Investigators performed advanced genetic tests on blood samples from seven children with neuro-development disabilities. This led to the discovery of mutations in the VARS gene, which had not previously been linked to human disease.
"These children showed epileptic seizures and abnormalities evident on brain MRI scans," said the senior author. "Although no treatment currently exists for this condition, the results are important as the first step in guiding research directed at targeted therapies."
The genetic mutations identified in the study led to a defect in the enzyme (aminoacyl-tRNA synthetase) responsible for generating proteins containing the amino acid valine which is necessary for cellular health. Genetic variations that damage these types of enzymes are associated with a variety of human diseases including microcephaly and neuropathy.
In this study, the team found that, enzymatic activity was significantly reduced in cells from the young patients. The findings suggest that children with this disorder may benefit from treatments to support the synthesis of new valine containing proteins in the brain.
Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function.
For many children with genetic disabilities, the cause of their disease is rarely identified. This limits the ability of doctors to develop precise treatment plans. Both whole exome and whole genome testing were conducted as part of this study. These tests search an individual's genetic code for imperfections that are the source of disease.
In future experiments, the researchers hope to test whether dietary supplementation with valine or gene therapy may help to restore the altered protein in the brain of these children.
Valyl-tRNA synthetase gene VARS implicated in childhood epileptic encephalopathy
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