Discovered a new epileptic disorder and its genetic cause

Discovered a new epileptic disorder and its genetic cause.


With ” neurodevelopmental disorders”  we refer to a series of disorders, listed below, with an onset in the developmental period and with possible persistence into adulthood:

  • Neurodevelopmental disorder with cognitive impairment
  • Communication disorders
  • Autism Spectrum Disorder
  • Attention Deficit/Hyperactivity Disorder (ADHD)
  • Specific learning disability
  • Movement disorders
  • Spectrum of Fetal Alcohol Disorders (FASD)

Neurodevelopmental disorders with cognitive disabilities alone affect 1-3% of the world’s population. A recent study conducted by the laboratories of Dr. Hsiao-Tuan Chao, a professor at Baylor College of Medicine (BCM) and a researcher at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) of Texas Children’s Hospital, and Dr. Pankaj Agrawal , a professor at Harvard Medical School, has identified alterations in the Eukaryotic Initiation Factor 4A2 (EIF4A2) gene as the cause of a new epileptic developmental encephalopathy syndrome.

The study involved international collaboration made possible by a virtual tool called MatchMaker Exchange , launched in 2013, to serve as an integrated platform for data exchange phenotypic and genotypic among physicians and researchers around the world, dramatically accelerating genomic discovery. “Using this tool, Dr. Anna Duncan, from the Laboratory of Dr. Agrawal, co-author of the study, identified approximately 15 individuals from 14 families who had structural brain changes (as seen by magnetic resonance imaging) and similar clinical presentations, including global developmental delays, poor muscle tone, speech impairment, and epilepsy. Chao said. “They found that these individuals had extremely rare spontaneous mutations in one or both copies of EIF4A2.”

The EIF4A2 gene encodes a protein involved in the regulation of the three-dimensional (3D) structure of a fundamental molecule, ribonucleic acid (RNA). Previous studies have implied that EIF4A2 is critical in brain development and its dysfunction has been associated with intellectual disability.


Using fruit flies to understand how elF4A mutations cause the syndrome

To confirm whether these gene variants are responsible for the neurological symptoms seen in these patients, first author Dr. Maimuna Sali Paul and Dr. Chao closely examined the variants of human EIF4A2 and its counterpart in the fruit fly ( Drosophila melanogaster ). elF4A , with which it shares significant sequence similarity. They identified four EIF4A2 variants that, based on molecular modeling data, are capable of perturbing the 3D structure of human EIF4A and its interaction with RNA. Dr. Paul found that overexpression of these EIF4A2 variants in the fruit fly resulted in a number of defects behavioral and developmental, such as motor defects and improper development of eyes, wings and peripheral nervous system organs such as bristles, a clear indication of their toxicity.

Furthermore, to study the functional consequences of human EIF4A2 variants, Dr. Paul exploited the knowledge that complete loss of eIF4A is lethal in the embryonic stages of flies, while reduction of its levels from specific tissues is lethal in both embryonic and pupal stages. “Most importantly, when we overexpressed human EIF4A in the eyes of flies lacking the gene, we were able to completely ‘rescue’ pupal lethality and restore the insects’ normal lifespan,” said Dr Paul. “However, overexpression of one disease-causing variant resulted in weak/partial salvage, while the others were unable to salvage lethality – a clear indication of the essential role they play during development.”

“Consistent with this study, our lab had previously found that loss of a kinase, EIF2AK2, which regulates downstream protein complexes involved in protein translation also causes similar neurological problems,” added Dr. Chao. Thus, the results of this study underscore the critical role of balanced regulation of protein translation for brain development and maintenance of function in neurons and glia. These results reveal that EIF4A2 is a hitherto unknown cause of a new developmental epilepsy syndrome.”



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