A Father’s Search to Find a Cure for a Rare Disease

Keith McArthur is a father, journalist, kidney disease survivor, and rare disease advocate, who put his life on hold to find a cure for his son Bryson’s rare condition. ABILITY Magazine spoke with Keith about his family’s journey getting a diagnosis, his podcast ‘Unlocking Bryson’s Brain,’ and finding a cure for Bryson’s rare GRIN disorder. Additionally, Linda Schoch, mother of 30-year-old Dana, who lives with GRIN as well, talks about ‘the island of Dana,’ and Dr. Tim Benke gives valuable insight into recent and future GRIN research.

Bryson’s journey

“Bryson is a happy 13-year-old who gives magical hugs,” says father Keith McArthur, a journalist, podcaster, and rare disease advocate. Bryson can’t talk or walk, has seizures, and aggressive outbursts due to a rare genetic developmental disability called GRIN disorder. When Bryson was two months old, his family noticed for the first time that he wasn’t a typically developing baby. “We went to have baby pictures taken, and the photographer tried to prop up Bryson’s head on his fists, but it kept falling over,” Keith says. A few weeks later, a doctor confirmed during his 3-month check-up that Bryson was missing milestones. “Although, we didn’t know whether it was something minor he would grow out of or something serious long-term,” Keith adds. Over the next years, his condition progressed, but the family was left in the dark. They wouldn’t receive a diagnosis until 10 years later.

A family photo of father Keith, who has short brown hair and wears a white shirt, his son Bryson, who has blonde hair and wears a similar white shirt, his wife Laura, who has shoulder-long brown hair and smiles brightly, and his older son Connor, who leans on his moms shoulder and has curly, brown-red hair. On Connor's and Laura's lap is a fluffy brown dog, sticking out its tongue.
Keith, Bryson, Laura, and Connor (Image: Keith McArthur)

GRIN

GRIN disorders are a group of rare genetic conditions affecting the building of a protein called the NMDA receptor, which is crucial for learning and memory function. Changes in one of seven GRIN genes, including GRIN1, GRIN2A, GRIN2B, and GRIN2D, either cause the receptor to work too much or not enough, which leads to different disease expressions. People with GRIN disorder might develop intellectual disabilities, epilepsy, hypotonia, and feeding difficulties, along with other symptoms. “Within those four genes, there is a lot of overlap between the symptoms, but there are some broad things that define each of the four different ones. For example, epilepsy is very common in GRIN1, which is the variant that my son has. It’s a lot less common in GRIN2B. With GRIN1, GRIN2B, and GRIN2D, almost all of the kids have a severe intellectual disability. But with GRIN2A, about half of the individuals don’t have an intellectual disability at all,” Keith, who is the CEO and Head of Science of the organization CureGRIN, explains. “The gene has thousands of letters, and however the protein changes has an impact on the brain function.”

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Getting a diagnosis

Unfortunately, for most people living with a rare condition, the path to finding a diagnosis is a rocky one. Bryson was almost ten years old when a positive gene test confirmed his GRIN mutation – a tiny change in the GRIN1 gene causing all his symptoms. By that time, Keith and his wife, Laura, felt they would never find the reason for Bryson’s condition. “It was great when they were finally able to provide the diagnosis for a few different reasons. The biggest one was that it allowed us to find a community with the same rare condition. It’s such a new and unknown disease, so doctors didn’t know much about it, but we were able to learn a lot from other families. And this also gave us a sense of community,” Keith says. According to Keith, only around 1000 people with GRIN disorder are diagnosed worldwide. However, the real number might be much higher since many families didn’t have access to proper diagnostic testing in the past. “The oldest people with GRIN disorder that we know of right now are 30 years old, but GRIN usually is not a degenerative disease. It’s normally not a disease that causes death. So there are probably hundreds of thousands of people in their 30s and 40s or upwards that have it but never had an exome sequencing,” Keith explains.

