Literature Review

New Insights Into Phenylketonuria’s Impact on the Brain



All infants are screened for a host of conditions at birth, such as phenylketonuria (PKU), an inherited disorder that increases the levels of the amino acid phenylalanine in the blood. PKU is rare, affecting only one in every 10,000 children in the United States. Currently, the primary way to manage the disease is through a restricted diet. A report published online ahead of print February 16 in Molecular Genetics and Metabolism explains how researchers are using MRI to learn more about the effects of this disorder on the brain and to enable the development of drugs that help treat and control the disease.

Patients with PKU cannot metabolize phenylalanine into tyrosine, a precursor of dopamine and other neurotransmitters. Without treatment, phenylalanine builds up and can cause problems with muscular control, seizures, behavioral problems, and intellectual disabilities. Once identified, patients with PKU are placed on a restricted diet that limits the amount of phenylalanine that they consume, thus lessening the impact of the disorder. Phenylalanine is found in many foods, especially those that are high in protein, such as eggs, milk, nuts, and meats, and in some artificial sweeteners.

“A majority of the studies surrounding early-treated PKU examined the effects seen in the white matter of the brain,” said Shawn Christ, PhD, Associate Professor of Psychological Sciences at the University of Missouri and Director of the Clinical Neuropsychology Laboratory, both in Columbia. “Yet only a handful of studies investigating the effects of PKU on gray matter have been conducted. We decided to add to the body of knowledge on this understudied aspect in those affected by PKU.”

Shawn Christ, PhD

Past attempts to examine the potential effects of PKU on gray matter have been few and have been limited by the available technology. In their most recent study, Dr. Christ and colleagues combined the most recent advancements in MRI imaging with the most sensitive detailed analytical techniques, including manual hand segmentation of the MRI data. Dr. Christ’s team spent nearly two years mapping the gray matter of more than 40 individuals with and without PKU and found evidence of gray matter abnormalities in individuals with early-treated PKU to be most severe in the posterior regions of the brain.

“To minimize these effects, it is important for someone with PKU to maintain dietary treatment throughout their lifetime, but especially during early childhood to help prevent irreversible brain damage,” Dr. Christ said. “However, even if you keep phenylalanine low, these individuals are still at risk for difficulties due to the lower-than-normal levels of dopamine associated with the inability to produce tyrosine. We think that our research has the potential to contribute to better understanding of the mechanisms underlying the abnormalities in brain and behavior associated with this disorder; thus, it may inform the development of new and exciting treatments for PKU.”

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