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

Israeli research finds that some children with this rare mental illness carry genetic mutations previously found in people with language, learning, and developmental challenges

Renee Ghert-Zand is the health reporter and a feature writer for The Times of Israel.

Children at sunset (Vitold Muratov, via Wikimedia Commons)
Children at sunset (Vitold Muratov, via Wikimedia Commons)

Most people with schizophrenia are diagnosed in their late teens or early twenties. One in 222 adults around the world suffer from the mental illness.

There is, however, a rarer and more severe form of the disorder that affects one in 40,000 kids under the age of 13. It is called childhood onset schizophrenia (COS), and little is known about its causes.

A peer-reviewed 10-year study conducted by researchers from the Hebrew University of Jerusalem and several Israeli hospitals, together with colleagues from Columbia University in New York, has identified a possible genetic basis for COS. The results published last month could lead to improved 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 that had not previously been associated with schizophrenia. One is known to be involved with the development of the central nervous system and can express itself as problems with behavior and language. The other is known to cause mitochondrial damage with muscle weakness, developmental issues, and learning disabilities.

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

“Apart from the age of onset of COS — which averages 10, but can be as young as three — the diagnostic criteria are the same as for adult onset schizophrenia. These include delusions, hallucinations, disorganized speech and behavior, and deteriorating function,” Kohn told The Times of Israel.

Prof. Yoav Kohn (Courtesy)

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

Making the COS diagnosis poses a challenge because young children — particularly during or after stressful situations —  can have overly active imaginations and fantasy lives. It is also sometimes difficult to differentiate 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 monozygotic [identical] twins and dizygotic [fraternal] twins. In identical twins, if one has schizophrenia then the other has a 50% chance of having it. In fraternal twins, if one has schizophrenia then the other has 10% of developing the disease,” Kohn said.

“But at the same time, we know that the genetics of schizophrenia are very complicated. It is not a monogenetic disorder like Tay Sachs, cystic fibrosis, or Huntington’s disease, which are caused by a mutation in just 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 the Galvin sons were diagnosed with schizophrenia. (Courtesy of the Galvin family)

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

“That’s why we recommend that young people not use cannabis, especially if they already have — or have a genetic predisposition to — mental illness,” Kohn said.

The study, published in February in Schizophrenia Research, builds upon research done 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 the genes of people with schizophrenia and those without.

Kohn noted that since then, a consortium of scientists from dozens of countries have collaborated in the search for the genetic etiology of schizophrenia. These studies have involved hundreds of thousands of people with the disorder, and without it as controls.

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

COS is rarer and more severe than adult onset schizophrenia, with young patients responding less well to medications and having poorer prognoses. At the same time, genetics seem to play an even stronger role in COS. Whereas someone with a first-degree relative with schizophrenia has a 10% chance of developing it themselves, someone with a first-degree relative with COS has a 25% chance of developing 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 couple of genetic mutations throughout a 20-year study.

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

Illustrative image: DNA (iStock via Getty Images)

“If you find a change in the coding sequence of DNA, especially if you can show that this change will cause a major change in the function or in the amount of production of the protein that the gene codes for, then you have a better reason to assume that it’s a variant that causes pathology. This is especially so if it is a gene that is expressed in the human brain or has been associated with other and neurological or neuropsychiatric disorders,” he said.

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

“Etiologically, [the study’s] findings demonstrate that the genetic architecture of COS is enriched for rare highly penetrant variants, particularly those that confer high risk for neuro-developmental disorders, compared to individuals with a more typical late adolescent or early adult onset of schizophrenia,” Kushner said.

The study found these variants in seven of the Israeli children with COS, but they didn’t all have the same ones. In addition, in some cases, the genetic mutations were spontaneous (having happened during the formation of the egg or sperm that came together to make the child), and in others, they were inherited from either affected or unaffected parents.

Kushner praised the Israeli-led study as “another important step forward towards optimizing the implementation of clinical genetics into the psychiatric standard of care.”

Its findings hold out hope for parents of COS kids contemplating having more children (and siblings who may want to have children one day) by providing valuable information for genetic counselors working with these families.

Illustrative image: a newborn baby (iStock via Getty Images)

Kohn believes the study’s discoveries can help identify targets for new pharmacological therapeutics for COS. The current drugs for the disorder block the receptor for dopamine in the brain and aren’t necessarily effective.

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

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

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

“But hearing from us that their child’s COS is not the result of something they did or didn’t do can help a lot.”

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