Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

Am J Hum Genet. 2016 Dec 1;99(6):1368-1376. doi: 10.1016/j.ajhg.2016.10.009. Epub 2016 Nov 23.


Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal-recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the δ subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.

Keywords: AP3B2; EOEE syndrome; developmental delay; epilepsy; microcephaly; optic atrophy.

MeSH terms

  • Adaptor Protein Complex 3 / genetics*
  • Adaptor Protein Complex beta Subunits / genetics*
  • Age of Onset
  • Child
  • Child, Preschool
  • Developmental Disabilities / genetics
  • Epilepsy / complications*
  • Epilepsy / genetics*
  • Female
  • Genes, Recessive / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Microcephaly / genetics
  • Mutation*
  • Optic Atrophy / complications*
  • Optic Atrophy / genetics*
  • Pedigree
  • Syndrome


  • AP3B2 protein, human
  • Adaptor Protein Complex 3
  • Adaptor Protein Complex beta Subunits