Professor Calls for More Research into Rare Brain Disorder
New research into a relatively rare genetic brain disorder finds the effects appear to be more extensive than previously thought and that current treatment regimens are insufficient. Shawn Christ, an associate professor in the Department of Psychological Sciences and director of the University of Missouri Brain Imaging Center, has been studying phenylketonuria (PKU) and its effects on neural and cognitive abilities for 12 years. PKU is an autosomal recessive disease (both genes are recessive or mutated) that occurs in one of every 10 to 15 thousand people in the U.S.
A typical individual ingests phenylalanine, a common amino acid in proteins such as meat and dairy products, which metabolizes into tyrosine, a precursor to dopamine and other important neurotransmitters. People with PKU, however, have an absence or mutation in an enzyme called PAH, which is required for the metabolism of phenylalanine into tyrosine. As a result, phenylalanine levels can rise to toxic levels in the body, leading to severe cognitive and neurological problems.
PKU was discovered in 1934, but a clinical blood test was not developed until 1960. By the late 1960’s, most states required PKU testing at birth, which is why untreated cases of PKU are rare today. Researchers found that restricting the dietary intake of phenylalanine of individuals with PKU limited the neurological and cognitive damage to the point where most individuals could function relatively normally in society.
“So there’s this false belief about PKU that we’ve solved it—we identify them at birth, we put them on this special diet, and they do okay,” Christ says. “But as we’ve done more research, we’ve discovered that it’s not that simple for a couple of reasons. Even if you bring down phenylalanine levels, you still have a dopamine deficiency and dopamine is an important neurotransmitter. Additionally, staying on the diet is extremely difficult, and even on the diet your phenylalanine levels are at least three to four times higher than normal, and there are consequences associated with that.”
Until now, Christ says most research on PKU has focused on the impact on the brain’s white matter—the neural pathways of the brain that are responsible for the transfer of information between different parts of the brain. PKU-related abnormalities are fairly easy to see in white matter, but much less attention has been paid to the potential effects of PKU on other aspects of the brain such as gray matter. Gray matter is located on the surface of the cerebral cortex and also includes deep brain structures such as the thalamus and basal ganglia. Whereas white matter is involved in the transfer of information, gray matter is where the processing of such information occurs. Recently, Christ and his team utilized advanced MRI techniques to examine in detail the effects of PKU on the brain’s gray matter.
“Going into this study, our hypothesis was that we were going to see abnormalities in the frontal cortex, because individuals with PKU are at risk for having difficulties with abilities such as strategy use and planning that are known to rely on that brain region. However when we analyzed the data, we were surprised to see abnormalities in the posterior brain instead,” Christ says. “The more we thought about it, the more this finding made sense given the inter-relationship between white matter and gray matter, and the fact that white matter abnormalities also tend to be more pronounced in the posterior regions of the brain. What we are trying to say is we do not know everything about this disorder, and something like diet, that we used to think was sufficient to treat PKU, is not enough.”
Christ’s current study was funded by the National PKU Alliance, a national non-profit organization that provides support and advocacy for families affected by PKU. Previous research in his lab has been funded by BioMarin Pharmaceutical, a company that develops and manufactures potential treatments for PKU and other rare diseases. Going forward, Christ says there are three areas of research that he wants to pursue: studying the impact of PKU in early development more extensively, studying the impact of PKU on the brain and cognition in advanced aging, and studying siblings who are carriers of PKU. Later this month, Christ and other representatives of the National PKU Alliance are scheduled to meet with leaders of the National Institutes of Health to discuss the need for additional research on PKU and the brain.