The epilepsy-autism spectrum disorder phenotype in the era of molecular genetics and precision therapy

Epilepsia. 2022 Jan;63(1):6-21. doi: 10.1111/epi.17115. Epub 2021 Nov 6.


Autism spectrum disorder (ASD) is frequently associated with infants with epileptic encephalopathy, and early interventions targeting social and cognitive deficits can have positive effects on developmental outcome. However, early diagnosis of ASD among infants with epilepsy is complicated by variability in clinical phenotypes. Commonality in both biological and molecular mechanisms have been suggested between ASD and epilepsy, such as occurs with tuberous sclerosis complex. This review summarizes the current understanding of causal mechanisms between epilepsy and ASD, with a particularly genetic focus. Hypothetical explanations to support the conjugation of the two conditions include abnormalities in synaptic growth, imbalance in neuronal excitation/inhibition, and abnormal synaptic plasticity. Investigation of the probable genetic basis has implemented many genes, although the main risk supports existing hypotheses in that these cluster to abnormalities in ion channels, synaptic function and structure, and transcription regulators, with the mammalian target of rapamycin (mTOR) pathway and "mTORpathies" having been a notable research focus. Experimental models not only have a crucial role in determining gene functions but are also useful instruments for tracing disease trajectory. Precision medicine from gene therapy remains a theoretical possibility, but more contemporary developments continue in molecular tests to aid earlier diagnoses and better therapeutic targeting.

Keywords: autistic spectrum disorders; developmental and epileptic encephalopathy; genes; precision medicine; tuberous sclerosis.

Publication types

  • Review

MeSH terms

  • Autism Spectrum Disorder* / diagnosis
  • Autism Spectrum Disorder* / genetics
  • Autism Spectrum Disorder* / therapy
  • Epilepsy* / diagnosis
  • Epilepsy* / genetics
  • Epilepsy* / therapy
  • Humans
  • Molecular Biology
  • Phenotype
  • Tuberous Sclerosis* / diagnosis
  • Tuberous Sclerosis* / genetics
  • Tuberous Sclerosis* / therapy