Abstract

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

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References

  1. 1.

    & Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy. Pediatrics 47, 675–680 (1971).

  2. 2.

    , & Alternating hemiplegia of childhood. J. Pediatr. 122, 673–679 (1993).

  3. 3.

    , , & Alternating hemiplegia of childhood: clinical manifestations and long-term outcome. Pediatr. Neurol. 23, 134–141 (2000).

  4. 4.

    et al. Alternating hemiplegia of childhood: early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics 123, e534–e541 (2009).

  5. 5.

    et al. Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults. Brain 133, 3598–3610 (2010).

  6. 6.

    & Alternating hemiplegia of childhood: insights into its pathophysiology. J. Child Neurol. 13, 39–45 (1998).

  7. 7.

    & The treatment and management of alternating hemiplegia of childhood. Dev. Med. Child Neurol. 49, 777–780 (2007).

  8. 8.

    et al. A syndrome of autosomal dominant alternating hemiplegia: clinical presentation mimicking intractable epilepsy; chromosomal studies; and physiologic investigations. Neurology 42, 2251–2257 (1992).

  9. 9.

    et al. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann. Neurol. 55, 884–887 (2004).

  10. 10.

    et al. A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. J. Med. Genet. 41, 621–628 (2004).

  11. 11.

    et al. Novel mutations in the Na+/K+ ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann. Neurol. 54, 360–366 (2003).

  12. 12.

    et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2. Nat. Genet. 33, 192–196 (2003).

  13. 13.

    , , Prilusky, J. & Lancet, D. GeneCards: integrating information about genes, proteins and diseases. Trends Genet. 13, 163 (1997).

  14. 14.

    et al. Mutations in the Na+/K+ ATPase α3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 43, 169–175 (2004).

  15. 15.

    , , , & Rapid-onset dystonia-parkinsonism in a child with a novel ATP1A3 gene mutation. Neurology 73, 400–401 (2009).

  16. 16.

    et al. Rapid-onset dystonia-parkinsonism: case report. J. Neurol. 257, 472–474 (2010).

  17. 17.

    et al. Novel ATP1A3 mutation in a sporadic RDP patient with minimal benefit from deep brain stimulation. Neurology 70, 1501–1503 (2008).

  18. 18.

    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. 18, 2370–2377 (2009).

  19. 19.

    , , & Crystal structure of the sodium-potassium pump Na+/K+ ATPase with bound potassium and ouabain. Proc. Natl. Acad. Sci. USA 106, 13742–13747 (2009).

  20. 20.

    et al. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am. J. Hum. Genet. 56, 368–373 (1995).

  21. 21.

    & The CpG dinucleotide and human genetic disease. Hum. Genet. 78, 151–155 (1988).

  22. 22.

    et al. Mutation I810N in the α3 isoform of Na+/K+ ATPase causes impairments in the sodium pump and hyperexcitability in the CNS. Proc. Natl. Acad. Sci. USA 106, 14085–14090 (2009).

  23. 23.

    et al. Human Gene Mutation Database (HGMD): 2003 update. Hum. Mutat. 21, 577–581 (2003).

  24. 24.

    et al. Infrastructure for the life sciences: design and implementation of the UniProt website. BMC Bioinformatics 10, 136 (2009).

  25. 25.

    et al. The consensus coding sequence (CCDS) project: identifying a common protein-coding gene set for the human and mouse genomes. Genome Res. 19, 1316–1323 (2009).

  26. 26.

    & Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

  27. 27.

    et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

  28. 28.

    et al. Inferring copy number variants in high-coverage genomes using ERDS. Am. J. Hum. Genet. (in the press).

  29. 29.

    et al. SVA: software for annotating and visualizing sequenced human genomes. Bioinformatics 27, 1998–2000 (2011).

Download references

Acknowledgements

We are deeply indebted to all the AHC-affected families for their participation in this study. We would like to thank the Alternating Hemiplegia of Childhood Foundation (AHCF) for their efforts in coordinating the collection of US samples and the facilitation of US research collaboration. We also would like to thank D. Poncelin (French Family Foundation) and R. Vavassori (Italian AHC Family Foundation) for facilitating the international collaboration.

