10.1111/j.1468-2982.2008.01596.x. PubMed DOI

Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology. 2005;65:529–34. doi: 10.1212/01.WNL.0000172638.58172.5a. PubMed DOI

Rotstein M, Doran J, Yang H, Ullner PM, Engelstad K, De Vivo DC. Glut1 deficiency and alternating hemiplegia of childhood. Neurology. 2009;73:2042–4. doi: 10.1212/WNL.0b013e3181c55ebf. PubMed DOI PMC

Weller CM, Leen WG, Neville BG, Duncan JS, de Vries B, Geilenkirchen MA, et al. A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood. Cephalalgia. 2015;35:10–5. doi: 10.1177/0333102414532379. PubMed DOI

Bassi MT, Bresolin N, Tonelli A, Nazos K, Crippa F, Baschirotto C, et al. A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. J Med Genet. 2004;41:621–8. doi: 10.1136/jmg.2003.017863. PubMed DOI PMC

Swoboda KJ, Kanavakis E, Xaidara A, Johnson JE, Leppert MF, Schlesinger-Massart MB, et al. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol. 2004;55:884–7. doi: 10.1002/ana.20134. PubMed DOI

Haan J, Kors EE, Terwindt GM, Vermeulen FL, Vergouwe MN, van den Maagdenberg AM, et al. Alternating hemiplegia of childhood: no mutations in the familial hemiplegic migraine CACNA1A gene. Cephalalgia. 2000;20:696–700. doi: 10.1046/j.0333-1024.2000.00095.x. PubMed DOI

de Vries B, Haan J, Stam AH, Vanmolkot KR, Stroink H, Laan LA, et al. Alternating hemiplegia of childhood: no mutations in the glutamate transporter EAAT1. Neuropediatrics. 2006;37:302–4. doi: 10.1055/s-2006-924609. PubMed DOI

Vuillaumier-Barrot S, Panagiotakaki E, Le Bizec C, El Baba C, ENRAHs for SME Consortium. Fontaine B, et al. Absence of mutation in the SLC2A1 gene in a cohort of patients with alternating hemiplegia of childhood (AHC) Neuropediatrics. 2010;41:267–9. doi: 10.1055/s-0031-1271767. PubMed DOI

De Grandis E, Stagnaro M, Biancheri R, Giannotta M, Gobbi G, Traverso M, et al. Lack of SLC2A1 (glucose transporter 1) mutations in 30 Italian patients with alternating hemiplegia of childhood. J Child Neurol. 2013;28:863–6. doi: 10.1177/0883073812452789. PubMed DOI

Kors EE, Vanmolkot KR, Haan J, Kheradmand Kia S, Stroink H, Laan LA, et al. Alternating hemiplegia of childhood: no mutations in the second familial hemiplegic migraine gene ATP1A2. Neuropediatrics. 2004;35:293–6. doi: 10.1055/s-2004-821082. PubMed DOI

Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012;44:1030–4. doi: 10.1038/ng.2358. PubMed DOI PMC

Rosewich H, Thiele H, Ohlenbusch A, Maschke U, Altmüller J, Frommolt P, et al. Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study. Lancet Neurol. 2012;11:764–73. doi: 10.1016/S1474-4422(12)70182-5. PubMed DOI

Ishii A, Saito Y, Mitsui J, Ishiura H, Yoshimura J, Arai H, et al. Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients. PLoS One. 2013;8 doi: 10.1371/journal.pone.0056120. PubMed DOI PMC

Dobyns WB, Ozelius LJ, Kramer PL, Brashear A, Farlow MR, Perry TR, et al. Rapid-onset dystonia parkinsonism. Neurology. 1993;43:2596–602. doi: 10.1212/WNL.43.12.2596. PubMed DOI

Brashear A, DeLeon D, Bressman SB, Thyagarajan D, Farlow MR, Dobyns WB. Rapid-onset dystonia-parkinsonism in a second family. Neurology. 1997;48:1066–9. doi: 10.1212/WNL.48.4.1066. PubMed DOI

de Carvalho Aguiar P, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, et al. Mutations in the Na+/K + − ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron. 2004;43:169–75. doi: 10.1016/j.neuron.2004.06.028. PubMed DOI

Brashear A, Dobyns WB, de Carvalho Aguiar P, Borg M, Frijns CJ, Gollamudi S, et al. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain. 2007;130:828–35. doi: 10.1093/brain/awl340. PubMed DOI

Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, et al. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis. 2014;9:15. doi: 10.1186/1750-1172-9-15. PubMed DOI PMC

Brashear A, Mink JW, Hill DF, Boggs N, McCall WV, Stacy MA, et al. ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia. Dev Med Child Neurol. 2012;54:1065–7. doi: 10.1111/j.1469-8749.2012.04421.x. PubMed DOI PMC

