Discovery aids early screening and may reveal how Chiari malformation occurs-ScienceDaily

In some cases, family disorders can occur, but scientists have little understanding of the genetic changes that contribute to this condition. In a new study, scientists at Washington University in St. Louis’ School of Medicine have shown that Chiari 1 malformations can be caused by changes in two genes involved in brain development.

This condition occurs when the bottom of the brain is below the base of the skull. The study also found that children with abnormally large heads were four times more likely to be diagnosed with Chiari 1 malformations than children with normal head circumferences.

Survey results will be available on December 21st American Journal of Human GeneticsIt can lead to new ways to identify people at risk of developing the Chiari 1 malformation, before the most serious symptoms occur. It also sheds light on the development of common but poorly understood conditions.

“Often people have repeated headaches, but they are unaware that Chiari malformation is the cause of the headaches,” Haller said. “Everyone is willing to undergo neurosurgery to correct it, even so. We need better treatment, and the first step towards better treatment is more than the root cause. It’s a good understanding. “

If you begin to experience severe symptoms such as chronic headaches, pain, abnormal or loss of sensation, or weakness, the malformation is treated with surgery to reduce the pressure on the Chiari malformation.

“There was an increased risk of Chiari malformation in the family, suggesting a genetic basis, but no one actually identified the causative gene,” said a senior assistant professor of neurosurgery, neurology, and genetics. The author, Dr. Gabriel Haller, said. “We were able to identify two causative genes, and we also found that Chiari people had a larger head circumference than expected. This is an important factor and easy to measure. If you have children who are, it may be worth checking with your pediatrician. “

To identify the genes responsible for the Chiari 1 malformation, Haller et al. Sequenced all 668 genes in this condition and 232 relatives. Of these relatives, 76 also suffered from the Chiari 1 malformation, and 156 were unaffected. The research team includes the first authors, pediatric instructors Brooke Sadler and PhD, and co-authors David D. Limbrick, Jr., MD, PhD, professor of neurosurgery and director of pediatric neurosurgery, and Included Christina Gurnett, MD. , PhD, Professor of Neurology, Director of Pediatric and Developmental Neurology, etc.

Sequencing revealed that people with Chiari 1 malformations are very likely to have mutations in a gene family known as the chromodomain gene. Some of the mutations were de novo. That is, the mutation occurred in the affected person during fetal development and was not present in his or her relatives. In particular, the chromodomain genes CHD3 and CHD8 contained numerous variants associated with malformations.

Further experiments on small transparent zebrafish have shown that the gene CHD8 is involved in the regulation of brain size. When researchers inactivated one copy of the fish chd8 gene, the animal developed an abnormally large brain with no change in overall body size.

Chromodomain genes help regulate access to long stretches of DNA, thereby regulating expression throughout the set of genes. Mutations in the chromodomain gene are associated with neurodevelopmental states such as autism spectrum disorders, developmental delay, and abnormally large or small heads, because proper gene expression is essential for normal brain development.

“The chromodomain gene has a very wide range of activity and affects so many things at once, so it’s not clear how the chromodomain gene works,” Haller said. Stated. “But to understand how certain mutations lead to autism and developmental delay, or, like many Chiari patients, increase brain size without cognitive or intellectual symptoms. , They are very interesting candidates for molecular research. We would like to understand that if the effects of each of these mutations in the future reveal that the child has a particular mutation, that mutation. You can predict if it will have a detrimental effect and what kind it will be. “

The association between the chromodomain gene and head size led Haller and colleagues to measure the heads of children with Chiari malformation and compare them to age-matched controls and the average population provided by the US Centers for Disease Control and Prevention. I did. Chiari’s children tended to be smarter than average. Children with the largest heads (more than 95% of children of the same age) were four times more likely to be diagnosed with malformations.

The findings suggest that children with larger heads or people with other neurodevelopmental disorders associated with the chromodomain gene may benefit from screening for Chiari malformation.

“Many children with autism or developmental disabilities associated with the chromodomain gene may not have found the Chiari malformation,” Haller said. “Currently, the only cure is surgery. Early detection of the condition confirms the potential for serious symptoms and can be done immediately if needed.”