A new neurodevelopmental epilepsy disorder and its genetic causes

Neurodevelopmental disorders include highly prevalent disorders such as autism and epilepsy, with cognitive impairment alone affecting 1-3% of the global population
.
Developmental epileptic encephalopathy (DEE) is an NDD
characterized by epilepsy and developmental delay or loss of developmental skills.
Although the prevalence of DEE remains to be determined, studies estimate that single-gene epilepsy occurs in about 1 in 2100 newborns per year
.
Recently, Dr.
Chao, an assistant professor at Baylor College of Medicine (BCM) and a researcher at the Jan and Dan Duncan Institute for Neurology at Texas Children's Hospital (Duncan NRI), and Pankaj Agrawal, Ph.
D.
, a professor at Harvard Medical School and Boston Children's Hospital, conducted a study that identified alterations in the eukaryotic initiation factor 4A2 (EIF4A2) gene as a cause
of a novel DEE syndrome.

The new findings, published in the American Journal of Human Genetics, are the first to experimentally demonstrate the pathogenic role
of alterations affecting EIF4A2 in human disease.

Identify individuals with a new neurodevelopmental disorder

The research involved an international collaboration, which was made possible by a virtual tool called MatchMaker Exchange, which was launched in 2013 to provide an integrated platform for clinicians and researchers around the world to exchange phenotypic and genotypic data, dramatically accelerating genome discovery
.

"Using this tool, Dr.
Anna Duncan, an instructor in Dr.
Agrawal's lab and co-first author of the study, identified approximately 15 individuals from 14 families who had structural changes in the brain (observed by MRI imaging) and similar clinical manifestations, including general developmental delay, poor muscle tone, language impairment, and epilepsy
.
" "They found that these people carried extremely rare spontaneous mutations
in one or two copies of EIF4A2.
"

The EIF4A2 gene encodes an atp-dependent RNA helicase, a protein involved in regulating the three-dimensional (3D) structure
of the fundamental molecule ribonucleic acid (RNA).
The EIF4A2 protein is expressed in all tissues and acts as a regulator of protein translation
.
It belongs to the DEAD-box family — a group of 50 closely related proteins — many of which regulate protein translation, the basic molecular process
by which messenger RNA is converted into the corresponding protein.
Previous studies have shown that EIF4A2 plays a key role in brain development, and its dysfunction is linked
to intellectual disability.

Learn from fruit flies how mutations in elF4A cause this syndrome

To confirm whether these gene variants are associated with neurological symptoms in these patients, Dr.
Zhao's co-first authors Maimuna Sali Paul, PhD, and Dr.
Zhao, postdocs in Zhao's lab, carefully examined the human EIF4A2 variant and its fruit fly variant elF4A, which have significant sequence similarities
.

They identified four EIF4A2 variants that affect conserved residues in the fruit fly gene eIF4A and predicted the 3D structure of human eIF4A and its interaction
with RNA through molecular modeling data.
Dr.
Paul found the result of overexpression of these EIF4A2 variants in fruit flies

In various behavioral and developmental defects such as motor defects, as well as inappropriate eyes, wings, and peripheral nervous system organs such as bristles, a clear indicator of their toxicity
.

In addition, Dr.
Paul used the knowledge that complete loss of eIF4A is fatal at the embryonic stage of fruit flies and reducing their levels from specific tissues is fatal at the embryonic or pupal stage to study the functional consequences
of the human EIF4A2 variant.
"Most importantly, when we overexpress wild-type human EIF4A in the eyes of fruit flies lacking this gene, we are able to completely 'save' the lethality of pupae and restore the normal lifespan of these flies," Dr.
Paul said
.
"However, the overexpression of one pathogenic body leads to weak/partial rescue, while others fail to save lethality – a clear indication of the important role
they play during development.
"

Dr.
Chao said: "Consistent with this study, our lab previously found that the deletion of the kinase EIF2AK2, which regulates downstream protein complexes in protein translation, also leads to similar nerve damage
.
" "Therefore, our findings in this study highlight the critical role
of balanced regulation of protein translation for brain development and the maintenance of neuronal and glial cell function.
" These findings reveal that EIF4A2 is a previously unrecognized cause
of a new type of developmental epilepsy syndrome.
”

Other authors involved in the study, their institutional affiliations and funding sources can be found
here.