Scientists are finding genetic roots of the Chiari 1 mutation

About one in 100 children have a common brain disorder called Chiari 1 malformation, but most of the time such children grow up normally and no one is suspected to there is a problem. But in about one in 10 of those children, the condition causes headaches, neck pain, hearing, vision and balance disturbances, or other brain symptoms.

In some cases, the disorder may run in families, but scientists have not understood much about the genetic changes that contribute to the condition. In a new study, scientists at the University of Washington School of Medicine in St. Louis has shown that Chiari 1 malformation can be caused by changes in two genes involved in brain development.

The condition occurs when the lower parts of the brain are found under the base of the skull. The study also showed that children with abnormally large headaches are four times more likely to experience Chiari 1 transformation than their peers with a normal head circumference.

The findings, published Dec. 21 in the American Journal of Human Genetics, that could lead to new ways to improve people at risk of Chiari 1 malignancy before the worst symptoms arise. It also sheds light on the development of the common but largely misunderstood situation.

“People often have recurrent headaches, but they don’t realize that Chiari transformation is to blame for their headaches,” Haller said. “And even if they do, not everyone is willing to schedule brain surgery. We need better treatments, and the first step to better treatments is a better understanding of the underlying causes.”

If people start getting bad symptoms such as headache, pain, abnormal sensations or loss of consciousness, or weakness, the malformation is treated with surgery to eliminate Chiari’s bad shape.

There is an increased risk for Chiari malformations in families, which show a genetic basis, but no one has identified a causal gene. We were able to identify two causal genes, and we also found that people with Chiari have a larger head circumference than expected. It is an important feature, and easy to measure. If you have a baby with an enlarged head, it may be worth checking with your toddler. “

Gabriel Haller, PhD, Lead Author, Associate Professor of Neurururgery, Neurology and Genetics, University of Washington, St. Louis

To identify genes that cause Chiari 1 malformation, Haller and colleagues added a series of all genders of 668 people with the condition, as well as 232 of their relatives. Of these relatives, 76 also had Chiari 1 malformations and 156 were unaffected. The research team included first author Brooke Sadler, PhD, a professor in pediatricians, and co-authors David D. Limbrick, Jr., MD, PhD, neuro- professor surgeon and director of the Department of Pediatric Non-Surgery, and Christina Gurnett, MD, PhD, professor of neurology and director of the Department of Pediatric Neurology and Development, among others.

Sequencing showed that people with Chiari 1 malformation were significantly more likely to carry mutations in a family of genes called chromodomain genes. Several of the mutations were de novo, meaning that the mutation had occurred in the affected person during fetal development and was not present in his or her relatives. Specifically, the chromodomine genes CHD3 and CHD8 underwent several mutations associated with the malformation.

Further experiments in tiny zebrafish have clearly shown that the CHD8 gene is involved in regulating brain size. When the researchers activated one copy of the fish ‘s chd8 gene, the animals developed strangely large brains, with no change in their overall body size.

Chromodomine genes help control access to long sequences of DNA, thus regulating expressions of whole genes. Because gene expression is essential for normal brain development, changes in chromodomine genes have been linked to neurodevelopmental conditions such as autism spectrum disorder, developmental delay, and abnormally large or small heads.

“It is not known how chromodomain genes work because they have such a wide range of activity and they affect so many things at once,” Haller said. “But they are very interesting candidates for molecular studies, to understand how specific mutations lead to autism or developmental delay or, as in many of our Chiari patients, just to brain size more without mental or intellectual symptoms.We would like to determine the effect of each of these mutations so that, in the future, if we know that a child has a particular mutation, we will be able to predict whether that change is going to have a negative impact and what kind. “

The association between chromodomine genes and Haller head size prompted colleagues to quantify the heads of children with Chiari malformations, comparing them with controls by age and population average provided by the Centers for Disease Control and Prevention. Children with Chiari tended to have larger than normal heads. Those children with the largest headaches – more than 95% of children of the same age – were four times more likely to experience malformation.

The findings suggest that children with larger heads or people with other neurodevelopmental disorders linked to chromodomine genes may benefit from screening for Chiari malformation.

“Many children with autism or developmental disorders related to chromodomain genes may have detected Chiari malformations,” Haller said. “Surgery is the only treatment right now. Determining the condition early will allow us to look, knowing that there is a potential for bad symptoms, and perform that surgery. as soon as it is needed. “