A rare trait leads family to save their sons
Posted 12:03 a.m. Sunday
NEW ORLEANS — Jody and Julia Taravella's two sons, Daniel, 22, and Alexander, 16, share a rare trait that is killing them.
Born happy and healthy in Belle Chasse, Louisiana, both boys were soon misdiagnosed with Autism and ADHD because of their language and speech delays, slow learning processes and motor functions. They also suffer from allergies, infections, low muscle tone, diarrhea and short attention spans.
Mom Julia instinctually knew something else was going on.
"For 16 years we tried to find what was actually causing these Autistic behaviors in our sons," she said. "They were given ADHD medicine, but it didn't help. I never gave up. We searched and searched and finally found they both lacked an enzyme, which was the cause of their Autistic behavior and symptoms."
Aspartylglucosaminuria (AGU) is a rare, fatal, childhood metabolic disorder where the body lacks aspartylglucosamidase (AGA), one of the lysosomal enzymes. The enzyme is required to break down some sugars attached to proteins (glucoproteins). The excess toxic sugar waste builds up in body tissues, the liver, spleen, thyroid and brain. The process is gradual but damages the tissues and organs progressively destructing cells.
Life expectancy is 25-35 years of age. Death is usually due to infection. There is no cure.
As the Taravellas try to beat the clock to find a cure, their 501(c)(3) Rare Trait Hope Fund is raising hundreds of thousands of dollars for gene therapy and small molecule therapy to deliver the needed AGA enzyme to their sons' body cells, and to countless others who suffer from rare diseases that could be cured by similar medical breakthroughs their nonprofit is financing.
As tragic as the situation, is the Taravella's journey to discovery.
For 16 years, Julia, a chemical engineer with Shell, and Jody, a retired Oil & Gas industry senior analyst, sought answers from more than 20 pediatricians, internal medicine doctors, geneticists, allergists, gastroenterologists, psychiatrists, psychologists and eye doctors all around the globe from the U.S. to Canada, England, France and Germany.
Julia enrolled in online classes to learn about genetics and created a program to analyze gene sequencing data from everyone in the family. That's when she found the abnormality.
In February 2012, Julia reached out to multiple doctors to confirm her theory that her kids had AGU. The disease had been documented since the 1960s, but no cure has ever been found.
"It was pretty bad in the beginning when we were told nothing can be done for the children," Julia said. "We fought so hard and went so far to find out what was wrong. And when we were told there was no cure, we knew we had no choice. If there was a cure, we were going to have to find it ourselves."
"We went to doctors, my wife diagnosed the disease, you do what you have to do for your kids," Dad Jody said. "There's this sense of urgency when the doctors tell you you're going to outlive your kids."
For the next six months, the Taravellas interviewed research groups who could take what the family found about the boy's genes and create a treatment or cure for them.
Steven Gray, Ph.D., at the University of North Carolina's Gene Therapy Center, agreed to work on the disease to create a way to replace the missing enzyme. A possible treatment is currently going through final rounds of animal testing.
The Taravellas also found Prof. Ritva Tikkanen, Ph.D., at the Justus-Liebig University Giessen in Germany, who is capitalizing on a small molecule treatment that has already been safety tested to activate the dormant enzyme. The paperwork in underway and clinical trials are expected to start within the next six months.
"In some cases, the mutated enzyme is in principle still functional, but it is not activated in a proper manner," Dr. Tikkanen said. "This is due to mainly small mistakes in the three-dimensional structure or conformation of the enzyme. We need to find means of giving the mutant protein the final kick on its way to an active enzyme, so that it can eventually do what it is supposed to, degrade glycoasparagines. This can be done with small molecular compounds called pharmacological chaperones.
"The compound that we are planning to test is actually already in clinical use for another completely unrelated pediatric disease," she said. "The exciting point is that the compound seems to be able to reactivate mutant enzymes that are structurally and functionally completely unrelated. We do not know exactly how this compound works, but it might make the sick cells less sick, and improve the general state and survival of the cells."
Julia said small molecule therapy addresses the boy's lysosomal storage disorders and has the potential to clear their organs of the toxic byproducts. "Hopefully it will reverse the behaviors, and the boys can both live normal lives and make a 100 percent recovery," she said.
In the last four years, the Taravellas also had to establish ties with an M.D. to facilitate and be the lead medical investigator of the studies to bring the research together and get Institutional Review Board approval.
"Tulane doctors are caring for patients with AGU," Eva Morava-Kozicz, M.D., Ph.D., a Professor of Pediatrics and clinical biochemical geneticist at Tulane University's Hayward Genetics Center, said. "Upon Tulane IRB approval a dietary trial with a specific food supplement, which has been shown already to give positive therapeutic effect in these patients' cells, can be tried out in a prospective interventional clinical study. Our department at Hayward Genetics has past experience in clinical trials in inborn errors, including lysosomal storage disorders, but also using food supplements in clinical trials. We are in the process of designing the trial and have approval from the ethics committee.
"Julia is a super mother and a good scientist, and she has been successful in leading us clinicians to the right direction of the proper diagnosis," Dr. Morava-Kozicz said.
Julia and husband Jody, both directors of their Rare Trait Hope Fund, have raised $500,000 in the last three years to go towards AGU research. Their goal is to raise at least $30,000 at the upcoming "Wildest Dreams" gala, and another $3 million to finish testing for both the gene therapy and small molecule therapy that can save their sons' lives.
"Our nonprofit is volunteer driven where 100 percent of monies collected go straight to medical research and clinical trials," Jody said. "All donations are tax deductible. We're on the verge of an important breakthrough not just for this disease but other rare diseases.
"We're fortunate in a lot of ways," he said. "We're close to a clinical trial. This could help millions of people, but we need the funding. The work we're doing can be applied to other rare diseases that many in the medical field have deemed too rare to care."
"AGU is a very rare metabolic disease, also called an 'orphan' disease," Dr. Morava-Kozicz said. "In these disorders usually no large pharmaceutical company is involved in developing treatment because there won't be a big market for it."
There are about 300 diagnosed cases of children and young adults with AGU around the world. Most of them are in Dr. Tikkanen's home country of Finland. There, one in 18,500 are born with AGU and one in 81 are carriers of AGU. Dr. Tikkanen thinks the number of undiagnosed cases probably range in the thousands.
"The biggest obstacle is surely the lack of funding for research aiming at understanding the molecular basis of these diseases and eventually finding a cure," Dr. Tikkanen said. "If it is too rare, 'why should we care' seems to be the motto. The therapy trial for AGU patients will hopefully start by the beginning of 2017. if we manage to scratch together the required funding. I would rather have started yesterday, but the funding is still the major point."
"I don't think we're special," Jody said. "We're not geniuses, but when you put your mind to do something, you do it. After learning what we learned about gene therapy, I believe the majority of rare diseases can be cured in just a few years and give back quality of life to millions of people."
"I don't think I would ever have restarted doing AGU research without Julia," Dr. Tikkanen said." She basically talked me into it, although I think it was not that difficult at the end. I have done my Ph.D. work on AGU, this was more than 20 years ago, but there still was a corner in my heart for AGU. And look where we are now, hopefully close to testing the first therapy. This should encourage all parents not to give up but keep pushing."
"The real low point was after 16 years of searching for answers and finally finding one we were told there was no cure and no one was working on a cure," Julia said. "We felt abandoned. We felt that nothing could be done. Now, every couple of months I get to meet other parents with kids who were just diagnosed with AGU, and I get to give them hope and say something can be done and there is a possibility of a cure that can help their kids as well as mine."