Mutations in NRXN1 and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression

Cold Spring Harb Mol Case Stud. 2019 Feb 1;5(1):a003442. doi: 10.1101/mcs.a003442. Print 2019 Feb.


Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, p.Arg896Trp) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1α/2α knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the NRXN1 and NRXN2 proteins lead us to hypothesize that digenic variants in NRXN1 and NRXN2 contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.

Keywords: aplasia/hypoplasia of the brainstem; frontoparietal cortical dysplasia; infantile encephalopathy; respiratory failure.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium-Binding Proteins / genetics*
  • Fatal Outcome
  • Female
  • Humans
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Neural Cell Adhesion Molecules / genetics*
  • Pedigree
  • Respiratory Insufficiency / genetics*
  • Respiratory Insufficiency / metabolism
  • Spasms, Infantile / genetics*
  • Spasms, Infantile / metabolism
  • Syndrome


  • Calcium-Binding Proteins
  • NRXN1 protein, human
  • NRXN2 protein, human
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecules

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy