Alex Yiu, age 10, enjoys watching Curious George and Frozen on his iPad. He started life as a normally developing, active, happy-go-lucky child, but now has an unknown, progressive neurodegenerative condition.
When Alex was around 3½, his parents noticed awkward walking, and, at age 4, falling. At age 5, his speech began to decline, and he stopped walking entirely at age 6. By age 7, he lost arm and hand control and the ability to chew. He then lost trunk and neck control, developed swallowing problems and went from needing pureed foods to requiring tube feeding due to food aspiration. He has suffered very painful muscle spasms and has begun having seizures. The past year, Alex has had respiratory issues requiring breathing therapies and sometimes oxygen support.
Alex can no longer talk, but can indicate a yes/no with his eyes. Until last year, he was able to participate at grade level at school. For a while, he used an eye-gaze device to communicate through a tablet, but loss of head and neck control have made it hard for him to use it. Alex is now trying out a headset device that measures brainwaves.
The family has spent four years going to neurologists and research institutes in multiple states and internationally with many rounds of blood work and invasive testing. Alex applied to the National Institutes of Health's Undiagnosed Diseases Program, but the program felt it could not help him.
In the last six months, Alex's illness has progressed noticeably. He has been in the hospital nine times this year alone for G-tube placement surgery, seizures, respiratory distress, pneumonia and infection. He can no longer move himself in a wheelchair or sit or stand independently, and now requires 24-hour-care for all activities of daily living and monitoring of his oxygen levels.
"It's exhausting just to keep up with his medicines and his therapies," says his mother, Caroline Yiu. "We haven't had the time and energy to do a lot of research."
Alex has a sister Elaine who is healthy. The family went into the CLARITY Undiagnosed Challenge with cautious optimism. "Over the years, we've become more cynical about testing, we always have this hope, 'maybe this time they'll figure it out,'" Caroline says.
What CLARITY Undiagnosed found
Alex was found to have "variants of unknown significance" (VUS) in three different genes that seemed possibly related to his condition, but would require more work to establish as causative. None of the genes has ever been associated with any human disease.
Two of the three variants confirmed candidates identified by another multi-institution research team that had investigated Alex's case. One of these was a large deletion of DNA that included a gene called RUNX3, known to be involved in nervous system development and the formation of neurons. It was de novo, meaning the variant was present in Alex but not in either of his parents—it arose some time during Alex's early embryonic development.
The second finding involved two different variants in a gene called SLC26A1, one inherited from each of Alex's parents. The gene is involved in ion channels (gate-like structures that let charged molecules in and out of cells) that are important in the brain and liver. The variants have also been found in healthy people, making them weaker candidates than the other variants described above, but they have been found only in isolation, not combined as in Alex.
The third variant had also been noted by the earlier research team but had been ruled out. This variant, in a gene called GASK3, was also de novo. GASK3 is highly expressed (very active) in the brain and regulates several important processes in the body. It has been hypothesized to play a role in certain forms of memory impairment, including Alzheimer's disease, and may be involved in regulating other genes. One genetic pathway GASK3 is thought to regulate has been implicated in a disorder that presents similarly to Alex's.
For Alex's parents, the results are mainly confirmatory. "Our secret hope was that there would be a more 'for-sure' answer, something that the other teams missed," says Caroline. "But in a way, it is reassuring that all 26 international teams have looked at Alex's case, and two of the three genes they identified are ones that our core team has been focusing on."
Alex's parents now hope to have functional studies done to see whether the genetic variants are actually disease-causing and if so, what they do and how. They plan to share the findings with the other researchers who are investigating Alex's case and connect them with the Manton Center for Orphan Disease Research at Boston Children's for collaborative research.
"I'd really like to see if there are more patients out there," Caroline adds. "I can't imagine Alex is the only one in the world with something like this. If there were other patients we might be able to find more data, and maybe these families have found something that works for them. I'd also like to find more researchers that are doing studies on these genes, and see if we can add to what they're doing, and vice versa.
"To find the disease causing genes will help Alex and other children like him with diagnostics and treatments that would, we hope, offer an improved quality of life."