Discovery of genetic root of son’s autism gives Calgary family hope for a cure

A Calgary family has discovered that a rare genetic mutation is causing their son’s severe autism, and now they’re hoping that discovery could lead to a cure.

Mousumee Dutta and Ian Holloway have learned that a rare genetic mutation is to blame for their son’s condition.

Ishaan Holloway, 17, has severe autism.

The family hopes that identifying the cause could eventually help treat it and possibly even cure it.

In many cases, treatments and therapies can lead to behavioral changes or reduce the deterioration of health. They tried various treatments, but Ishaan’s condition did not improve. Her parents were eager to find out if a genetic mutation was blocking treatments for her neurological pathways.

“I knew there had to be more,” Dutta said.

They wanted to try whole genome sequencing (studying the entire sequence of one’s DNA) which they had heard about from other parents of autistic children on Facebook.

From 2013 to 2018, the family did not have access to testing. Ishaan was not eligible for the test because he was not diagnosed with a syndrome.

His parents were keen to find answers about Ishaan’s serious medical condition.

But after years of advocacy, doctors discovered that Ishaan suffered from epilepsy and seizures every 10 seconds. This paved the way for a funding request for a whole genome test. It was discovered that Ishaan has a rare NLGN4 X mutation.

“Is it rare because it hasn’t been well studied, it’s not accessible, or is it actually rare? We don’t know,” Mousumee said.

To date, more than a hundred mutations have a direct link to autism and block synaptic function (helps transmit messages between neurons and muscles).

From left to right: Ian, Mohana, Mousumee Dutta and Ishaan. (Submitted by Mousumee Dutta)

Time and money needed to pursue research

The family is calling for a second and final stage of research to determine if repurposing the drugs can reduce the effects of the mutation on the brain.

“Such research is very expensive, and we don’t have that kind of money anymore,” Mousumee said.

The family spent more than $100,000 on tests and treatments. This custom search alone will cost them $200,000.

This research will determine if existing medications for the syndromes can be repurposed to cure the effects of the Ishaan genetic mutation.

Steve Scherer, chief researcher at Sick Kids Hospital in Toronto, said new technology is playing a role.

“A lot of pharmaceutical and biotech companies have now gotten into the game because they’re very good at screening their existing compounds against cells,” he said.

“The Holloway family is involved in such studies, and I know that their cells are transformed in the laboratory into what we call stem cells and then evolve into brain cells to screen for.”

Ishaan is an award-winning poet and has made significant behavioral and learning progress through therapy and intervention. (Mosumee Dutta)

Although advances in technology have accelerated research, “it’s basically a 10-year process, and we [still] learn more,” he said.

As autism cases are unique, research focuses on precision medicine. This means that there will not be a single drug or medication that will impact all people who have an autism diagnosis.

“We kind of have to break that down and look at it in terms of the genetic form of that person. Some of these ongoing trials are targeting some of the genes like the MECP 2 gene, for example, in the neuroligin genes. Those are some of the genes that encode these proteins, which is why it’s important to enroll the right patient or individual in the study for a drug that might actually work with them,” Scherer said.

Innovative research in Canada provides answers

The MSSNG project is a collaboration between the Hospital for Sick Children, the University of Toronto, Autism Speaks, Verily and DNAstacks. He collected data from over 12,000 families using whole genome sequencing to create an autism database with extensive phenotyping. One of these families is the Holloway family.

This database is only accessible to researchers certified to develop personalized treatments.

“We believe that 90% of the causes of autism are linked to genetic factors,” Scherer said.

This project is one of a kind in the world. He found that in 20% of participants, the mutation caused autism.

Once the study shows that the family has achieved one of the listed genetic conditions, a genetic counselor provides them with the information needed to predict the behavioral trajectory and the appropriate interventions to treat it. Parents can also predict the chances that their next child will have autism.

Dutta contacted hundreds of doctors, including Nobel laureate Thomas Südhof. He responded to her email and encouraged the family to move forward with the search.

Dr. Soham Chanda, one of Südhof’s former students, agreed to include Ishaan’s genetic mutation in his study of the impact of how it blocks amino acids.

He is an assistant professor at Colorado State University which has launched a lab with a team of researchers to carry out the first stage of intensive research into the effects of genetic mutations on our neurological pathways.

Dr Stephen Scherer poses in this undated photo. (Robert Teteruck/The Canadian Press)

In his 2019 study, Chanda was able to identify certain amino acids blocked by the mutation, which led to behavioral issues such as hyperactivity and acid secretion.

“We were super excited to find out why Ishaan has this type of autism. If somehow we can unlock this with treatment…there’s hope,” Dutta said.

Stigma around genetic testing

Dutta doesn’t want to wait years for someone to volunteer for this research for his son to get answers about the cure.

“Time is running out,” she said.

“We’re not just doing this for our son, but if it’s successful, many parents will be able to help the most severe kids on the spectrum.”

As the family pushes for education and health rights, it has been called “abusive” by some.

“Not giving it a chance will be abuse,” Dutta said.

Scherer said the study should not be stigmatized but help eliminate the stigma.

“That explains why autism arose in this child, so it wasn’t something the mother did during pregnancy or something the parents did while raising the child,” he said. . “It’s really a genetic change and it’s sporadic genetic changes that happen throughout our DNA.”

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