Bryson, a boy with short blonde hair and a black hat sits in a wheelchair. His brother Connor kneels next to him. He has curly brown-red hair and wears a hat too.
Bryson and his older brother Connor (Image: Keith McArthur)

‘Welcome to the island of Dana’

That’s how Linda Schoch, an eloquent woman with curly brown hair, refers to the 28 years of life without a diagnosis for Dana, her 30-year-old daughter. She and her family felt like they were alone on a secret island, where nobody else would understand Dana’s disability. Dana is one of the 1000 known people living with GRIN disorder, specifically GRIN1. Unlike Bryson, Dana can walk, but also experiences seizures that can have quite severe consequences. “We had an incident on the weekend where she had a seizure and fell through a closed window. Miraculously, she only has a tiny cut on her cheek,” Linda says. Because of these uncontrolled seizures, someone always has to be around Dana to make sure that she is safe. “She is very much like a 2-year-old, where she can get in a lot of mischief, and like a toddler, we have to always make sure to watch her. She gets up at night; she doesn’t have normal sleep patterns. She needs assistance with feeding, dressing, bathing, and more,” Linda explains. However, since Dana is ambulatory and outgrew Linda in height, the family needs to ‘Dana-proof’ their house, which doesn’t always work out. A minute later, I find out what Linda meant by mischief, and I learn that Dana has an incredible sense of humor.

A family photo on the beach. All family members wear white shirts. Linda, a mother with curly brown hair and glasses smiles brightly. Next to her is daughter Dana, who tries to get out of the picture. Her younger brother gently holds her back. Her other brother looks at her and smiles. Her dad in the background smiles as well.
Linda, Dana, and the rest of the family. Dana wants out of the picture. (Image: Linda Schoch)

Dana does not like the dentist

Whenever it gets silent in Linda’s house, she has to assume Dana got herself in trouble. “Dana will unroll an entire roll of toilet paper, and then you have to laugh because she thinks it’s funny. Even though she is lacking some things, there is so much in her thought process that she can figure out. So the things she gets into, you have to appreciate, because it took a lot of thought on her part,” Linda says. However, the extent of Dana’s humor and sneakiness really came to light when Linda and her husband took her to an annual teeth cleaning appointment. Whenever the family has to see the dentist, they need to prepare gloves and a little wedge to keep Dana’s mouth open, so she won’t bite down. “So I bring a towel with me, and put these wedges in a bag,” Linda says. Linda put the bag into her purse and left it on the table. Arriving at the dentist’s office, Linda’s husband asked her where the wedges were. “What do you mean?! They are in the purse,” Linda would respond. But they weren’t, because Dana had taken out the bag with the gloves and the wedges and put them right back into the drawer where they usually are.

What to do after?

According to Linda, Dana keeps developing new skills and tries to be more vocal lately. She doesn’t speak much but has different signs with which she expresses what she wants. “And Dana is very opinionated. She knows people’s personalities,” Linda says. “She also doesn’t do change. So you can’t just bring a new person in. You don’t do that. You have to train the person that cares for Dana, and she needs to get used to them,” Linda explains the challenges of being Dana’s primary caregiver. “Being a caregiver is a marathon, and therefore you have to train like you would for a marathon.” One of the biggest challenges as primary caregiver is the question of ‘What happens once we are gone?’ “It’s hard because she can’t advocate for herself. And abuse is a huge thing for people with special needs. And that’s the most challenging part for all of us with kids that have any disability: What do you do after – once she outlives us? How do you trust people?” Linda says.

Listen to the interview with Linda on ABILITY Magazine’s podcast.

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Second chances

After 9/11, Linda, back then, a successful engineer, decided to retire and focus on her family and caring for Dana. For Keith, the crucial moment that changed his life happened in 2015. All of a sudden, a medical condition he believed to be harmless threatened his life. “I first learned that my kidney function was slowly declining about 20 years ago. I had my kidney function tested every six months, and my doctors thought that if it stayed at this slow pace, I might have to get dialysis or a transplant when I am on old man,” Keith says. However, a few years later, his kidney function plummeted, and he was nearing kidney failure. Keith needed a transplant or he would die. Toxins started to build up in his blood, his brain was feeling foggy, and he was getting more tired. Fortunately, Keith’s younger sister, Stephanie, was a perfect match and donated a kidney to him. “Going through that changed my perspective on life. I felt like I have been given a second chance that I wanted to live as well as I could,” Keith says. His experiences with trauma and chronic illness led him to write books about self-help and laid the cornerstone of focusing on finding therapies or even a cure for Bryson and other people with GRIN disorder.

