Scouting the Frontiers of Childhood Metabolic Disorder

OCTRI pilot project recipient explores rare childhood disease.

It’s time: After the bittersweet drama of labor and delivery, the precious newborn is in your arms—and a few days later, so are an unexpected letter and brochure warning not to let baby get hungry lest  she develop low blood sugar and experience seizures, coma or death.  And then you’re on your own.

That, more or less, has been the experience of many Alaskan Native parents since 2003, when newborn screening began for what was considered a rare metabolic deficiency. “At this point the Alaska State Department of Health, the Northwest Regional Screening program located here in Portland and the genetic consultants here at OHSU are asking, ‘What does it mean, how serious is it, what should we do about it?’” said Melanie Gillingham, Ph.D., assistant professor in Molecular & Medical Genetics and the Graduate Programs in Human Nutrition at Oregon Health & Science University (OHSU) and a fellow of the Native American Center for Health Research (NARCH) at the Portland Area Indian Health Board. “Is it related to infant mortality, higher morbidity from childhood illnesses, problems with routine surgeries? We don’t have definitive answers right now.” She and the Alaskan state government are determined to give affected families—who are often fairly isolated in remote villages—some sorely needed clarification and support.

Melanie had long known that a child with carnitine palmitoyltransferase 1A (CPT1A) deficiency is unable to metabolize stored fat efficiently enough to nourish the brain and nervous system. When no ingested food is available—such as during a bout of stomach flu or similar episodes of involuntary fasting—the child is in danger of losing consciousness, damaging the brain or nervous system, and even dying. The condition is caused by a genetic mutation that hinders this crucial liver enzyme’s ability to perform its usual fat-oxidation duty. Children are most acutely affected; their livers are still small in relation to body mass, and can easily be overtaxed.

Melanie had previously traveled to Alaska to present previous findings about related conditions to pediatricians and metabolic experts, and had built strong working relationships with the State Public Health Department and local institutions. Her contacts kept her informed that since October of 2003 approximately 80 Alaska Native infants have been identified with the deficiency; previously only 30 published cases were known worldwide. However, the version identified in Alaska differs from the “classic” deficiency: It reduces the enzyme’s activity to about 20 percent of normal, rather than practically zero. Melanie resolved to find out how this difference translates into management and treatment, because parents desperately need guidelines. For example, how long without eating is too long? Is there a safe length of time beyond dinner-to-breakfast?

The importance of researching this further was clear, but affected families were located far from any adequately equipped facility. Dr. Gillingham would need to bring them to her facility in Portland, Oregon, which meant finding funding and support for not only the research but also the travel and logistics. Dr. Gillingham applied for and was awarded $30,000 in pilot project funding from the Oregon Clinical and Translational Research Institute (OCTRI). 

Her first family arrived in spring 2009. That “arrival” part proved nearly as challenging as the science. Most affected families live in remote areas where they can’t simply hop in the car and drive to an airport. Melanie became an authority on small prop-plane services—just like in the movies—and their weekly schedules at village landing strips, as well as the best hotels in Anchorage to put up a family until their airline flight to Oregon. “It was educational for me,” said Melanie. The study requires keeping a three-year-old from eating for 18 hours (with appropriate safety precautions), which can be quite a challenge. Melanie brings in whole families not just because an older sibling makes a great “control group” (for non-invasive scans of liver fat), but also because family members are an essential part of the team that distracts the child as the hours of fasting wear on. She quickly learned, however, that the family factor cuts both ways: With a little one’s tummy rumbling, family members are often that close to caving in and offering food and drink before the study is complete. After a close call or two, she now asks parents and especially siblings to eat and drink only when they are well away from the study area.

The study also calls for a set of overnight blood draws (through an IV line that also provides hydration), which is among the study details that require more hands than Melanie has—along with writing medical orders, transporting families to pre- and post-study appointments and more. In addition to funding the study, OCTRI provides the support of a pediatric nurse practitioner and skilled pediatric research nurses – trained RNs who specialize in working with children and have experience with the requirements of an intensive research study. “I couldn’t do it without them,” said Melanie.

Melanie hopes this initial study and its pilot grant will lead to broader, more definitive studies funded by tribal, state, national and/or international entities, and a registry of affected children. (Canada, Greenland and other Arctic Circle countries are screening newborns as well.) This will involve a collaborative effort with tribal elders, doctors, and the State Health Department. “The first entity you have to report to is the tribe,” explains Melanie. “We’ll work with them to get word out to the population, whether that means sending bulletins to clinics, or something else. Ultimately we need to publish in a scientific journal—but for that you need tribal approval.”

Further studies would likely need to be done on location—and that’s fine with Melanie, who is of Native American ancestry herself. “I love Alaska; it’s a fascinating place with fascinating people. I’m really looking forward to visiting the northern parts where the tribes are located. I didn’t think of it as the frontier, but it really is way out there.” And clearly, that frontier is still ripe for discovery.

Dr. Gillingham participated in the Human Investigations Program (HIP) at OHSU, a curriculum designed to meet the growing need for clinical and translational investigators.

Learn more about the Human Investigations Program.