Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium–potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified. This led to the identification of a third case with a possibly damaging missense mutation in ATP1A3 and three others cases with predicted pathogenic missense variants in the FXYD gene family (FXYD1, FXYD6, and FXYD6-FXYD2 readthrough). FXYD genes encode proteins that modulate the ATP-dependant pump function. This report is the first to identify variants in the same pathway for COS. Our COS study illustrates the interest of stratifying a complex condition according to the age of onset for the identification of deleterious variants. Whereas ATP1A3 is a replicated gene in rare neuropediatric diseases, this gene has previously been linked with COS in only one case report. The association with rare variants in FXYD gene family is novel and highlights the interest of exploring these genes in COS as well as in pediatric neurodevelopmental disorders.

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  1. 1.

    Driver DI, Gogtay N, Rapoport JL. Childhood onset schizophrenia and early onset schizophrenia spectrum disorders. Child Adolesc Psychiatr Clin N Am. 2013;22:539–55.

  2. 2.

    Giannitelli M, Consoli A, Raffin M, Jardri R, Levinson DF, Cohen D, et al. An overview of medical risk factors for childhood psychosis: implications for research and treatment. Schizophr Res. 2017. https://doi.org/10.1016/j.schres.2017.05.011.

  3. 3.

    McKenna K, Gordon CT, Lenane M, Kaysen D, Fahey K, Rapoport JL. Looking for childhood-onset schizophrenia: the first 71 cases screened. J Am Acad Child Adolesc Psychiatry. 1994;33:636–44.

  4. 4.

    Asarnow RF, Forsyth JK. Genetics of childhood-onset schizophrenia. Child Adolesc Psychiatr Clin N Am. 2013;22:675–87.

  5. 5.

    Ahn K, Gotay N, Andersen TM, Anvari AA, Gochman P, Lee Y, et al. High rate of disease-related copy number variations in childhood onset schizophrenia. Mol Psychiatry. 2014;19:568–72.

  6. 6.

    Zhou D, Gochman P, Broadnax DD, Rapoport JL, Ahn K. 15q13.3 duplication in two patients with childhood-onset schizophrenia. Am J Med Genet Part B Neuropsychiatr Genet Publ Int Soc Psychiatr Genet. 2016;171:777–83.

  7. 7.

    Addington AM, Gauthier J, Piton A, Hamdan FF, Raymond A, Gogtay N, et al. A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Mol Psychiatry. 2011;16:238–9.

  8. 8.

    Ambalavanan A, Girard SL, Ahn K, Zhou S, Dionne-Laporte A, Spiegelman D, et al. De novo variants in sporadic cases of childhood onset schizophrenia. Eur J Hum Genet (EJHG). 2015. https://doi.org/10.1038/ejhg.2015.218.

  9. 9.

    Tenney JR, Schapiro MB. Child neurology: alternating hemiplegia of childhood. Neurology. 2010;74:e57–59.

  10. 10.

    Brashear A, Sweadner KJ, Cook JF, Swoboda KJ, Ozelius L. ATP1A3-Related neurologic disorders. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al.. (eds). GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1115/.

  11. 11.

    Smedemark-Margulies N, Brownstein CA, Vargas S, Tembulkar SK, Towne MC, Shi J, et al. A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia. Cold Spring Harb Mol Case Stud. 2016;2. https://doi.org/10.1101/mcs.a001008.

  12. 12.

    Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E, et al. Integrative analyses of de novo mutations provide deeper biological insights into autism spectrum disorder. Cell Rep. 2018;22:734–47.

  13. 13.

    Gochman P, Miller R, Rapoport JL. Childhood-onset schizophrenia: the challenge of diagnosis. Curr Psychiatry Rep. 2011;13:321–2.

  14. 14.

    Li H, Durbin R. Fast and accurate short read alignment with Burrows-wheeler transform. Bioinformatics. 2009;25:1754–60.

  15. 15.

    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinforma Oxf Engl. 2009;25:2078–9.

  16. 16.

    Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinforma. 2013;43:11.10.1–33.

  17. 17.

    Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164–e164.

  18. 18.

    Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRINGv10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–452.

  19. 19.