Finding a cure

Keith finally put his life on hold to follow his mission of finding a cure in 2018 when he met researchers at a conference in Toronto, who, for the first time, gave him a message of hope by telling him that the part of the brain affected by GRIN disorders might respond well to therapies drug companies developed for other conditions, such as Alzheimer’s. “But I think the biggest thing that gave us hope was the research that got presented by a University of Toronto researcher that worked with a GRIN mouse. They basically put an on and off switch in within the mouse. So the mouse was born having a GRIN1 mutation, but then when the mouse reached adulthood, they were able to turn off the mutation, and this restored the mouse to something closer to a typical wild type mouse. It wasn’t a full recovery, but, even in adulthood, this research showed that if you fix the genotype, you can fix the phenotype as well,” Keith explains.

GRIN research: Gene therapy

What Keith is referring to is called gene therapy, specifically gene replacement therapy. “These kinds of experiments were truly transformative in terms of how we approach the whole class of developmental encephalopathies,” Dr. Tim Benke, Pediatric Neurologist at the University of Colorado and at Children’s Hospital Colorado, explains. His primary clinical focus is on rare neurogenetic conditions and developmental encephalopathies, like GRIN disorders. Additionally, he has partnered with Dr. Steve Traynelis at Emory to lead the U. S. Registry to categorize GRIN disorders. According to Dr. Benke, a similar experiment and outcome like the mouse study Keith described was seen in one of the better known developmental encephalopathies: Rett syndrome. “This was the first time anyone did this experiment. And we thought, how can you reverse something that has happened in early development? How can you turn the clock back?” Benke adds. Nevertheless, after switching on the ‘healthy’ gene in Rett mice, the animals had restored function. “This showed that these developmental encephalopathies can be approached in a later stage of development. In other words, when you finally get a diagnosis, it is not too late to apply a treatment,” Benke states. According to the physician, gene replacement means that a person misses a good copy of a gene that will be replaced with an extra copy to fix the problem. This therapy could be a future option for GRIN disorders as well, however, only if the specific GRIN mutation leads to a hypofunctioning NDMA receptor. For other changes on the GRIN genes, gene editing would be required, which isn’t available for humans yet. “Gene replacement therapies for some developmental encephalopathies will be available in clinical trial form within the next year or two. And if experiments in animal models proceed favorably, it might also be available for GRIN disorders, but we still have a lot of work to do. One major concern is that gene replacement might be helpful in a short period in an animal model, but how far do we have to go to make sure that it really is safe?” Benke emphasizes. Until families can access gene therapy, they have to overcome a massive hurdle: the cost. According to Tim Benke, gene replacement therapy for spinal muscular   atrophy currently costs more than 2 Million Dollars, and many insurance companies and state medicaid don’t cover it, leaving the families with a decision of life or death in some circumstances. Additionally, gene therapy later in life might not cure all symptoms. “My guess is that a complete cure might not be possible. There have been too many things in the developmental process that required the presence of GRIN receptors, and those already happened. It seems unlikely that the brain would regenerate completely,” Benke says. 

Alzheimer medication to treat GRIN

‘Memantine,’ a drug that blocks the NMDA receptor in the brain, might be one potential treatment option for GRIN disorders, particularly if the receptors are hyperfunctioning. The medication is usually used in late-stage Alzheimer’s, as it was found that NMDA receptors don’t only play a crucial role in GRIN but also other conditions, like Alzheimer’s. “There are a few case studies about GRIN patients with severe epilepsy and hyperfunctioning GRIN receptors. Their seizures improved while taking the medication. But the other aspects of the disease, like cognition, the ability to sit, walk, see or use the hands, haven’t been studied yet,” Benke explains.

On the other hand, in the case of GRIN mutations that cause the receptors to underperform, the neurotransmitter Glycine, a simple dietary supplement, could improve cognition by helping the receptor to work at its peak efficiency. “There was only one case study. Even though the results were exciting, the concern is that it could have been a placebo effect. In order to know if these drugs are working, you have to do randomized placebo-controlled double-blind studies, something parents don’t like but what’s necessary to ensure safety and efficacy,” Benke says.

