Phenylketonuria trial boosts natural enzyme
Autopsies suggest a biological cause for SIDS
Kim Stiles has to weigh and measure her 3-year-old son's foods every day—even counting the number of Goldfish he eats for a snack—to ensure he doesn't get too much of the amino acid phenylalanine, or "phe." Her son, Theo, can't have any high-protein foods like dairy, meat, beans or nuts, and can have only tightly controlled amounts of other foods. Theo is lucky in that he has a relatively mild form of phenylketonuria, or PKU, a genetic disease in which the enzyme that breaks down phe, called PAH, is missing or damaged. Still, Theo's blood needs to be monitored weekly, and unless his phe level is kept in check by sticking to the strict diet, it can become dangerously high, causing brain damage and mental retardation.
But now, an international study led by Children's Hospital Boston suggests that some patients with PKU can lower their phe levels with a drug called BH4, allowing them to ease up on or even abandon their strict diets. BH4 is a chemical cousin of a natural co-enzyme that boosts the action of PAH and can potentially help the body break down phe.
"Some people with PKU have such a severe genetic defect that they don't even make PAH, or the enzyme is so deformed that it doesn't function," explains Harvey Levy, MD, in the Division of Genetics, who directs Children's Maternal PKU Program. "In these cases, BH4 won't help."
In his Phase III trial, 89 patients with PKU who were known to respond to BH4 received either a BH4 pill or a placebo. All patients were asked to continue with their special diets. Before treatment, 17 percent of the BH4 group and 19 percent of the placebo group had blood phe levels in the desired range. After six weeks of treatment, these proportions rose to 54 percent in the BH4 group, versus just 23 percent in the placebo group.
BH4 is now being reviewed by the Food and Drug Administration and could be approved by the end of 2007.
"If Theo is allowed to get BH4, he'll be able to eat a piece of pizza and not have to worry about taking off all the cheese," says Stiles.
An autopsy study led by Children's Hospital Boston provides the strongest evidence yet that the cause of sudden infant death syndrome (SIDS) is not a mystery after all, but rather has a biological basis. Neuropathologist Hannah Kinney, MD, neuroscientist David Paterson, PhD, and colleagues found that babies who die from SIDS have abnormalities in the brainstem, the part of the brain that regulates breathing, blood pressure and arousal.
The researchers examined brainstem tissue from 31 infants who died from SIDS and 10 who died from other causes. The SIDS infants had an abnormally high number of serotonergic neurons, which are nerve cells that make and release serotonin, one of the brain's messaging chemicals, but these neurons were more likely to be under developed. They also didn't have enough of a protein that "recycles" serotonin, and they were deficient in a certain type of serotonin receptor. Interestingly, male SIDS infants had significantly fewer of these receptors than female SIDS infants, perhaps explaining why SIDS strikes boys twice as often as girls.
Kinney and Paterson believe that defects in the brainstem serotonin system may impair natural reflexes that protect against asphyxiation. When babies sleep face-down or have their faces covered by bedding, they may re-breathe exhaled carbon dioxide (CO2). Normally, rising CO& levels activate nerve cells in the brainstem, which then stimulate the brain's respiratory and arousal centers. The baby then wakes up, turns its head and breathes faster to get more oxygen. SIDS babies, however, may fail to rouse. The researchers now hope to develop a diagnostic test to identify infants at risk.
The study, widely reported by the media, appeared in the November 1 issue of The Journal of the American Medical Association.