Popular brain malformation traced to genetic origins – affecting approximately 1 in 100 children


Early detection may be helped by Discovery and shed light on Chiari malformation.

There is a common brain condition called Chiari 1 malformation in about one in 100 children, but most of the time, those children grow up normally and no one suspects a problem.

But the condition causes headaches, neck pain, hearing, vision and balance issues, or other neurological symptoms in around one in 10 of these kids.

The disorder may run in families in some cases, but scientists have known little about the genetic changes that lead to the disease.

Scientists at Washington University School of Medicine in St. Louis have shown in recent research that Chiari-1 malformation can be caused by changes in two genes involved in the development of the brain.

When the lowest parts of the brain are below the skull’s base, the disorder arises.

The study also found that children with abnormally wide heads are four times more likely than their peers with a typical head circumference to be diagnosed with Chiari-1 malformation.

The results, published in the American Journal of Human Genetics on Dec. 21, may lead to new ways of recognizing individuals at risk of Chiari-1 malformation before the most serious symptoms appear.

They also shed light on the popular but poorly understood disorder’s growth.

“Many people have recurrent headaches, but they don’t know that a Chiari malformation is the cause of their headaches,” says senior author Gabriel Haller, PhD, assistant professor of neurosurgery, neurology, and genetics. And not everyone is able to undergo brain surgery to address the problem, even though they know it.

We need better treatments, and a better understanding of the underlying causes is the first step towards better treatments.

The malformation is treated with surgery to decompress the Chiari malformation when individuals begin to experience serious symptoms such as persistent headaches, discomfort, irregular stimuli or loss of sensation or weakness.

“There is an increased risk of Chiari malformation within families, suggesting a genetic underpinning, but no one had really identified a causal gene,” said Haller. We were able to classify two causal genes, and we also discovered that there is a greater head circumference than predicted for people with Chiari.

It is a big factor, and it is simple to quantify.

It could be worth consulting with your pediatrician if you have a child with an enlarged head.

Haller and colleagues sequenced all the genes from 668 individuals with the disorder, as well as 232 of their families, to determine the genes causing Chiari-1 malformation. Of those relatives, 76 had malformation of Chiari-1 as well, and 156 were unaffected.

First author Brooke Sadler, PhD, assistant professor of pediatrics, and co-authors David D. Limbrick, Jr, MD, PhD, professor of neurosurgery and director of the Pediatric Neurosurgery Division, and Christina Gurnett, MD, PhD, professor of neurosurgery and director of the Pediatric and Developmental Neurosurgery Division were part of the research team.

Sequencing found that in a family of genes known as chromodomain genes, people with Chiari-1 malformations were slightly more likely to carry mutations. Several of the mutations were de novo, indicating that during fetal development the mutation had arisen in the affected person and was not present in their relatives.

In particular, various variants associated with the malformation were present in the chromodomain genes CHD3 and CHD8.

Further studies in thin, translucent zebrafish have shown that the CHD8 gene is involved in brain size control.

When a copy of the fish’s chd8 gene was inactivated by the researchers, the animals grew extraordinarily large brains without altering their overall body size.

The genes of Chromodomain help regulate access to long stretches of DNA, thereby regulating the expression of whole gene sets. Since sufficient gene expression is essential for normal brain growth, neurodevelopmental conditions such as autism spectrum disorders, developmental delays, and abnormally large or small heads have been related to variations in chromodomain genes.

“It’s not well known how chromodomain genes work because they have such a broad spectrum of activity and affect so many things at once,” Haller said. But they are very fascinating candidates for molecular science, too.


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