One family’s odyssey to find a diagnosis for their sick child is a case study of the challenges of addressing a rare or undiagnosed illness. The California Center for Rare Diseases at UCLA aims to change that trajectory.
By Casey Rentz
Photography by Ann Johansson
Rylan Gowri was just 2 years old and already had logged more trips to the hospital than most adults would in a lifetime. Ten times in just 12 months, the child’s parents Ram and Ishani rushed him to the hospital when what seemed like a common cold or flu turned into cyclical vomiting and seizure-like shaking. “We had done it so often, we had a packed bag ready to go,” Ram Gowri says.
The hospital tests proved to be inconclusive. EEGs showed that Rylan’s shakes were not true seizures, so the doctors ruled out epilepsy. He also had weak muscles and lagged behind in speech and motor development, which pointed to a possible genetic disease, but tests came back negative. Rylan’s grandmother is a pediatric neurologist who diagnoses such conditions as cerebral palsy and autism; she also was stumped.
Nobody knew what was wrong with Rylan, and the uncertainty was dizzying. “It felt like chaos fatigue,” Ram says.
“Enjoy your time with him,” the family was told. They returned home with a half-dozen medications but no plan for Rylan’s ongoing care. “We had no answers,” Ishani says.
Back at home, Rylan continued to suffer bouts of nausea and shakes, and he still hadn’t learned to speak or walk. But his irrepressible ear-to-ear smile charmed everyone. “He doesn’t seem to know his limitations,” Ishani says. “He is the happiest kid ever.”
The Gowris struggled to find the answers on their own. They researched Rylan’s test results and Googled his symptoms, hoping to match the constellation of signs to known diseases. Ishani frequented Facebook groups for parents of children with mitochondrial disease, leukodystrophy and something called hypoxic-ischemic encephalopathy, trying to find a familiar story.
One day, a friend told the Gowris about the website of the Undiagnosed Diseases Network (UDN) at UCLA. After reading the information on the website, the Gowris felt that maybe, at last, they had found a place that could offer them some answers — and hope. The criteria for eligibility, as outlined on the site, was straightforward: Rylan had gone through many tests, been seen by numerous specialists and he remained undiagnosed. Ishani filled out the online application and hoped that UCLA’s program would select them to participate.
Left: Dr. Stanley F. Nelson: “Families live without knowing what is wrong, but when we can figure out their exact genetic mutation, we can develop strategies that may make it possible to treat the disease and provide appropriate guidance for the family.”
Right: Dr. Julian A. Martinez: “It all starts with a gene. That’s the magic of what happens here.”
UCLA IS AMONG 15 INSTITUTIONS NATIONWIDE WITHIN THE NATIONAL INSTITUTES OF HEALTH (NIH)-SUPPORTED UDN, which has been engaged in research studies to improve and accelerate the diagnosis of rare and undiagnosed conditions. NIH created the network in 2014 after its original Undiagnosed Disease Center was overwhelmed with patients, and it expanded the network in 2018.
UCLA’s program — which is a key element of the California Center for Rare Diseases at UCLA — is headed by Stanley F. Nelson, MD, professor of human genetics, pathology and pediatrics and director of the California Center for Rare Diseases; Julian A. Martinez, MD (RES ’03, FEL ’06), PhD, professor of human genetics and pediatrics; and Christina Palmer, PhD, professor of psychiatry and biobehavioral sciences. In the last two years, it has accepted 130 patients from Southern California, as well as from other parts of the country. Thus far, UCLA’s program has identified the exact DNA mutation in 30 patients and provided them with a diagnosis. “Families live without knowing what is wrong, but when we can figure out their exact genetic mutation, we can develop strategies that may make it possible to treat the disease and provide appropriate guidance for the family,” Dr. Nelson says.
It takes cutting-edge technology to diagnose patients with rare diseases. “UCLA is one of the first places in the world to use whole-exome sequencing,” says Daniel H. Geschwind, MD (RES ’95, FEL ’97), PhD, Gordon and Virginia MacDonald Distinguished Chair in Neurology, Psychiatry and Human Genetics and associate vice chancellor for precision medicine. Dr. Geschwind also is director of the UCLA Institute for Precision Health, of which the California Center for Rare Diseases is a core component. “Advances in genomics now allow us to diagnose people who 10 years ago were undiagnosable.”