    Fabregat A, Sidiropoulos K, Garapati P, Gillespie M, Hausmann K, Haw R, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2016;44:D481–487.

  20. 20.

    Melé M, Ferreira PG, Reverter F, DeLuca DS, Monlong J, Sammeth M, et al. Human genomics. Human Transcr Across Tissues Individ Sci. 2015;348:660–5.

  21. 21.

    Colantuoni C, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT, et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature. 2011;478:519–23.

  22. 22.

    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem. 2004;25:1605–12.

  23. 23.

    Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10:845–58.

  24. 24.

    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.

  25. 25.

    Andreasen NC. Methods for assessing positive and negative symptoms1. Mod Probl Pharm. 1990;24:73–88.

  26. 26.

    Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM, et al. A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014;46:944–50.

  27. 27.

    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285.

  28. 28.

    May P, Dencker S, Hubbard J. A systematic approach to treatment resistance in schizophrenic disorders. In: Dencker SJ, Kulhanek F, editors. Treatment Resistance in Schizophrenia. Braunschweig/Wiesbaden: Viewag Verlag; 1988. p. 22–3.

  29. 29.

    Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteom MCP. 2014;13:397–406.

  30. 30.

    Lingrel JB, Kuntzweiler T. Na+,K(+)-ATPase. J Biol Chem. 1994;269:19659–62.

  31. 31.

    Geering K. FXYD proteins: new regulators of Na-K-ATPase. Am J Physiol – Ren Physiol. 2006;290:F241–F250.

  32. 32.

    Garty H, Karlish SJD. Role of FXYD proteins in ion transport. Annu Rev Physiol. 2006;68:431–59.

  33. 33.

    Geering K, Béguin P, Garty H, Karlish S, Füzesi M, Horisberger J-D, et al. FXYD proteins: new tissue- and isoform-specific regulators of Na,K-ATPase. Ann N Y Acad Sci. 2003;986:388–94.

  34. 34.

    Li Z, Langhans SA Transcriptional regulators of Na,K-ATPase subunits. Front Cell Dev Biol. 2015;3. https://doi.org/10.3389/fcell.2015.00066.

  35. 35.

    Deng V, Matagne V, Banine F, Frerking M, Ohliger P, Budden S, et al. FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice. Hum Mol Genet. 2007;16:640–50.

  36. 36.

    Mounsey JP, Lu KP, Patel MK, Chen ZH, Horne LT, John JE, et al. Modulation of Xenopus oocyte-expressed phospholemman-induced ion currents by co-expression of protein kinases. Biochim Biophys Acta. 1999;1451:305–18.

  37. 37.

    Crambert G, Fuzesi M, Garty H, Karlish S, Geering K. Phospholemman (FXYD1) associates with Na,K-ATPase and regulates its transport properties. Proc Natl Acad Sci USA. 2002;99:11476–81.

  38. 38.

    Kadowaki K, Sugimoto K, Yamaguchi F, Song T, Watanabe Y, Singh K, et al. Phosphohippolin expression in the rat central nervous system. Mol Brain Res. 2004;125:105–12.

  39. 39.

    Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, CAPOS and beyond. Pediatr Neurol. 2015;52:56–64.

  40. 40.

    Panagiotakaki E, De Grandis E, Stagnaro M, Heinzen EL, Fons C, Sisodiya S, et al. Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood – a study of 155 patients. Orphanet J Rare Dis. 2015;10:123.

  41. 41.

    Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185–90.

  42. 42.

    Sweney MT, Silver K, Gerard-Blanluet M, Pedespan J-M, Renault F, Arzimanoglou A, et al. Alternating hemiplegia of childhood: early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics. 2009;123:e534–e541.

  43. 43.

    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.

  44. 44.

    Muriel V, Garcia-Molina A, Aparicio-Lopez C, Ensenat A, Roig-Rovira T. Neuropsychological deficits in alternating hemiplegia of childhood: a case study. Rev Neurol. 2015;61:25–28.

  45. 45.

    Hoei-Hansen CE, Dali Cí, Lyngbye TJB, Duno M, Uldall P. Alternating hemiplegia of childhood in Denmark: clinical manifestations and ATP1A3 mutation status. Eur J Paediatr Neurol. 2014;18:50–54.

