MUTATION MAY EXPLAIN
SOME SUDDEN INFANT DEATHS

WINSTON-SALEM—Deletion of a gene essential for metabolizing long-chain fatty acids may explain some cases of sudden death in human infants. Newborn mice who had been genetically altered to lack the gene for mitochondrial trifunctional protein (MTP) showed no outward signs of physiological distress before sudden death, suggesting that genetic screening, in some cases, may be the best hope for targeting neonates for intervention.

Jamal A. Ibdah, MD, PhD, an Associate Professor of Internal Medicine at Wake Forest University School of Medicine in Winston-Salem, and colleagues recently reported the effects of deleting the gene for MTP, which normally catalyzes three steps of long-chain fatty acid metabolism, in mice.[1] “None survived past 36 hours, showing that the enzyme is essential,” said Dr. Ibdah. “We tried measuring O2 saturation in the pups … and it appears that there’s no desaturation. No overt physiological signs preceded death, although our investigation showed that biochemical problems [were] already there.”

Knockout mouse pups completely lacking MTP had low birth weight and hypoglycemia, as well as abnormalities in serum markers of liver function.

The sudden neonatal death in the knockout mice resembles some instances of unexplained infant death. In addition to liver abnormalities, histologic specimens from dying or dead neonatal knockout mice showed considerable damage to myocytes: “There was significant necrosis just before death. There were degenerative changes in diaphragmatic tissue, and moderate to severe lesions in cardiac tissue. Cardiac arrhythmia, which has been found to occur in human infants with deficiencies in fatty acid metabolism, was probably the cause of death in these mice,” Dr. Ibdah said.

“This isn’t the answer to SIDS [sudden infant death syndrome],” he emphasized. MTP deficiencies may account for no more than 5% of unexplained infant deaths, based on the proportion of babies with SIDS whose biochemical profiles resembled those found in fatty acid oxidation disorders.[2] Defects in MTP occur once in approximately 38,000 human pregnancies.[3]

The knockout mouse model is the most severe form of genetic deficiency in humans, a complete loss of MTP, which causes cardiomyopathy or neuromyopathy. A more common class of mutations, which may cause a Reye’s-like syndrome, disrupts only one of MTP’s enzymatic functions. Beside affecting neonatal health, these fetal mutations may also contribute to maternal liver disease.[3]

HOPE FOR INTERVENTION?

“Our ongoing studies in humans are looking at developing molecular analysis techniques—that’s the most definitive way of diagnosing this disorder,” said Dr. Ibdah. Of course, screening all pregnancies for MTP mutations would be impractical. “We are trying to see if family history or other circumstances can be used to identify a subset of patients to screen. In cases of SIDS, I’d suggest a low-threshold test for fatty acid disorders, especially if the child had a sibling with SIDS.”

A prenatal test for MTP deficiency could provide options, Dr. Ibdah said. “We are able to identify the genotype at 10 weeks in pregnancies at risk and offer genetic counseling. If the pregnancy is followed through, perinatal care can be implemented. If you eliminate long-chain fatty acids from the diet, the child might survive.”

—Mimi Zucker, PhD