Specifically, adding RNA sequencing to the diagnostic mix is an advance that UCLA innovated. “UCLA is one of the UDN sites that has pioneered RNA sequencing for rare diseases and also has been instrumental in leading the genetic counseling aspect,” says Jon Bernstein, MD, PhD, of the Stanford Center for Undiagnosed Diseases.
A tighter connection between multidisciplinary research laboratories and clinicians is something that UCLA’s new California Center for Rare Diseases and the UCLA Institute for Precision Health help to promote. The goal is to “leverage the expertise of our clinicians at UCLA and the research and innovation that have been going on at UCLA for decades in the fields of genomic medicine,” says Clara M. Lajonchere, PhD, deputy director of the UCLA Institute for Precision Health. “There are so many children in the United States, as well as adults, who suffer from undiagnosed rare diseases. For parents, and individuals, the diagnostic odyssey can last for more than a decade. We want this to be a safe place where patients can come and receive the care they need.”
THE GOWRIS BEGAN THEIR JOURNEY AT UCLA WITH DR. MARTINEZ, who keeps a statue of the Hindu god Ganesh on a windowsill in his office. Ram Gowri, who is from a Hindu family in Sri Lanka, took notice. While Dr. Martinez is not Hindu, he keeps the statue that was given to him as a gift “as a reminder to me of friends who care” — similar to the caring role that he and other members of the UDN team play in helping to overcome obstacles for the patients who come seeking answers.
Dr. Martinez began his career as a physician-scientist with an interest in neurodevelopment. He joined UCLA’s UDN in 2017. “Our goal is to help end these diagnostic journeys,” he says. “People with rare diseases are an underserved population, and we want to change that.”
The Gowris’ first day began with a simple skin scrape of both parents and the child that would be used for RNA sequencing. Then came visits with different clinicians, during which Rylan underwent X-rays of his bones, a sonogram to check his kidney function and an echocardiogram of his heart. Doctors also drew blood from each member of the family for genome sequencing.
“Everyone was really kind and generous with their time,” Ram says. Every doctor took time to explain the tests fully and to manage expectations, he says. They also met other families from other parts of the U.S. and abroad who were going through the testing process. The next day, the Gowris returned for an MRI of Rylan’s brain.
The days were exhausting, but the Gowris came away feeling supported and that, for the first time, they might receive some answers and a cohesive plan to help their son. “Now there was a team behind Rylan. It wasn’t like that before,” Ishani says. “After that, I didn’t feel the need to look up things all the time. Someone actually was working on it for me.”
UCLA’s genetic counselors kept in touch with the Gowris over the next nine months, sending updates about Rylan’s physical and genetic-test results and analysis. Still, Ram and Ishani were cautious about getting their hopes up about a diagnosis. They determined to put it out of their minds for the time being and started to grow accustomed to life with their unique but super-happy son. Rylan’s febrile seizures had left him disabled: At 3 years old, he still can’t speak or walk, he can’t focus his eyes very well and his head swivels a bit as he moves. He also continues to sometimes get the shakes when he is sleeping or sick. His parents ferry him around the house from table to couch to bed, and they give him a number of supplements throughout the day. His father takes him to physical therapy, and he loves when his parents read books to him and his two younger sisters, tucking his body against his mother or father as they tell the story of The Very Hungry Caterpillar. He smiles often. “Bad things happen, and he just chooses to be happy,” Ram says.
AS LIFE MOVED FORWARD IN THE GOWRIS’ HOME, evidence for Rylan’s diagnosis filtered in to UCLA. The family’s blood samples were sent to the regional UDN genetic laboratory, which sequenced each person’s entire genome — every region of DNA that codes for a gene. The results generate a vast amount of information, many orders of magnitude greater than what can be determined from a standard genetic work-up that sequences only certain sections of DNA where mutations are known to occur in common genetic diseases. Such tests had turned up nothing for Rylan.