  46. 46.

    Rapoport J, Chavez A, Greenstein D, Addington A, Gogtay N. Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. J Am Acad Child Adolesc Psychiatry. 2009;48:10–18.

  47. 47.

    Barbano RL, Hill DF, Snively BM, Light LS, Boggs N, McCall WV, et al. New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism. Park Relat Disord. 2012;18:737–41.

  48. 48.

    Brashear A, Cook JF, Hill DF, Amponsah A, Snively BM, Light L, et al. Psychiatric disorders in rapid-onset dystonia-parkinsonism. Neurology. 2012;79:1168–73.

  49. 49.

    Cook JF, Hill DF, Snively BM, Boggs N, Suerken CK, Haq I, et al. Cognitive impairment in rapid-onset dystonia-parkinsonism. Mov Disord J Mov Disord Soc. 2014;29:344–50.

  50. 50.

    MacDonald ML, Ding Y, Newman J, Hemby S, Penzes P, Lewis DA, et al. Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. Biol Psychiatry. 2015;77:959–68.

  51. 51.

    Holm TH, Isaksen TJ, Glerup S, Heuck A, Bøttger P, Füchtbauer E-M, et al. Cognitive deficits caused by a disease-mutation in the α3 Na+/K+-ATPase isoform. Sci Rep. 2016;6. https://doi.org/10.1038/srep31972.

  52. 52.

    Biesemann C, Grønborg M, Luquet E, Wichert SP, Bernard V, Bungers SR, et al. Proteomic screening of glutamatergic mouse brain synaptosomes isolated by fluorescence activated sorting. EMBO J. 2014;33:157–70.

  53. 53.

    Stansberg C, Ersland KM, van der Valk P, Steen VM. Gene expression in the rat brain: high similarity but unique differences between frontomedial-, temporal- and occipital cortex. BMC Neurosci. 2011;12:15.

  54. 54.

    Ito Y, Nakamura Y, Takahashi N, Saito S, Aleksic B, Iwata N, et al. A genetic association study of the FXYD domain containing ion transport regulator 6 (FXYD6) gene, encoding phosphohippolin, in susceptibility to schizophrenia in a Japanese population. Neurosci Lett. 2008;438:70–75.

  55. 55.

    Choudhury K, McQuillin A, Puri V, Pimm J, Datta S, Thirumalai S, et al. A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia. Am J Hum Genet. 2007;80:664–72.

  56. 56.

    Zhong N, Zhang R, Qiu C, Yan H, Valenzuela RK, Zhang H, et al. A novel replicated association between FXYD6 gene and schizophrenia. Biochem Biophys Res Commun. 2011;405:118–21.

  57. 57.

    Jiao L, Wang B, Niu X, Ma X, Li J, Shen B, et al. A family-based association study of FXYD6 gene polymorphisms and schizophrenia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi Zhonghua Yixue Yichuanxue Zazhi Chin J Med Genet. 2011;28:539–42.

  58. 58.

    Iwata Y, Yamada K, Iwayama Y, Anitha A, Thanseem I, Toyota T, et al. Failure to confirm genetic association of the FXYD6 gene with schizophrenia: the Japanese population and meta-analysis. Am J Med Genet Part B Neuropsychiatr Genet Publ Int Soc Psychiatr Genet. 2010;153B:1221–7.

  59. 59.

    Hemby SE, Ginsberg SD, Brunk B, Arnold SE, Trojanowski JQ, Eberwine JH. Gene expression profile for schizophrenia: discrete neuron transcription patterns in the entorhinal cortex. Arch Gen Psychiatry. 2002;59:631–40.

  60. 60.

    Chang JT, Lowery LA, Sive H. Multiple roles for the Na,K-ATPase subunits, Atp1a1 and Fxyd1, during brain ventricle development. Dev Biol. 2012;368:312–22.

  61. 61.

    Banine F, Matagne V, Sherman LS, Ojeda SR. Brain region-specific expression of Fxyd1, an Mecp2 target gene, is regulated by epigenetic mechanisms. J Neurosci Res. 2011;89:840–51.

  62. 62.

