A Family's Long Journey to a Novel Diagnosis . . . And Hope

When Colleen and Tagar Olson’s daughter was born prematurely in 2007 following a difficult pregnancy and weighing just three pounds, the Olsons attributed the developmental delays Kathryn soon exhibited to her challenging start in life. By the time she was three and they first met with a geneticist, “she had endless diagnoses,” Colleen says, “including cerebral palsy, speech and movement problems, and a seizure disorder, but these symptoms just didn't really encapsulate a known disorder.”

Two years after Kathryn’s birth the Olsons had a second child, a healthy boy named Aiden, then Jack was born in 2011. Within six months Jack was also failing to meet developmental milestones, and had several serious respiratory issues. Over the next several years, as the family sought help and advice from specialists around the country, Kathryn and Jack underwent surgeries and hospitalizations for a range of issues including seizures, breathing problems, diagnostic testing, and drug therapies. “The children were medical anomalies for the many internationally recognized doctors we met with. We took solace in phrases like, ‘We don’t know or understand yet, but we are working on it.’”

The Olsons continued their search for answers, and after consulting with several other geneticists, met with Wendy Chung, MD, PhD in 2017. Dr. Chung recommended a genetic analysis of every member of the family that would look at not only the genes that code for proteins (whole exome sequencing) but a sequencing of Kathryn and Jack’s entire genome as well. “She did a kind of backward search,” Colleen says. “No one previously sequenced my children’s genome.”  

At 7 am one morning that June, Colleen received a call. She remembers Dr. Chung saying, “Colleen, I think I’ve got this.” What she had found was a mutation in a gene called deoxyhypusine synthase (DHPS). The gene codes for an enzyme that synthesizes a rare amino acid (hypusine) that plays a role in the production of the protein e1F5A, and the mutated gene is unable to perform its function. Both parents have a mutation in one of their two copies of this gene, so each of their children has a 25 percent chance of having the disorder. The Olson children were the first to be diagnosed with DHPS disorder. (Dr. Chung has identified more than 45 other disorders caused by mutation in a single gene.)

Connecting the dots 

Once geneticists identify a new disorder they share this information with the genetics community through journal articles and at conferences. Gradually members of a few other families who shared a similar array of symptoms were found to have the DHPS mutation and received the same diagnosis. To date five patients have been identified and Dr. Chung has connected the five patients and their families with each other. Through Colleen’s conversations with these families, the team now believes that there is an “Irish founder mutation,” she says. “Among these families each has one parent of Irish descent, and we all carry the exact same mutation, while the other parent has a different mutation in the DHPS gene.” 

Creating a research team

The diagnosis also gave Dr. Chung and the Olsons the possibility of identifying researchers whose work touches on DHPS. Over the past few years, they have been able to bring together multiple researchers from around the world who are studying the gene, amino acid, protein, or closely related syndromes to answer research questions that are helping develop better treatment options. 

The Olsons recently established a foundation that is supporting studies to understand how the gene change affects the developing brain function and behavior. Among the tools they now have are models of the disorder in zebrafish and mice that carry the mutations as well as three-dimensional tissue culture of brain cells, called organoids, with the mutation.

Emerging treatments

One emerging gene therapy approach for rare disorders, antisense oligonucleotide therapy, may hold promise for those with DHPS disorder. Researchers working on a similar neurogenetic disorder, Angelman syndrome, have treated children whose symptoms are more severe than Kathryn’s, Colleen says, and following treatment children who had been non-verbal began talking, and their motor skills improved. “So, there's a proof of concept,” she adds. 

“Before Dr. Chung found the diagnosis, it was like we were walking in a really dark forest,” says Colleen. “When she found the diagnosis it was like someone turned on the flashlight, and at least now we have a vision of how to move forward. The forest is still dark but with all the research beinig done by our phenomenal team, it is getting lighter all the time, and we are getting closer and closer to therapeutics every day.”