Correcting the cofactor. Infants in the United States are routinely screened at birth for phenylketonuria (PKU), an inherited metabolic disease in which phenylalanine, an amino acid present in protein-rich foods, cannot be properly metabolized. Although it is a relatively rare disorder, affecting about one in every 10,000 American children, it is urgent to identify and begin treatment soon after birth to avoid the severe mental retardation and other neurological problems that can result. Current treatment is a strict, lifelong diet that eliminates meat, milk, fish, poultry, eggs, and other high-protein foods.
Recently, a new chemical link in the metabolism of phenylalanine has been identified by John Caradonna, a CAS associate professor of chemistry, and this discovery may someday allow more dietary choice and more normal lives for people with PKU.
It has been known for some time that an enzyme called phenylalanine hydroxylase (PAH) is responsible for the metabolism of phenylalanine into tyrosine, an amino acid that is important for the production of melanin and adrenaline in the body. Caradonna and his colleagues, including researchers at Stanford University, have been studying this process, looking closely at the active site in PAH, the place where phenylalanine and a cofactor -- pterin -- bind and initiate a series of reactions. Using detailed spectroscopic studies, they found that even though the phenylalanine is positioned properly in the active site of two mutations of PAH known to induce PKU in humans, defects in pterin binding (positioning) disrupt the entire sequence of chemical events. Rather than producing tyrosine, the chemical reaction yields hydrogen peroxide, which then easily decomposes into free radicals that can inactivate the PAH or disrupt other chemical reactions in the body.
By introducing sterically modified synthetic pterins into the system, the researchers hope ultimately to find a method to reestablish normal PAH activity in individuals with this genetic defect.
This research appeared in the May 14 issue of the Journal of the American Chemical Society. It can be found online at: http://pubs.acs.org/cgi-bin/article.cgi/jacsat/2003/125/i19/html/ja029106f.html.
Brain trauma. More than 40 percent of households where domestic violence occurs contain children under the age of 12, each year exposing more than 10 million children in the United States alone to violence between their parents or significant caretakers. When these figures are considered in light of recent findings in neurobiology that indicate that trauma causes structural and chemical changes in the brain, including the cortex (the site of rational thinking), the hippocampus (memories and emotion), and the amygdala (emotional control), as well as the production of hormones associated with altering mood and behavior, it is clear that the toll domestic violence takes on children and on society is staggering.
Karestan Koenen, a MED assistant professor of psychiatry, has recently completed a study that reveals that domestic violence also significantly impairs children’s intellectual abilities.
In the first study to employ twins to control for genetic influences on IQ, Koenen and her colleagues at the Institute of Psychiatry in London tested more than 1,000 pairs of five-year-old identical and fraternal twins. They found that the IQs of children exposed to high levels of domestic violence were eight points lower on average than those who had no family history of violence.
“This finding is important because low IQ at age five is a significant risk factor for negative outcomes, such as school failure and later, juvenile delinquency,” Koenen says.
The authors point out that although eight IQ points does not sound like a large deficit, it represents a delay in mental development of six to nine months. Compared to a scale of physical growth, the mental deficit is the equivalent of three inches on the height chart for five year olds -- a deficit that doctors would take very seriously.
The researchers believe that interventions to reduce domestic violence may be of benefit to children’s cognitive development and potentially prevent some of the long-term adverse consequences for these children.
This research was reported in the spring 2003 issue of Development and Psychopathology.
Briefs" is written by Joan Schwartz in the Office of the Provost. To read
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