Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations

Fabiola P. Monteiro, Cynthia J. Curry, Robert Hevner, Stephen Elliott, Jamie H. Fisher, John Turocy, William B. Dobyns, Larissa A. Costa, Erika Freitas, João Paulo Kitajima, Fernando Kok

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2−/− mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.

Original languageEnglish (US)
Article number103624
JournalEuropean Journal of Medical Genetics
Issue number1
StatePublished - Jan 2020
Externally publishedYes

Bibliographical note

Funding Information:
This study did not receive any extramural grant support. We would like to thank Professor Cristoforo Scavone and Paula Kinoshita from the Institute of Biological Sciences at University of S?o Paulo (USP) for the critical review; and Sueli Fazio Ferraciolli from the Radiology Institute (INRAD) at University of S?o Paulo (USP) for neuroimaging review. Finally, we gratefully acknowledge the irrestrict cooperation and assistance of these motivated families.

Publisher Copyright:
© 2019


  • ATP1A2
  • Arthrogryposis
  • Fetal akinesia sequence
  • Malformations of cortical development
  • Na/K- ATPase


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