UCLA’s geneticists waded through the sea of results, eventually honing in on a specific gene, SLC25A46. A University of Miami study in 2015 had found that this gene was faulty in four families with members who had symptoms like Rylan’s — optic atrophy, muscle weakness and development problems. The SLC25A46 gene makes a protein that is important in membranes of mitochondria, which provide energy to muscle cells, and it also is vital for growth of nerve cells. A damaged gene and lack of protein would explain Rylan’s weak muscles and other nerve-related problems.
Upon examining SLC25A46 in the Gowris’ genomes, the geneticists found a mutation in Rylan that was inherited from Ishani. That fit one piece into the puzzle; Rylan had inherited a faulty copy of this gene from his mother. But it didn’t complete the whole puzzle. To be disease-causing, Rylan also would have to have inherited a faulty copy of this same gene from his father. Geneticists checked the protein-coding sequence of Rylan’s DNA that was inherited from Ram, and, to their surprise,
it looked normal — there was no mutation. That didn’t make sense. But there was another possible explanation; something was wrong with Ram’s DNA that they couldn’t see, something nearby the gene that was affecting its ability to make proteins. They had to look closer.
That is where RNA sequencing comes in — the tool that UCLA has pioneered in conjunction with rare-disease diagnosis. RNA is the middle product of our DNA — between gene and protein. The family’s skin biopsies taken by Dr. Martinez allowed geneticists to take special kinds of cells called fibroblasts, grow them, extract their RNA and look for errors. Sure enough, the RNA from both Ram and Rylan was scrambled at what corresponded to the SLC25A46 gene, which means that something was going on with the SLC25A46 gene inherited from Ram, too. Through the new techniques developed at UCLA, they found a DNA deletion in a non-coding area essential for gene splicing. Although Ram’s SLC25A46 gene that was passed to Rylan looked OK from typical genetic testing, it was, in fact, non-functional as well, and Rylan had inherited two faulty copies of that gene: his mother’s copy, mutated at the gene, and his father’s copy, with missing material somewhere close to the gene. It was as precise a diagnosis as you can get. UCLA’s lab re-ran the tests to make sure everything was right.
When the program’s diagnostic roundtable — a group of 30 or so UDN-associated doctors, bioinformatics staff, lab members, trainees and genetics counselors — reviewed the findings, there was a palpable sense of excitement. Everyone checked the work, and all agreed: They indeed had diagnosed Rylan Gowri.
“It all starts with a gene,” Dr. Martinez says. “That’s the magic of what happens here.”
Genetic counselor Rebecca Signer is coordinator of the Undiagnosed Diseases Network at UCLA and a key participant in the program’s work with patients and families.
DR. MARTINEZ AND HIS COLLEAGUES PREPARE CAREFULLY when it is time to tell families about what they have found. They know that although the result is impressive, there is another side to diagnosis — the family’s future. “At that moment of diagnosis, we share in the closure we hope we communicate to families,”
Dr. Martinez says. “But then we realize it’s not the end for them.” For the family of a sick child, after all, a diagnosis of a rare genetic disease means a more determined fate — a future with an illness that likely will be with them for the rest of their lives.
While learning the diagnosis for what previously was a mystery disease can be cathartic, that knowledge also carries with it a significant burden. During their research into Rylan’s case, the UCLA team found 10 other families in the U.S. with children who had a similar diagnosis. Most of them were highly disabled. The Gowris now must contend with knowing that if they have more children naturally, each new baby would have a 25 percent chance of inheriting Rylan’s condition. If in vitro fertilization, combined with preimplantation genetic testing, is used, it would greatly reduce the chance of this disease in subsequent pregnancies.
Genetic counselor Rebecca Signer, coordinator of the UDN at UCLA, has worked with Dr. Martinez to help plan such meetings, discussing psychological considerations and drafting handouts and other materials to help families understand their diagnosis and potential treatments. When she called the Gowris to invite them in to talk, Ishani initially thought that, rather than being given news of a diagnosis, they would be told that nothing had been found. “I thought we’ll go in, they’ll tell us they didn’t find anything and then we’ll move on,” she says. Ram, on the other hand, had an inkling of what was to come. “I come from a medical family,” he says, “and most of the time, when you get a phone call from a doctor, it’s not a negative result — it’s something.”
