How Precision Medicine Helped Detect a Rare Form of Epilepsy

How can researchers embrace the unknown in genetic testing — and how might this advance the future of precision medicine?

Sending a sample for genetic testing has often felt like standing before a cave without a flashlight. Why risk walking into the darkness if you may not find your way? These days, however, researchers like Scott Demarest, MD, Clinical Director of the Precision Medicine Institute at Children’s Hospital Colorado, are repositioning the discomfort of the unknown as an opportunity for understanding. Because if there’s one thing his team has learned from its work in genetics, it’s that without more questions, there can be no more answers.

A shift toward this new realm of thought can be traced back to two Children’s Colorado patients, Vina and Lena Gozeh, who suffered from near-constant seizures — almost 100 per day. Dr. Demarest and his team knew that the sisters, who experienced the same symptoms, had a genetic condition. Lena and Vina, born in 2008 and 2011, respectively, had seizures that were similar to those associated with two known mutations in the ALDH7A1 gene that cause vitamin-responsive epilepsy.

These genetic differences cause an inborn error of metabolism that results in an inability to process vitamin B6 — a nutrient essential for maintaining normal development of the brain, immune system and nervous system. As a result, patients with these genetic mutations can experience seizures, as well as impairments to speech and other areas of cognition, until they consistently supplement with vitamin B6. These clues seemed to add up, except for one important detail: The sisters had already been taking vitamin B6 since they were newborns, and their seizures were only partially responsive to the treatment.

When Dr. Demarest sent the sisters’ genetic material to an external lab for whole-exome sequencing, they weren’t a match for the known vitamin-responsive epilepsy mutations. Even though the sequencing captured the gene responsible for Lena and Vina’s challenges, it wasn’t reported. “Since there was no literature that said this variant is associated with disease, there was nothing to report about it,” Dr. Demarest says.

This is one of the greatest challenges of genetic testing — providers notice that there’s a mutation or correlation that is indeed genetic, but they haven’t discovered how or why that genetic difference is causing the symptoms the patient is having, nor how to fix it.

The missing piece

In 2017, the external lab contacted Dr. Demarest about promising new findings. Researchers at a different institution had uncovered a new genetic variant that expanded the known group of vitamin-responsive epilepsies. Specifically, the research showed that these patients, who had a mutation in the PLPBP gene, were missing a binding protein for pyridoxal 5’-phosphate, the active form of B6. Patients in the new study had symptoms that looked exactly like the Gozeh sisters.

Dr. Demarest requested a reanalysis of the sisters’ genes, which confirmed that they had the gene-associated disease discovered in the study. He then consulted University of Colorado School of Medicine colleagues Curtis Coughlin, PhD, who researches genetics, inborn errors of metabolism and vitamin B6 disorders, and Johan Van Hove, MD, who studies metabolic disorders.            

As experts in the group of epilepsy disorders that respond to vitamins, Drs. Coughlin and Van Hove guided the decision to increase the dose of the vitamin the girls were already taking. When that improved but didn’t fully eliminate the seizures, they then switched to a more active form of the vitamin, meaning it’s more readily available and can go straight to work regulating neurotransmitters without having to be metabolized. As the sisters’ care team continued increasing the dose of active B6, their seizures continued to lessen until they stopped all together, granting them the ability to begin progressing developmentally.

Connecting care to research

Fast forward to 2024, and the Gozeh sisters now serve as a case study demonstrating the power of genetic research to change lives. Albeit today, the Precision Medicine Institute has created the infrastructure to uncover such connections more quickly and on a much greater scale than ever before. For instance, the institute, established in 2023, is now home to the Precision Diagnostic Lab, an in-house genetic testing facility.

Looking ahead, the institute intends to create a consent process where patients at Children’s Colorado are enrolled in a genetic research pool whenever they seek a genetic test in clinical settings.

“The system we’re trying to build is that you can answer those questions you have today, but anytime you can’t get an answer, you automatically feed a patient’s information into a research protocol,” Dr. Demarest explains. “It allows for these types of scenarios where we can then learn from every patient, because you can’t clinically act on things you don’t know.”

The institute is moving from its current practice of whole-exome sequencing toward whole-genome sequencing, where the complete genomic sample will be processed. “There’s a lot of hidden information in the whole-genome about how genes are processed, what turns them on and off — things that we currently can’t see when we do whole-exome sequencing,” Dr. Demarest says.

The combination of having a greater amount of genetic material to test, and testing more of it, will inevitably lead to more discoveries. Shortening the loop between clinical care and research is also important for making genetic testing more accessible to individual patients, whose information may lead to findings that uncover a cure not only for them, but for an immeasurable number of other patients who’ve been awaiting an answer.

Embracing the unknown

Despite the many promises of precision medicine, Dr. Demarest explains that genetic testing can feel fruitless for providers, because finding an answer is so rare. Plus, it has historically been challenging to get genetic testing for conditions that don’t have a defined cure. “Even when we get genetic test results, we tell families and we give them an explanation, but it’s not always treatable,” he says.

This is exactly why researchers at the Precision Medicine Institute, together with the Clinical Genetics and Inherited Metabolic Diseases Program, are cultivating a new kind of relationship with the unknown. Even if they don’t know what they’ll find, or how they might treat it, a willingness to embrace the darkness now will inevitably light the way for their patients, and for other researchers, in years to come.

“We need to bring genetic testing into clinical care earlier to make discoveries for things that we don’t know,” Dr. Demarest says. “We can’t afford not to take those steps to discover what’s going on.”