Study points to coding DNA variants as cause for childhood onset schizophrenia

Most people with schizophrenia are diagnosed in their late teens or early twenties. One in every 222 adults worldwide suffers from mental illness.

However, there is a rarer and more severe form of the disorder that affects one in 40,000 children under the age of 13. It’s called childhood-onset schizophrenia (COS), and little is known about its causes.

A 10-year peer-reviewed study by researchers from the Hebrew University of Jerusalem and several Israeli hospitals, along with colleagues from Columbia University in New York, identified a possible genetic basis for COS. diagnosis, early genetic counseling, and new drug treatment.

The study examined the DNA of 33 individuals with COS and their families in Israel. In 20% of the children, the study identified genetic mutations not previously associated with schizophrenia. It is known that one is involved in the development of the central nervous system and can express itself as behavioral and language problems. The other is known to cause mitochondrial damage with muscle weakness, developmental issues and learning disabilities.

The study’s senior investigator is Professor Yoav Kohn, director of the child and adolescent psychiatry ward at Eitanim Psychiatric Hospital and former chairman of the psychiatry department at the Hebrew-Hadassah University School of Medicine.

“With the exception of the age of onset of COS — 10 years on average, but can be as young as three — the diagnostic criteria are the same as for adult-onset schizophrenia. These include distractions, hallucinations, disorganized speech and behavior, and deteriorating function,” Kohn said in The Times of Israel.

Yoav Kohn (Courtesy)

“With children, before the psychotic symptoms appear, you often see developmental, cognitive and social problems. The patients may also have ADHD, OCD, anxiety or depression,” he said.

Diagnosing COS is a challenge because young children – especially during or after stressful situations – can have an overactive imagination and fantasy life. It is also sometimes difficult to distinguish COS from autism and anxiety disorders at young ages.

It was already known that the etiology of schizophrenia is highly genetic.

“It’s about 80%. We know this based on the difference between what we see in mono-gothic [identical] twin and dizygotic [fraternal] a few. In identical twins, if one person has schizophrenia, the other has a 50% chance of having it. In fraternal twins, if one has schizophrenia, the other has 10% of the disease,” Kohn said.

“But at the same time, we know that the genetics of schizophrenia is very complex. It is not a monogenetic disorder like Tay Sachs, cystic fibrosis, or Huntington’s disease, which is caused by a mutation in one gene or one genetic variant,” he said.

Don and Mimi Galvin with their 12 children are the subject of the book ‘Hidden Valley Road’ by Robert Kolker. Six of Galvin’s sons were diagnosed with schizophrenia. (Courtesy of the Galvin family)

Scientists also know that schizophrenia is triggered by a combination of genetic and environmental factors. One such environmental or behavioral factor is the use of cannabis.

“That’s why we recommend that young people don’t use cannabis, especially if they already have a mental illness or are genetically predisposed,” Kohn said.

The study, published in February in Schizophrenia Research, builds on research carried out since the completion of the Human Genome Project in 2003. With the genome mapped out, scientists wanted to see if they could find differences in genes people with schizophrenia and those without. .

Kohn noted that since then a consortium of scientists from many countries have collaborated in the search for the genetic etiology of schizophrenia. These studies involved hundreds of thousands of people with the disorder, with no controls.

“More than 100 genetic variants were found, but this was not enough information to be helpful because many of the same variants were found in people without schizophrenia. These findings were not very helpful in developing new treatments because they did not tell us what went wrong in the development of the brains of people with the disorder,” explained Kohn.

COS is rarer and more severe than adult-onset schizophrenia, and younger patients respond less well to medication and have a worse prognosis. At the same time, genetics appear to play an even stronger role in COS. While a first-degree relative has a 10% chance of developing schizophrenia, a first-degree relative has a 25% chance of developing schizophrenia. COS. to develop schizophrenia.

According to Kohn, a group at the National Institute of Mental Health in the US recruited somewhere between 100 and 120 North American children with COS, but found only a few genetic mutations during a 20-year study.

Kohn and his team took the work forward and looked at coding sequences in DNA.

Featured image: DNA (iStock via Getty Images)

“If you find a change in the DNA coding sequence, especially if you can show that this change will cause a major change in the function or amount of production of the protein the genes code for, you’ll have a better reason. assume that it is variation that causes pathology. This is especially true if it is a gene that is expressed in the human brain or is involved in other neurological or neuropsychiatric disorders,” he said.

Dr. Steven Kushner, professor of psychiatry at Columbia University Irving Medical Center and New York State Psychiatric Institute (who was not involved in the study) told The Times of Israel that this apparent genetic link between COS and the other disorders this is important.

“Etologically, [the study’s] Results show that the genetic architecture of COS is enriched for rare highly penetrant variants, particularly those conferring high risk for neurodevelopmental disorders, compared to individuals with more typical late-adolescent or early-adult schizophrenia,” a Kushner said.

​​​​The study found these variants in seven of the Israeli children with COS, but not all of them had the same ones. In addition, in some cases, the genetic mutations were spontaneous (having occurred during the formation of the egg or the sperm that came together to make the child), and in other cases, inherited from parents or from parents who were not affect them.

Kushner hailed the Israel-led study as “another important step forward toward optimizing the application of clinical genetics in the psychiatric standard of care.”

The results show hope for parents of COS children who are thinking about having more children (and siblings who would like to have children one day) by providing valuable information to genetic counselors working with these families.

Illustrative image: newborn baby (iStock via Getty Images)

Kohn believes the study’s findings can help identify targets for new pharmacological therapy for COS. Current drugs for the disorder block a dopamine receptor in the brain and are not necessarily effective.

“These drugs don’t work for all patients, they don’t treat all symptoms, and they have side effects,” Kohn said.

Perhaps the most satisfying result of the study is that Kohn and his colleagues can assure the parents and families of their COS patients that there is a genetic cause for the disease.

“Guilt is something that people have no matter when their children have problems,” Kohn said.

“But it’s really helpful to hear from us that their child’s COS isn’t the result of something they did or didn’t do.”

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