On the morning of February 11, 2019, Ram and Ishani walked into Dr. Martinez’s office and settled into chairs opposite him and Signer. Dr. Martinez spoke first.
“Well, the diagnosis we found …,” he began. Before he could finish, Ishani burst into tears. Dr. Martinez paused and smiled.
“I didn’t believe it. I didn’t believe they had done it,” Ishani says.
Dr. Martinez started again, explaining Ram’s genetic contribution, the deleted DNA, and Ishani’s contribution, the faulty gene. He explained how this would have caused Rylan to develop his current symptoms. Signer showed them the handouts.
“The most interesting part was the combination of the gene deletion and the misspelling [on the DNA segment],” Ram says. “And there wasn’t a name for the disease; it was SLC25A46, and that
in itself took a few hours to memorize.”
While finally identifying what is wrong with their son was a relief for Ram and Ishani, Dr. Martinez also had to explain to them that there currently is no treatment or cure for Rylan’s condition, which is true for almost all patients with a rare and previously undiagnosed disease. That, says Dr. Nelson, often can be the hardest
part. “Telling a parent why his or her child is sick is very meaningful and necessary, but it can be hollow if we don’t have the next step, which is what to do to repair it,” he says.
Dr. Martinez reassured the Gowris that “UCLA would still be their team.” They could continue to see their UCLA neurologist and neuro-optometrist, who now would be armed with greater knowledge about Rylan’s condition. And UCLA would continue to seek out experimental therapies or medicines that might help Rylan.
Ram and Ishani left Dr. Martinez’s office a bit overwhelmed, but optimistic. “Emotions were all over the place,” Ishani says. “Overall, it was a good experience.”
ALTHOUGH DR. MARTINEZ COULD NOT OFFER RYLAN ANY TREATMENT, THE GOOD NEWS IS that there are a number of precision medicine techniques for treating rare diseases in the works. UCLA is using its technology and experience to push these treatments into reality. Dr. Nelson, for example, currently is testing a custom drug for another patient with a rare genetic mutation like Rylan’s. The drug is an RNA therapy that works by altering the RNA of mutated genes to restore protein expression. Such drugs usually are developed only when they will benefit a large number of people, but advances in genomics technology point to the possibility that one day these drugs could be individualized based on the specific gene sequence of the individual and the exact mutation or mutations identified. Researchers elsewhere on the UCLA campus are conducting similar work.
Sometime in the near future, perhaps, a diagnostic meeting such as Dr. Martinez and Signer had with the Gowris also will include a genetically personalized treatment plan. In that way, the California Center for Rare Diseases at UCLA and the UCLA Institute for Precision Health would lead in the field of precision medicine and serve as a model for the future of clinical diagnostics.
“At the end of the day,” says Dr. Lajonchere, “this is about giving patients hope.”
For now, the Gowris have a diagnosis, and they have their family’s future to consider. “Many times, diagnosis is the beginning of a new journey, with its own challenges,” Dr. Martinez says.
A new journey, yes, but after their experience at UCLA, the Gowris feel, finally, that they have some stability. “We still have bad days, but we don’t have days where we wonder if we are going to have to call 911 again” because they don’t know the underlying reason for what is happening to their son, Ram says.
Life continues. During a recent physical therapy session, Rylan reached out with his arm and swept a nearby glass off a table, sending it crashing to the floor. In spite of the broken glass, such directed movement was a major leap for him. He also has started to stick out his tongue to signal that he is ready to eat — a precursor to improved eating and, perhaps, even talking.
It still is hard, but every advance, no matter how small, offers a glimmer of hope. “Rylan has changed our lives because he’s given us such a different perspective on things,” Ishani says. “And he’s also given us a community and a purpose.”
Casey Rentz is a science writer in Los Angeles. Her work has been published in New Scientist, Smithsonian, The Scientist and NPR, and her story “How to Stop a Hurricane” was included in The Best Science Writing Online 2012 (Scientific American / Farrar, Straus and Giroux).
For more information about the California Center for Rare Diseases at UCLA and the UCLA Institute for Precision Health, go to: uclahealth.org/precision-health