Ethical considerations

‘Curing disabilities,’ especially those caused by genetic conditions, has been the focus of heated discussions, particularly in disability circles for a long time. Many people with disabilities view their disability as a part of their culture and would not want to be cured. Keith, however, doesn’t want to change who Bryson is. “We love who he is,” Keith says. “But if there were treatments that could make his life easier, then we would want to pursue those. For example, Bryson is in a wheelchair. If he spends his whole life in a wheelchair, that’s great, but if we had the opportunity to give him a treatment that would allow him to pilot his wheelchair himself, instead of us pushing it, I believe he would want that.” Keith is aware of the ethical challenges and discusses those with experts in Episode 6 of his podcast ‘Unlocking Bryson’s Brain.’ “Essentially, the decision to search for a cure was something I really struggled with because obviously, Bryson doesn’t have a voice in this. And so one of the messages that I heard from these experts was that we need to make sure that Bryson has a voice as much as possible, that we think about everything we do, and that we don’t think about our needs but what he would really want,” Keith adds. Linda agrees but doesn’t have a clear answer whether she would cure Dana or not. “I would love for her seizures to stop. And I would love for her to be able to talk and express herself to advocate for herself. It would be amazing if she could tell us when she hurts or if she could express her needs. But I would never want to remove the essence of who Dana is. There are things about her, you would never want to undo,” Linda says. While GRIN has a severe impact on Dana’s life, Linda feels it is a blessing at the same time because of the influence her daughter has on other people. When I ask Linda how she feels about Keith’s efforts to find a cure, she says, “It’s just so remarkable. Obviously, if you meet him, there is something about him that draws you in. The way he smiles or his voice just makes you want to be on his team. It is amazing that a single parent can have such a huge influence.”

‘Unlocking Bryson’s Brain’

It is, indeed, astonishing how one person advocating for a condition with only 1000 cases worldwide can have this impact on researchers, GRIN families, and in a wider context, all people living with rare diseases. Keith has documented every step of his journey in ‘Unlocking Bryson’s Brain,’ his CBC podcast, which not only follows him on his way of finding a cure, but he also gives a voice to other families living with GRIN disorder. Additionally, experts complement the storyline and provide useful insight into GRIN research and the ethical considerations of trying to find a cure. Furthermore, by underlining the challenges all people with chronic health issues face, he makes his podcast relatable to a broad audience, and to everyone who is “looking for a miracle,” he says. Unlike other media groups, The Canadian Broadcasting Cooperation (CBC) and Keith paid particular attention to accurately representing people with disabilities. “Going through the process of producing this podcast helped me realize that, yes, I can be a disability advocate, but I still have an ableist bias that I bring to these things. I am Bryson’s father, but I am not Bryson,” Keith says. To avoid any misrepresentation, Keith used a sensitivity listener, who made sure the podcast was as accurate with its language as possible.

Rare is not so rare.

One of the most important goals he tried to achieve with ‘Unlocking Bryson’s Brain’ was to give hope to people and make them feel less alone in their own journey with a rare condition. Each rare disease might only affect a small number of people, but together all rare disease patients make up 400 million people worldwide. “We felt so alone before we got the diagnoses and were very scared after we had one,” Keith states. Finding a community to belong to can be essential for chronically ill people, but it’s even more crucial for those affected by rare diseases. For Linda and her family, finding a diagnosis after 28 years meant that they weren’t alone on ‘the island of Dana’ anymore. They connected with Keith and other families and became part of the GRIN family. “And then I guess selfishly I was hoping that someone who is listening will have a clue and will help us move things along more quickly regarding a cure for Bryson,” Keith adds. If one thing is for sure, Keith will not stop to fight for his son Bryson – whether this means a cure or merely a therapy that improves his quality of life just a bit.

In many ways, Keith’s family’s journey represents most people with rare conditions that just want to be heard. With ‘Unlocking Bryson’s Brain,’ Keith hasn’t only managed to get a step closer to finding a possible cure for his son Bryson, he has also portrayed an often neglected minority, who, I am sure, appreciates his work just as much as I do. Rare disease stories rarely make it into mainstream media. So ‘Unlocking Bryson’s Brain’ is, for all of us, a step into a brighter future, where we can find the recognition and treatment we deserve.

“He has definitely given a voice to the whole world. And people need to hear that!” Linda says.

Find out more:

Unlocking Bryson’s Brain

https://www.cbc.ca/radio/podcasts/unlocking-brysons-brain/

Keith McArthur

https://keithmcarthur.ca

Cure GRIN

https://www.curegrin.org

GRIN2B Foundation

http://grin2b.com/

CFERV and the GRIN registry

http://functionalvariants.emory.edu/database/index.html


by Karina Ulrike Sturm

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