Boelman C, Lagman-Bartolome AM, MacGregor DL, McCabe J, Logan WJ, Minassian BA. Identical ATP1A3 mutation causes alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism phenotypes. Pediatr Neurol. 2014;51:850–3. doi: 10.1016/j.pediatrneurol.2014.08.015. PubMed DOI

Viollet L, Glusman G, Murphy KJ, Newcomb TM, Reyna SP, Sweney M, et al. Alternating hemiplegia of childhood: retrospective genetic study and genotype-phenotype correlations in 187 subjects from the US AHCF registry. PLoS One. 2015;10 doi: 10.1371/journal.pone.0127045. PubMed DOI PMC

Kamm C, Fogel W, Wächter T, Schweitzer K, Berg D, Kruger R, et al. Novel ATP1A3 mutation in a sporadic RDP patient with minimal benefit from deep brain stimulation. Neurology. 2008;70:1501–3. doi: 10.1212/01.wnl.0000310431.41036.e0. PubMed DOI

Rosewich H, Ohlenbusch A, Huppke P, Schlotawa L, Baethmann M, Carrilho I, et al. The expanding clinical and genetic spectrum of ATP1A3-related disorders. Neurology. 2014;82:945–55. doi: 10.1212/WNL.0000000000000212. PubMed DOI

Sasaki M, Ishii A, Saito Y, Morisada N, Iijima K, Takada S, et al. Genotype-phenotype correlations in alternating hemiplegia of childhood. Neurology. 2014;82:482–90. doi: 10.1212/WNL.0000000000000102. PubMed DOI

Yang X, Gao H, Zhang J, Xu X, Liu X, Wu X, et al. ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients. PLoS One. 2014;9 doi: 10.1371/journal.pone.0097274. PubMed DOI PMC

Svetel M, Ozelius LJ, Buckley A, Lohmann K, Brajković L, Klein C, Kostić VS. Rapid onset dystonia-parkinsonism: case report. J Neurol. 2010;257:472–4. doi: 10.1007/s00415-009-5385-y. PubMed DOI

Rosewich H, Weise D, Ohlenbusch A, Gärtner J, Brockmann K. Phenotypic overlap of alternating hemiplegia of childhood and CAPOS syndrome. Neurology. 2014;83:861–3. doi: 10.1212/WNL.0000000000000735. PubMed DOI

Rosewich H, Baethmann M, Ohlenbusch A, Gärtner J, Brockmann K. A novel ATP1A3 mutation with unique clinical presentation. J Neurol Sci. 2014;341:133–5. doi: 10.1016/j.jns.2014.03.034. PubMed DOI

Anselm IA, Sweadner KJ, Gollamudi S, Ozelius LJ, Darras BT. Rapid-onset dystonia parkinsonism in a child with a novel atp1a3 gene mutation. Neurology. 2009;73:400–1. doi: 10.1212/WNL.0b013e3181b04acd. PubMed DOI PMC

Roubergue A, Roze E, Vuillaumier-Barrot S, Fontenille MJ, Méneret A, Vidailhet M, et al. The multiple faces of the ATP1A3-related dystonic movement disorder. Mov Disord. 2013;28:1457–9. doi: 10.1002/mds.25396. PubMed DOI

Blanco-Arias P, Einholm AP, Mamsa H, Concheiro C, Gutiérrez-de-Terán H, Romero J, et al. A C-terminal mutation of ATP1A3 underscores the crucial role of sodium affinity in the pathophysiology of rapid-onset dystonia parkinsonism. Hum Mol Genet. 2009;18:2370–7. doi: 10.1093/hmg/ddp170. PubMed DOI

European Network for Research on Alternating Hemiplegia. Accessed 9 September 2015. [http://www.enrah.net]

European Network for Rare Paediatric Neurological Diseases (nEUroped). Accessed 9 September 2015. [http://www.eurordis.org/content/european-network-rare-paediatric-neurological-diseases-neuroped]

IAHCRC International Consortium research and care for the ATP1A3 diseases. Accessed 9 September 2015. [http://www.iahcrc.net]

Benjamini Y, Yekutieli D. The control of the false dicovery rate in multiple testing under dependency. Ann Stat. 2001;29:1165–88. doi: 10.1214/aos/1013699998. DOI

Weigand KM, Messchaert M, Swarts HG, Russel FG, Koenderink JB. Alternating hemiplegia of childhood mutations have a differential effect on Na (+), K (+) -ATPase activity and ouabain binding. Biochim Biophys Acta. 1842;2014:1010–6. PubMed

Li M, Jazayeri D, Corry B, McSweeney KM, Heinzen EL, Goldstein DB, Petrou S. A functional correlate of severity in alternating hemiplegia of childhood. Neurobiol Dis. 2015;77:88–93. doi: 10.1016/j.nbd.2015.02.002. PubMed DOI

Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, et al. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol. 2014;13:503–14. doi: 10.1016/S1474-4422(14)70011-0. PubMed DOI PMC