    Cohen D, Lazar G, Couvert P, Desportes V, Lippe D, Mazet P, et al. MECP2 mutation in a boy with language disorder and schizophrenia. Am J Psychiatry. 2002;159:148–9.

  63. 63.

    Shiina N, Yamaguchi K, Tokunaga M. RNG105 deficiency impairs the dendritic localization of mRNAs for Na+/K+ATPase subunit isoforms and leads to the degeneration of neuronal networks. J Neurosci J Soc Neurosci. 2010;30:12816–30.

  64. 64.

    Rosewich H, Sweney MT, DeBrosse S, Ess K, Ozelius L, Andermann E, et al. Research conference summary from the 2014 international task force on ATP1A3-related disorders. Neurol Genet. 2017;3:e139.

  65. 65.

    Kumra S, Oberstar JV, Sikich L, Findling RL, McClellan JM, Vinogradov S, et al. Efficacy and tolerability of second-generation antipsychotics in children and adolescents with schizophrenia. Schizophr Bull. 2008;34:60–71.

  66. 66.

    Ju J, Hirose S, Shi X-Y, Ishii A, Hu L-Y, Zou L-P. Treatment with oral ATP decreases alternating hemiplegia of childhood with de novo ATP1A3 Mutation. Orphanet J Rare Dis. 2016;11:55.

  67. 67.

    Consoli A, Raffin M, Laurent C, Bodeau N, Campion D, Amoura Z, et al. Medical and developmental risk factors of catatonia in children and adolescents: a prospective case-control study. Schizophr Res. 2012;137:151–8.

  68. 68.

    Bonnot O, Klünemann HH, Sedel F, Tordjman S, Cohen D, Walterfang M. Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review. Orphanet J Rare Dis. 2014;9:65.

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We thank the patients and the family members who participate in the study as well as the involved medical teams. We thank Daniel Rochefort and Sylvia Dobrezenicka for the technical support; also Edouard Henrion and Ousmane Diallo for their bioinformatics support. We also thank Dr Maryam Soleimani and Dr Laure Bera for their comments, as well as Dr Elodie Hainque for her advice.


The American cohort was supported by the National institute of Mental health (NIMH). Its genetic assessment was supported by the Genome Canada and Genome Quebec (Grant No. RMF_92086). Bioinformatics analysis was supported by the Canadian Institutes of Health Research (CIHR). Boris Chaumette receives a postdoctoral fellowship from the Healthy Brains for Healthy Lives project (Talent program).

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Author notes

  1. These authors contributed equally: Boris Chaumette, Vladimir Ferrafiat.


  1. Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    • Boris Chaumette
    • , Alexandre Dionne-Laporte
    • , Dan Spiegelman
    • , Patrick A. Dion
    •  & Guy A. Rouleau
  2. Department of Child and Adolescent Psychiatry, CHU Rouen, Rouen, France

    • Vladimir Ferrafiat
    •  & Priscille Gerardin
  3. Centre Référent Maladies Rares à Expression Psychiatrique, CHU Rouen, Rouen, France

    • Vladimir Ferrafiat
    • , Alice Goldenberg
    •  & Priscille Gerardin
  4. Department of Child and Adolescent Psychiatry, Arthur Rimbaud, CH Sotteville les Rouen, Rouen, France

    • Vladimir Ferrafiat
    •  & Priscille Gerardin
  5. Department of Human Genetics, McGill University, Montreal, QC, Canada

    • Amirthagowri Ambalavanan
    •  & Guy A. Rouleau
  6. Service de génétique, CHU de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France

    • Alice Goldenberg
  7. Department of Child and Adolescent Psychiatry, Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France

    • Claudine Laurent
    •  & David Cohen
  8. Department of Psychiatry, Stanford University, Stanford, CA, USA

    • Claudine Laurent
  9. Institut des Systèmes Intelligents et Robotique, ISIR, Université ́Pierre et Marie Curie, CNRS UMR 7222, Paris, France

    • David Cohen
  10. Child Psychiatry Branch Research Group at the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, USA

    • Judith Rapoport


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The authors declare that they have no conflict of interest.

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Correspondence to Guy A. Rouleau.

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