Jake: Life Changing Research Identifies Teenager’s Rare Disease

When Jake was just eight months old he crawled off the blanket where his mother, Tanja, had put him and began rubbing his forehead on the carpet. He continued to rub his forehead even when it became raw and bloody. This was when Tanja first suspected something was wrong with her son. The self-injuring behaviour worsened so severely that by the age of seven years Jake went to live in a specially designed care home: he was self-injuring thousands of times a day.
Although Jake had been diagnosed with Autism at the age of eighteen months, his parents questioned the diagnosis - they didn’t see that type of behaviour in other autistic children. So they continued to search for answers. Their diagnostic odyssey would last over sixteen years, until clinician-researchers, using state-of-the-art genomic sequencing provided by the Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), a 5-year program at CFRI and BC Children’s Hospital, funded by BC Children’s Hospital Foundation, determined that Jake has an extremely rare PAK3 genetic mutation.
The diagnosis proved life changing, for the entire family. By the time Jake was just five, their search had included over 50 different appointments with a range of specialists including neurologists, psychiatrists and gastroenterologists. Every diagnostic test came back normal. “There was clearly something wrong with him, but all the tests were negative,” Tanja says. “He was a true medical mystery.”
“Jake was a true medical mystery.”
As Jake grew, he missed developmental milestones, he didn’t respond to his name, and his self-injury became so severe, Tanja recalls, “He was banging his head thousands of times a day.”

Then, when Jake was sixteen years old, Dr. Mary Connolly, head of the paediatric neurology division at BC Children’s Hospital, referred him to the multi-disciplinary TIDE BC Complex Diagnostic Clinic at BC Children’s Hospital, led by CFRI investigator and UBC Assistant Professor of Pediatrics Dr. Clara van Karnebeek. TIDE-BC is dedicated to improving outcomes for children with intellectual disability using both conventional and more extensive genome-wide sequencing to diagnose underlying genetic disorders, some of which are treatable.
Tanja admits she wasn’t optimistic that genomic sequencing could provide answers. “I remember Tanja told me, ‘I wish you luck, but after 16 years, I don’t believe you’ll find anything,’” Dr. van Karnebeek said.

However, about five weeks after Tanja, her husband and Jake provided blood samples that the Dr Maja Tarailo-Graovac and researchers at Dr. Wyeth Wasserman’s lab at CFRI used to perform genome-wide sequencing, Tanja got a phone call from Dr. van Karnebeek. “She told me, ‘We found it. We have a diagnosis. We know what’s causing your son’s problems,’” Tanja said.

The genome sequencing showed that both Tanja and Jake have the PAK3 mutation, which is located on the X chromosome. Because women have two X chromosomes, they have two copies of the PAK3 gene, which means they have a back-up if one copy is mutated. As a result, Tanja doesn’t experience any symptoms from her PAK3 mutation. However, men have only one X chromosome and when Jake inherited his mother’s mutated PAK3 gene, he didn’t have a healthy back-up.
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“I remember Tanja told me, ‘I wish you luck, but after 16 years, I don’t believe you’ll find anything’ ”
Dr. van Karnebeek
The PAK3 mutation affects the structure and health of the brain, and, as in Jacob’s case, causes severe developmental delays, autism and self-injury. The PAK3 mutation is so rare that only a few other people in the world have been reported to have it. Notably, most, like Tanja, are of Finnish descent.

Not only has the diagnosis provided an understanding of Jacob’s condition and identification of others with the same condition, it has also allowed for important medical therapy. Following Jake’s diagnosis, further testing by Dr. Gabriela Horvath, a CFRI investigator and Clinical Associate Professor in the Department of Pediatrics at UBC, showed that a medication called Levo-CarbiDopamine might relieve some of his symptoms.

While Jake still lives in his special home, the medication enables him to have dinner every night with his family and spend the evening with them. “The medication has reduced the self-injury and improved his mood - the change is unbelievable,” Tanja says. “He’s been smiling and listening to music. He watched the Super Bowl with his father for the first time ever this year. That was really special,” she said. “The quality of our family time has really improved.”
Tanja and her husband also have a healthy teenage daughter, who had decided prior to Jacob’s diagnosis that she would never have children because of the risk of passing on her brother’s illness. However, the genetic testing offered by TIDE BC revealed she is not a carrier of the PAK3 mutation and there is no chance her children will inherit her brother’s disorder. “She’s gone from thinking she can never have kids to thinking about the possibility of having a family for the first time in her life,” Tanja says. “This is life-changing news for her.”

When asked what the biggest hurdle was for her family in obtaining a diagnosis for Jake, Tanya recalls without hesitation that it was having to see so many different specialists, separately, over a period of years. “The beauty of TIDE is that there are specialists from several different departments working together as a team of medical detectives to find answers,” Tanja said. “The Complex Diagnostic Clinic is the dream team. It’s what you want when you’re searching for a diagnosis.”
Tanja is equally emphatic about the importance of genetic testing in determining the diagnosis, stating that as a parent she would rather know exactly what she was dealing with, than have to deal with all the uncertainty. “Genetic research provides that certainty, even if no cure exists. A genetic mutation is very specific,” she said.

“The reality is that had Jake received this diagnosis earlier, he could have had the medication earlier which would have reduced his self-injury and resulting brain damage,” Tanja said. “He would have had a normal life expectancy.” But, with knowledge you can plan. Now the Bartel family can plan to spend as much quality time with their son as possible.
“The beauty of TIDE is that there are specialists from several different departments working together as a team of medical detectives to find answers. The Complex Diagnostic Clinic is the dream team. It’s what you want when you’re searching for a diagnosis.”

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TIDE BC / Biochemical Diseases Clinic
BC Children's Hospital
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