We thank the Italian Patient Association for Alternating Hemiplegia (AISEA Onlus) for coordinating and funding the project I.B.AHC Biobank and Clinical Registry for Alternating Hemiplegia. Specifically, we thank M.T. Bassi and E. Tenderini for preparing all of the samples from AHC-affected individuals for analysis. Many thanks also to the Scientific Institute E. Medea, which hosts the I.B.AHC Biobank according to the I.B.AHC protocol.

We also thank the ENRAH for the SMEs Consortium, the ENRAH validation committee and all collaborating physicians for the data collection5. We are also grateful to the DNA and cell bank of Genethon for the processing of French blood samples.

The following individuals contributed next-generation sequenced control samples to this study: D. Attix, E. Behr, R. Brown, J. Burke, D. Daskalakis, V. Dixon, Z. Farfel, R. Gbadegesin, A. Holden, E. Holtzman, J. Hoover-Fong, C. Hulette, S. Kerns, D. Lancet, D. Levy, N. Liang, W. Lowe, P. Lugar, D. Marchuk, J. McEvoy, J. Milner, H. Oster, R. Ottman, S. Palmer, E. Pras, V. Shashi, N. Sobriera, D. Valle, K. Welsh-Bohmer and M. Winn, as well as the MURDOCK study community registry. Funding for the collection and sequencing of control samples was provided by the Center for Human Genome Variation, the Center for HIV/AIDS Vaccine Immunology and the Joseph and Kathleen Bryan Alzheimer's Disease Research Center under grants from the National Institutes of Health (NIH), including the National Institute of Allergy and Infectious Disease (UO1AIO67854); the National Institute on Aging (P30 AG028377); the National Institute of Neurological Disorders and Stroke (RC2NS070344 and 1RC2NS070342-01) and the National Institute of Mental Health (RC2MH089915).

This study was funded in part by grants from the AHCF (to K.J.S., S.P.R. and T.M.N.); the ENRAH for SMEs Consortium under the European Commission Sixth Framework Programme; the Institut National de la Santé et de la Recherche Médicale (to S.N. and B.F.); the Centre National de la Recherche Scientifique (to S.N. and B.F.); the University Pierre and Marie Curie (to S.N. and B.F.); the Association Française Contre les Myopathies (to S.N. and B.F.); the Association Française de l'Hémiplégie Alternante (to S.N., A.M.J.M.v.d.M. and B.d.V.); AISEA Onlus (to F.G. and G.N.); the Center for Human Genome Variation; the Wellcome Trust (084730 to S.M.S.); the National Center for Research Resources (UL1RR025764 to the University of Utah Center for Clinical and Translational Sciences; K.J.S.); the NIH (1T32HL105321-01 to C.H.); the University of Luxembourg Institute for Systems Biology Program (to C.H.) and the Center for Medical Systems Biology established in The Netherlands Genomics Initiative and The Netherlands Organisation for Scientific Research (project 050-060-409 to A.M.J.M.v.d.M. and M.D.F.). S.N. is a recipient of a Contrat d'Interface from Assistance Publique-Hôpitaux de Paris.

Author information

Author notes

    • Erin L Heinzen
    • , Kathryn J Swoboda
    •  & Yuki Hitomi

    These authors contributed equally to this work.

    • Sanjay M Sisodiya
    • , Mohamad A Mikati
    •  & David B Goldstein

    These authors jointly directed this work.

Affiliations

  1. Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.

    • Erin L Heinzen
    • , Yuki Hitomi
    • , Nicole M Walley
    • , Kevin V Shianna
    • , Curtis E Gumbs
    • , Latasha Little
    •  & David B Goldstein
  2. Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

    • Erin L Heinzen
    •  & Kevin V Shianna
  3. Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.

    • Kathryn J Swoboda
    • , Matthew T Sweney
    •  & Tara M Newcomb
  4. Department of Neurology, University of Utah, Salt Lake City, Utah, USA.

