Brain malformations are written in our genes

Having a brain malformation can go unnoticed. Chiari malformation is a brain disease that mainly affects children but most of the time never starts. However, in about one in ten children, the disease causes headaches, neck pain, impaired hearing, vision and balance, or other neurological symptoms. Researchers from the University of Washington (USA) have shown that Chiari malformation can be caused by variations in two genes involved in brain development. The results of their study were published on December 21, 2020 in theAmerican Journal of Human Genetics.

A larger than average head

Chiari malformation is often accompanied by syringomyelia, which is the formation of a fluid-filled cavity in the spinal cord. According to this study, children with exceptionally large heads (95% larger than children of the same age) are four times more likely to be diagnosed with a Chiari malformation than those with normal head circumference.

To identify the genes that cause Chiari malformation, the researchers sequenced all the genes of 668 people with the disease, as well as those of 232 of their family members. Of these parents, 76 also suffered from the Chiari malformation and 156 were unaffected. Thanks to this sequencing, it was possible to understand that people with Chiari malformation were significantly more likely to carry mutations in a family of genes known as chromodomain genes.

Several of the mutations were de novo, that is, the mutation had occurred during the development of the fetus and was not present in its relatives. In particular, the CHD3 and CHD8 chromodomain genes included many malformation-associated variants. In particular, it is the CHD8 gene that is responsible for brain size. When the researchers knocked out a copy of the CHD8 gene in zebrafish, the animals grew exceptionally large brains, with no change in their overall body size.

“There is an increased risk of Chiari malformations running in families, suggesting a genetic basis, but no one had really identified a causative geneunderlines Gabriel Haller, assistant professor of neurology and genetics at the school of medicine of the university of Washington. We were able to identify two causative genes, and we also found that people with Chiari have a larger head circumference than expected. This is an important factor, and easy to measure. If you have a child with an enlarged head, it may be worth checking with your pediatrician..”

People affected but not diagnosed

In people who experience severe symptoms such as chronic headaches, pain, abnormal sensations or loss of feeling, or weakness, an evaluation to diagnose Chiari malformation is done. Later, if it turns out to be the right disease, doctors use surgery to decompress the Chiari malformation.

“Often people have recurring headaches, but they don’t realize that a Chiari malformation is the cause of their headaches, says Gabriel Haller. Even if they do, not everyone is willing to undergo brain surgery to cure them. We need better treatments, and the first step towards better treatments is a better understanding of the underlying causes.”

Going further in their research, the researchers also noticed that children with larger heads or people suffered from other neurodevelopmental disorders, which encourages them to broaden their exploration of the disease. “Many children with autism or developmental disabilities associated with chromodomain genes may have undiscovered Chiari malformationsanalyzes Gabriel Haller. The only treatment currently is surgery. Discovering the disease at an early stage would allow us to observe, knowing that there is potential for serious symptoms, and perform this operation as soon as necessary..”