OHSU Makes Rare Genetic Disease Discovery

Photo: Ford, Brad

Photo: Raiden Science Foundation

Oregon Health & Science University researchers have established a framework to predict the severity and symptoms of a rare and deadly genetic disease that affects about 40 children worldwide, including Raiden Pham, a patient receiving care at OHSU Doernbecher Children’s Hospital.

The study, a collaboration with Baylor College of Medicine, was published in the journal eLife.

UBA5 disease — also known as developmental and epileptic encephalopathy 44, or DEE44 — is produced by genetically inherited mutations of the UBA5 gene. While the exact mechanisms and biological significance of the gene are still unclear, scientists know it is fundamental to many of the body’s signaling processes, including the response to certain types of cellular stress. DEE44 is associated with a number of severe health outcomes, such as motor control issues, cognitive challenges, growth impairments and other medical complications. The disease ultimately progresses into chronic seizures and early death, typically within the first few years of life. 

“While you can discover through genetic testing that the UBA5 mutation is present, you don’t necessarily know how severe that mutation will be,” said study author Jonathan Pruneda, Ph.D., assistant professor of molecular microbiology and immunology in the OHSU School of Medicine. “This study is a huge step toward bridging that gap in knowledge. We now have a mechanism to understand severity of mutations and predict a child’s clinical outcome with some degree of confidence.”

Parents of a child with DEE44 each carry one copy of a specific UAB5 gene mutation. While a single copy poses no threat, if a child inherits both copies of the mutation, it can lead to a rapidly developing neurodegenerative disease.

This study lays the foundation to better evaluate the different types of UBA5 mutations, which can predict the symptoms and severity of disease — a critical step to supporting DEE44 patients in the future and developing new, potentially life-saving treatments.

The Pham family is hopeful that with continued support from the medical research community, there might soon be a treatment that could help Raiden. More importantly, the family says this work provides much-needed hope and inspiration for other parents and families.

Building the framework

At OHSU, a team of researchers established a new method to observe the function of UBA5 in a controlled, “test tube” environment. This allowed them to determine exactly how individual UBA5 mutations lead to its inability to function properly. The degree of dysfunction arising from different UBA5 mutations could be classified into mild, intermediate and severe subtypes.

Collaborators in the laboratory of Hugo Bellen, Ph.D., professor of molecular and human genetics at Baylor College of Medicine, then introduced DEE44 patient mutations into the UBA5 gene of fruit flies to establish a novel “humanized” animal model of the disease. While some mutations led to death, others caused progressive motor defects, including the developmental delays and seizure-like symptoms seen in humans. Remarkably, the severity of symptoms in the fruit flies aligned with the work in test tubes and could be classified into the same mild, intermediate or severe subtypes.

Because the disease is considered to be ultra-rare, there are few research studies and treatment options. Researchers emphasize that their work is important because it provides a molecular explanation for the effects of UBA5 mutations, and, more importantly, establishes a clear pathway for the development of new drugs and gene therapies.

“It’s really helpful for parents to know, for better or worse, that the disease will follow a particular course,” said study author Ruth Napier, Ph.D., assistant professor of molecular microbiology and immunology in the OHSU School of Medicine. “A child with a more severe mutation may want to begin an aggressive gene therapy right away, whereas a child with a less severe mutation, which progresses slower, may be able to explore other options first.”

Hope for families

For parents like Tommy Pham, this information is game-changing.

Pham recalls visiting as many as 17 different doctors before arriving at OHSU Doernbecher Children’s Hospital to receive genomic sequencing tests for his son, Raiden, who carries UBA5 mutations. They received his official diagnosis in August 2021.

Pham says while Raiden’s quality of life is limited, they’ll never give up on trying to find a treatment that could improve his son’s life and the lives of other children with the disease.

“We live in a time where we have the resources and technology to advance personalized medicine,” said Pham, who founded The Raiden Science Foundation with his wife, Linda, in honor of their son.

The foundation is dedicated to rare disease research, advocacy and education, and has been working with academic research centers across the country, including OHSU, to advance UBA5 disease modeling and identify treatment options.

"Really what this work does is provide hope, and our journey shows what’s possible if you don’t give up hope,” Pham said. “By having this paper out there, we’re sharing crucial information and connecting doctors and researchers to families who need answers. We’re creating change for the kids who have this disease now and also those who will inherit it in the future.”

Looking forward, researchers hope to leverage the framework established in this study to guide personalized approaches for treatment. Specifically, at OHSU, Pruneda, Napier and their teams are developing a novel drug screening platform to discover potential drugs that can restore UBA5 function.

Together with Sanjay Malhotra, Ph.D., director of the OHSU Center for Experimental Therapeutics, the team has already begun this important work, screening over 1,000 FDA-approved drugs.

“It’s been inspiring to see this work come to fruition and to think about all the institutions that came together to make it happen,” Napier said. “We hope our work can one day give these children a chance to live a healthy life.”

Source: OHSU

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