Finding "Inborn Errors of Metabolism"

The scenario Dr. Rinaldo describes is an inborn error of fatty acid metabolism, a genetically determined failure to break down fatty acids that makes it dangerous for the child to go without eating. This condition leads to severe episodes of what physicians call "metabolic decompensation" and could be life-threatening. For example, an otherwise healthy child could have the familiar signs and symptoms of an upper respiratory infection and die suddenly and unexpectedly shortly after.

The mechanism underlying these disorders is explained by the failure of critical systems (heart, liver) to utilize fatty acids for energy production. Once the correct diagnosis is made, the treatment is simple and highly effective, based on a schedule of frequent feedings and strict avoidance of fasting, plus aggressive preventive measures when the patient is sick for other reasons. "Such metabolic disorders can be quite difficult to detect. The very recent discovery of many of these disorders and the intermittent nature of their manifestations are significant obstacles to the prompt referral of a patient to a specialized center," Dr. Rinaldo says. "As a matter of fact, you cannot diagnose what you don't know, and unfortunately a large proportion of cases remain undiagnosed because these disorders are not yet included in mainstream medical practice."

Dr. Rinaldo says one of his functions at Mayo is to provide a resource to his pediatric colleagues who may not always be familiar with metabolic disorders of this kind. Dr. Rinaldo says the biggest benefit to being at Mayo is the opportunity to investigate a large number of cases. "I am able to compare the clinical and laboratory findings of multiple cases affected with the same relatively rare disorder, and get a better idea of the natural history, response to treatment, and long-term prognosis of a given disease." Sometimes genetic disorders in children can cause problems that may appear to be abuse. That was the case when Dr. Rinaldo was called to serve as an expert witness in the case of a Missouri mother wrongly accused of murder several years ago.

Patricia Stallings had found her infant son listless and lying in his crib, his lips tightly shut. The baby boy had already experienced problems with vomiting. Physicians placed him on a respirator but could not determine what was wrong with him. A test, later proved to be in error, showed that Ryan had ingested ethylene glycol, an active ingredient in antifreeze.

Even when he died at 5 months of age, physicians were not sure what caused his death. Mrs. Stallings was tried for his murder, found guilty and sent to prison. In the meantime, she had given birth to another baby boy, who was immediately placed in foster care. That child, too, started having symptoms similar to those Ryan had experienced. (Later, it would be determined that the surviving boy must be fed a special diet, using a stomach tube.)

Fortunately for Mrs. Stallings, a biochemist at St. Louis University who had followed the case in the newspapers conducted tests on Ryan's blood serum, which had been stored at a lab there. The biochemist suspected that Ryan may have had methylmalonic acidemia (MMA), a rare genetic disorder in which the body does not break down proteins properly. He was correct. The biochemist, and another university official, contacted prosecutors.

Dr. Rinaldo, then an assistant professor of genetics at Yale University, was called upon in the case and concurred that Ryan did indeed have MMA. Mrs. Stallings was released from prison after 14 months when the prosecutor asked the judge to dismiss the murder charge. Some of Dr. Rinaldo's colleagues are doing genetic pediatric research that is expected to have applications in the more distant future.

Cell Exploration

Grazia Isaya, M.D., Ph.D., is the Director of the Mitochondrial Genetics Lab. Mitochondria are known as the "powerhouse" of the cell, as they represent the main source of energy for all cellular functions. Inside mitochondria, the energy derived from oxidation of foods is channeled into formation of high-energy compounds that are used by the cell in the synthesis of all types of essential molecules.

More than 1,000 genes are believed to be required to maintain this process, but only a small fraction have been identified thus far. Mutations in these genes can lead to a variety of diseases, including mitochondrial cytopathies, neurodegenerative diseases, and cancer. The aging process itself appears to result from disturbances in mitochondrial energy production. Dr. Isaya is interested in the characterization of the molecular mechanisms underlying mitochondrial energy production and how defects in these mechanisms can ultimately result in disease.

Her lab uses the yeast known as Saccharomyces cerevisiae and mice as working models. In these organisms, one can easily mutate specific genes and create mutants with defects in mitochondrial functions. The analysis of these mutants can provide information useful for the diagnosis and treatment of patients with mitochondrial defects. While her research can be difficult to explain to those outside of the medical profession, another colleague at Mayo Clinic Rochester works on a syndrome that has received a lot of media attention.

Investigating Sudden Death Syndromes

Dr. Michael J. Ackerman, a pediatric cardiology fellow, works to gain an understanding of sudden cardiac death in children. "We have learned a lot about this in the last 10 years, and there is much more to be learned," he says.

Dr. Ackerman's work looks at the ion channel, or "electrical tunnel of the heart," which is responsible for the heart's rhythms. One abnormality of the heart known as "long QT syndrome" that his work centers upon can be dangerous. "The person with long QT syndrome feels like they have a bomb in their heart," he says. "They don't know if it's ever going to detonate, when it will detonate, and what the results will be when it does detonate."

Dr. Ackerman says 5 to 10 percent of people with this syndrome die suddenly as the result of it. Another third of those faint as the result of the abnormality. However, depending upon when the person faints, consequences can be serious. For example, swimming is believed to be one of the triggers for development of irregular heart rhythms in patients with long QT syndrome. In some cases, drowning victims were later found to have fainted while swimming, the result of having the syndrome.

Other triggers are some sounds, emotion, and activity. "We don't know for sure what will be the particular trigger for any given patient," Dr. Ackerman says, adding that he hopes routine blood tests for the syndrome will be in place by the year 2010. "In the future when we know more, we can determine what the triggers will be and then work to counter them."