Scientists have identified the genetic origin of a new kind of neurodevelopmental epilepsy

Photo by Tima Miroshnichenko on

Conditions like autism and epilepsy are included under the umbrella term “neurodevelopmental disorders” (NDD), with estimates ranging from 1-3% of the world’s population suffering from cognitive difficulties. Disorders of neurodevelopment (NDD) known as developmental epileptic encephalopathies (DEE) cause seizures, developmental delays, and loss of developmental abilities. Single-gene epilepsies are estimated to occur in around 1 in 2100 births yearly; however, the prevalence of DEEs has yet to be identified. Dr. Pankaj Agrawal, professor at Harvard Medical School and Boston Children’s Hospital, and Dr. Hsiao-Tuan Chao, assistant professor at BCM and investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI), recently discovered that mutations in the Eukaryotic Initiation Factor 4A2 (EIF4A2) gene cause a new form of DEE syndrome.

Published in the American Journal of Human Genetics, this finding is the first experimental evidence that changes in EIF4A2 have a direct role in human illness.

MatchMaker Exchange, introduced in 2013, allowed researchers and clinicians from all around the world to work together on the project by providing a unified platform for the sharing of phenotypic and genotypic data, which dramatically sped up the process of genomic discovery.

Dr. Anna Duncan, an instructor in Dr. Agrawal’s lab and co-first author of the study, used this method to identify approximately 15 individuals from 14 families who had alterations in the brain’s structure (as observed by MRI imaging) and similar symptoms including global developmental delays, poor muscle tone, speech difficulties, and epilepsy, as stated by Chao. They discovered that one or both copies of EIF4A2 in these people had highly unusual spontaneous mutations.

Proteins like the one encoded by the EIF4A2 gene have a role in controlling the three-dimensional (3D) structure of a fundamental molecule called ribonucleic acid (RNA). A protein called eukaryotic translation initiation factor 4A2 (EIF4A2) is present in every organ and regulates the process of protein synthesis. It’s part of a family of 50 similar proteins called DEAD-box proteins, and many of them control protein translation, the crucial biochemical process by which mRNA is translated into its functional protein. Earlier research has linked disruptions in EIF4A2 to cognitive deficits, indicating that this gene plays an important role in brain development.

Dr. Maimuna Sali Paul, a postdoctoral fellow in the Chao lab and co-first author on this study, and Dr. Chao analyzed sequence similarities between human EIF4A2 variants and its fruit fly equivalents, elF4A, to determine whether or not these gene variants are responsible for the neurological symptoms experienced by these patients.

The molecular modeling data suggested that these four variations of EIF4A2 would alter the three-dimensional structure of human EIF4A and its interaction with RNA. These variants all altered conserved residues in the fly gene eIF4A. Dr. Paul discovered that when these EIF4A2 mutations were overexpressed in fruit flies resulted in a wide range of abnormalities, including motor impairments, underdeveloped eyes and wings, and abnormalities in organs of the peripheral nervous system like hairs, which all point to their toxic effects.

In addition, Dr. Paul used the fact that a total lack of eIF4A was deadly at the fruit fly embryonic stages, whereas lowering its levels from particular organs was lethal at both the embryonic and pupal stages, to investigate the functional effects of the human EIF4A2 variations. Dr. Paul said that they were able to rescue the flies from their early death as babies by overexpressing wild-type human EIF4A in their eyes. A strong evidence of their core function throughout development is that overexpression of a single disease-causing variation resulted in a weak/partial rescue whereas the others were unable to rescue the lethality.

Dr. Chao noted that prior work from his lab indicated that the absence of the kinase EIF2AK2, which controls downstream protein complexes involved in protein translation, also results in comparable neurological abnormalities; therefore, the findings of this study are consistent with those of his lab. The results highlight the importance of protein translation control during brain development and in the maintenance of neuronal and glial function. These results identify EIF4A2 as the genetic basis for a new kind of childhood epilepsy.


Maimuna S. Paul et al. (2022). Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy, The American Journal of Human GeneticsDOI: 10.1016/j.ajhg.2022.11.011