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Genes linked to common brain disorder, Chiari 1 malformation, identified

According to researchers, there's an increased risk for Chiari malformations within families, which suggests a genetic underpinning, but nobody had really identified a causal gene.

In a new study, experts have discovered that Chiari 1 malformation can be caused by variations in two genes involved in brain development. Read on to know more.

Written by Jahnavi Sarma |Updated : December 31, 2020 8:05 AM IST

Chiari malformation is a common brain disorder where brain tissue extends into the spinal canal. It happens when part of the skull is abnormally small or misshapen and presses against the brain and forces it downward. It is usually categorized into three types, depending on the anatomy of the brain tissue that is displaced into the spinal canal and if developmental abnormalities of the brain or spine are present. Chiari malformation type I develops as the skull and brain are growing. If a child has this condition, he or she may not show any symptoms till late childhood or adulthood. But Chiari malformation type II and type III are congenital. Now researchers at Washington University School of Medicine in St. Louis, US, have found that Chiari 1 malformation can be caused by variations in two genes involved in brain development.

Symptoms of Chiari 1 malformation

The condition occurs when the lowest parts of the brain are found below the base of the skull. About one in 100 children has this malformation, but most of the time such children grow up normally and no one suspects a problem. But in about one in 10 of those children, the condition causes headaches, neck pain, hearing, vision and balance disturbances, or other neurological symptoms. Many people with this disorder may exhibit no symptoms. Such people do not require any treatment and most of the time diagnosis is made when they go to a doctor for some other problem.

But usual symptoms are severe headaches. Sudden bouts of coughing and sneezing are also signs of this disorder. Many patients experience pain in the neck, tingling in hands and feet, dizziness and difficulty swallowing. An unsteady gait and poor hand coordination are other signs of this condition. Many children also have speech problems and suffer from tinnitus, slow heart rhythm and abnormal breathing. Curvature of the spine (scoliosis) related to spinal cord impairment is common too. In some cases, the disorder may run in families, but scientists understood little about the genetic alterations that contribute to the condition until now. The new study also revealed that children with unusually large heads are four times more likely to be diagnosed with Chiari 1 malformation than their peers with normal head circumference.

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An enlarged head may also indicate this condition

According to researchers, there's an increased risk for Chiari malformations within families, which suggests a genetic underpinning, but nobody had really identified a causal gene. In this study, researchers were able to identify two causal genes, and they also discovered that people with Chiari have larger head circumference than expected. It's a significant factor, and easy to measure. If you have a child with an enlarged head, it might be worth checking with your pediatrician.

Understanding the underlying causes

The findings, published in the American Journal of Human Genetics, could lead to new ways to identify people at risk of developing Chiari 1 malformation before the most serious symptoms arise. It also sheds light on the development of the common but poorly understood condition. A lot of times people have recurrent headaches, but they don't realise a Chiari malformation is the cause of their headaches. And even if they do, not everyone is willing to have brain surgery to fix it. Hence, there is a need for better treatments, and the first step to better treatments is a better understanding of the underlying causes.

Genes play a role in development of this condition

If people start experiencing severe symptoms like chronic headaches, pain, abnormal sensations or loss of sensation, or weakness, the malformation is treated with surgery to decompress the Chiari malformation. To identify genes that cause Chiari 1 malformation, researchers sequenced all the genes of 668 people with the condition, as well as 232 of their relatives. Of these relatives, 76 also had Chiari 1 malformation and 156 were unaffected. Sequencing revealed that people with Chiari 1 malformation were significantly more likely to carry mutations in a family of genes known as chromodomain genes. Several of the mutations were de novo, meaning the mutation had 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 included numerous variants associated with the malformation.

Further experiments in tiny, transparent zebrafish showed that the gene CHD8 is involved in regulating brain size. When the researchers inactivated one copy of the fish's chd8 gene, the animals developed unusually large brains, with no change in their overall body size. Chromodomain genes help control access to long stretches of DNA, thereby regulating expression of whole sets of genes. Since appropriate gene expression is crucial for normal brain development, variations in chromodomain genes have been linked to neurodevelopmental conditions such as autism spectrum disorders, developmental delays, and unusually large or small heads.

Complications of Chiari malformation type 1

Chiari malformation type 1 can sometimes lead to serious health complications. It can cause the accumulation of excess fluid within your brain, which may require placement of a flexible tube to divert and drain the cerebrospinal fluid to another area of your body. Another complication is a condition called spina bifida, where the spinal cord or its covering isn't fully developed. Some people with this condition may also go on to develop a condition called syringomyelia where a cavity or cyst forms within the spinal column. Nerve and muscle damage may also happen.

(With inputs from IANS)

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