    • Kathryn J Swoboda
    • , Louis Viollet
    • , Sandra P Reyna
    •  & Kelley J Murphy
  5. Instituto di Genetica Medica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy.

    • Fiorella Gurrieri
    • , F Danilo Tiziano
    • , Giovanni Neri
    • , Stefania Fiori
    • , Emanuela Abiusi
    •  & Lorena Di Pietro
  6. Université Pierre et Marie Curie, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière UMR S975, Paris, France.

    • Sophie Nicole
    •  & Bertrand Fontaine
  7. Institut National de la Santé et de la Recherche Médicale, U975, Paris, France.

    • Sophie Nicole
    •  & Bertrand Fontaine
  8. Centre National de la Recherche Scientifique, UMR7225, Paris, France.

    • Sophie Nicole
    •  & Bertrand Fontaine
  9. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

    • Boukje de Vries
    • , Stephany Koelewijn
    • , Jessica Kamphorst
    • , Marije Geilenkirchen
    • , Arn van den Maagdenberg
    •  & Arn M J M van den Maagdenberg
  10. Assistance Publique-Hôpitaux de Paris, Département de Neurologie & Centre de Référence Canalopathies Musculaires, Groupe Hospitalier de la Pitié-Salpêtrière, Paris, France.

    • Bertrand Fontaine
  11. Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.

    • Sinéad Heavin
    •  & Ingrid E Scheffer
  12. Epilepsy, Sleep and Pediatric Neurophysiology Department, Woman-Mother-Child Hospital, University Hospitals of Lyon (HCL), Lyon, France.

    • Eleni Panagiotakaki
    •  & Alexis Arzimanoglou
  13. Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah, USA.

    • Chad Huff
    •  & Lynn B Jorde
  14. Department of Neurology, Comer Children's Hospital, University of Chicago, Chicago, Illinois, USA.

    • Kenneth Silver
  15. Department of Pediatrics, Comer Children's Hospital, University of Chicago, Chicago, Illinois, USA.

    • Kenneth Silver
  16. Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

    • Louis J Ptáček
  17. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA.

    • Louis J Ptáček
  18. Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands.

    • Joost Haan
  19. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

    • Nadine Pelzer
    • , Laura Laan
    • , Joost Haan
    • , Michel Ferrari
    • , Arn van den Maagdenberg
    • , Cacha Peeters-Scholte
    • , Michel D Ferrari
    •  & Arn M J M van den Maagdenberg
  20. Department of Paediatric Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia.

    • Ann M Bye
  21. University of Sydney, Royal North Shore Hospital, St. Leonards, Sydney, New South Wales, Australia.

    • Geoffrey K Herkes
  22. Northern Clinical School, University of Sydney, and Royal North Shore Hospital, Sydney, Australia.

    • Charlotte M Whitelaw
  23. Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.

    • David Webb
  24. The Children's University Hospital, Temple Street, Dublin, Ireland.

    • Bryan J Lynch
    •  & Mary D King
  25. Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

    • Peter Uldall
  26. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.

    • Ingrid E Scheffer
  27. Florey Neuroscience Institutes, Melbourne, Australia.

    • Ingrid E Scheffer
  28. Institut National de la Santé et de la Recherche Médicale, U1028, Centre de Recherche en Neurosciences de Lyon, Lyon, France.

    • Alexis Arzimanoglou
  29. Centre National de la Recherche Scientifique, UMR 5292, Lyon, France.

    • Alexis Arzimanoglou
  30. Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK.

    • Sanjay M Sisodiya
  31. Division of Pediatric Neurology, Duke University Medical Center, Durham, North Carolina, USA.

    • Mohamad A Mikati
  32. Department of Neurobiology, Duke University, Durham, North Carolina, USA.

    • Mohamad A Mikati
  33. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.

    • David B Goldstein
  34. Clinical Neurophysiology Unit, Scientific Institute E. Medea, Lecco, Italy.

    • Claudio Zucca
  35. Laboratory of Molecular Biology, Scientific Institute E. Medea, Lecco, Italy.

    • Maria Teresa Bassi
  36. Associazione Italiana per la Sindrome di Emiplegia Alternante (AISEA) Onlus, Lecco, Italy.

