PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies

Pediatr Neurol. 2016 Jul;60:83-7. doi: 10.1016/j.pediatrneurol.2016.03.011. Epub 2016 Apr 9.

Abstract

Background: Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a distinct neurodevelopmental disorder. Patients without optic nerve atrophy and brain imaging abnormalities but fulfilling other PEHO criteria are often described as a PEHO-like syndrome. The molecular bases of both clinically defined conditions remain unknown in spite of the widespread application of genome analyses in both clinic and research.

Methods: We enrolled two patients with a prior diagnosis of PEHO and two individuals with PEHO-like syndrome. All four individuals subsequently underwent whole-exome sequencing and comprehensive genomic analysis.

Results: We identified disease-causing mutations in known genes associated with neurodevelopmental disorders including GNAO1 and CDKL5 in two of four individuals. One patient with PEHO syndrome and a de novoGNAO1 mutation was found to have an additional de novo mutation in HESX1 that is associated with optic atrophy.

Conclusions: We hypothesize that PEHO and PEHO-like syndrome may represent a severe end of the spectrum of the early-onset encephalopathies and, in some instances, its complex phenotype may result from an aggregated effect of mutations at two loci.

Keywords: PEHO; encephalopathy; neurodevelopmental disorder; optic atrophy; whole-exome sequencing.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Edema / diagnostic imaging
  • Brain Edema / genetics*
  • Brain Edema / pathology
  • Child
  • Child, Preschool
  • Female
  • GTP-Binding Protein alpha Subunits, Gi-Go / genetics
  • Humans
  • Infant
  • Male
  • Mutation
  • Neurodegenerative Diseases / diagnostic imaging
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / pathology
  • Optic Atrophy / diagnostic imaging
  • Optic Atrophy / genetics*
  • Optic Atrophy / pathology
  • Phenotype
  • Protein-Serine-Threonine Kinases / genetics
  • Spasms, Infantile / diagnostic imaging
  • Spasms, Infantile / genetics*
  • Spasms, Infantile / pathology

Substances

  • GNAO1 protein, human
  • Protein-Serine-Threonine Kinases
  • CDKL5 protein, human
  • GTP-Binding Protein alpha Subunits, Gi-Go

Supplementary concepts

  • PEHO syndrome