    • Filippo Franchini
    •  & Rosaria Vavassori
  37. Child Neurology Unit, Maggiore Hospital, Bologna, Italy.

    • Melania Giannotta
    •  & Giuseppe Gobbi
  38. Department of Child Neurology, National Neurological Institute C. Besta, Milan, Italy.

    • Tiziana Granata
    •  & Nardo Nardocci
  39. Department of Child Neuropsychiatry, G. Gaslini Hospital, University of Genoa, Genoa, Italy.

    • Elisa De Grandis
    • , Edvige Veneselli
    •  & Michela Stagnaro
  40. Division of Neurology, Bambino Gesù Children's Hospital, Rome, Italy.

    • Federico Vigevano
  41. Department of Child Neurology, Heidelberg University Hospital, Heidelberg, Germany.

    • Claudia Oechsler
    •  & Friedrich Ebinger
  42. Neurosciences Unit, University College London Institute of Child Health, London, UK.

    • Miriam Ninan
    •  & Brian Neville
  43. Department of Child Neurology, Sant Joan de Déu Hospital, Barcelona, Spain.

    • Carmen Fons
    •  & Jaume Campistol
  44. Department of Neurology, Charles University, First Faculty of Medicine and Teaching Hospital, Prague, Czech Republic.

    • David Kemlink
    •  & Sona Nevsimalova
  45. Department of Child Neurology, University Hospital Gasthuisberg, Leuven, Belgium.

    • Paul Casaer
  46. Department of Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

    • Giorgio Casari
    •  & Filippo Martinelli Boneschi
  47. Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy.

    • Giorgio Casari
    •  & Filippo Martinelli Boneschi
  48. Department of Neurology and Psychiatry of Children and Adolescents, General Hospital, Klagenfurt, Austria.

    • Guenter Sange
    •  & Georg Spiel
  49. The ENRAH Association, Brussels, Belgium.

    • Tsveta Schyns
  50. Good Clinical Practice Alliance—Europe (GCPA), Kessel-Lo, Belgium.

    • Francis Crawley
  51. Association Française de l'Hémiplégie Alternante (AFHA), St. Germain les Arpajon, France.

    • Dominique Poncelin

Consortia

  1. European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium

    A full list of members and affiliations appears at the end of this paper.

  2. Biobanca e Registro Clinico per l'Emiplegia Alternante (I.B.AHC) Consortium

    A full list of members and affiliations appears at the end of this paper.

  3. European Network for Research on Alternating Hemiplegia (ENRAH) for Small and Medium-sized Enterpriese (SMEs) Consortium

    A full list of members and affiliations appears at the end of this paper.

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Contributions

E.L.H., Y.H., S.M.S., M.A.M. and D.B.G. conceived and designed the study. Genetic data were generated and analyzed by E.L.H., K.J.S., Y.H., F.G., S.N., B.d.V., F.D.T., S.F., E.A., L.D.P., C.H., L.B.J., K.V.S., C.E.G., L.L., G.N., A.A. A.M.J.M.v.d.M and D.B.G. DNA samples and phenotypic information for AHC patients were collected, compiled and analyzed by K.J.S., F.G., S.N., N.M.W., B.d.V., F.D.T., B.F., S.H., E.P., M.T.S., T.M.N., L.V., S.P.R., K.J.M., K.S., L.J.P., J.H., M.D.F., A.M.B., G.K.H., C.M.W., D.W., B.J.L., P.U., M.D.K., I.E.S., G.N., A.A., S.M.S., M.A.M., the European AHC Genetics Consortium, the I.B.AHC Consortium and the ENRAH for SMEs Consortium. E.L.H., A.M.J.M.v.d.M., S.M.S., M.A.M. and D.B.G. wrote the paper. All authors reviewed the compiled manuscript.

Competing interests

D.B.G., E.L.H., K.V.S., M.A.M. and Duke University are named on a patent application filed by Duke University on the basis of this work.

Corresponding authors

Correspondence to Mohamad A Mikati or David B Goldstein.

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DOI

https://doi.org/10.1038/ng.2358

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