The Impact of Phenylalanine Elevations on Metabolic, Cognitive, and Neural Functioning in Adults Heterozygous for Phenylketonuria (PKU)

Phenylketonuria (PKU) is an autosomal recessive condition characterized by a deficiency in the ability to metabolize phenylalanine (Phe) into tyrosine (Tyr). Even with treatment, individuals with PKU experience higher-than-normal levels of Phe in the blood and brain. Whereas PKU is relatively rare (1 in 15,000 in U.S.), the rate of heterozygous carriers in the general population is much higher with an estimated incidence of 1 in 60 – representing approximately 5.5 million individuals in the U.S. Despite prior assumptions that such carriers were spared any adverse consequences, nascent evidence suggests that PKU carriers experience a marked reduction in their capacity to metabolize Phe. Previous work from our group has shown that elevated Phe levels in individuals with PKU are associated with significant cognitive and neurologic deficits including impairments in executive function (e.g., working memory), processing speed, attention, and fine motor control. Little is known, however, regarding the potential impact on heterozygous carriers, and whether carriers experience Phe-related disruptions in neurocognitive function. To begin to address this gap in the literature, we propose to conduct a principled investigation of the acute effects of Phe ingestion on metabolic, neurophysiologic, and cognitive markers in a sample of genetically-confirmed heterozygous PKU carriers (n=18) and non-carriers (n=18). A double-blind crossover study will be conducted in which participants perform an fMRI n-back working memory task, resting state scan, and a battery of select cognitive tests at 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo. Blood and brain levels of Phe and Tyr will also be assessed at each timepoint. The study’s specific aims center around the overarching hypothesis that PKU carriers will be less efficient at metabolizing the ingested Phe, which will result in higher and more prolonged elevations in blood Phe as compared to the non-carriers. Resulting elevations in brain Phe concentrations (Aim 1) will then lead to disruptions in neurocognitive processing as evidenced by poorer cognitive performance (Aim 2), atypical patterns of neural activity (Aim 3a), and decreased functional connectivity (Aim 3b). The present work has potential to significantly impact health guidelines and personalized medicine for a significant portion of the general population (1 in 60 of whom are PKU carriers). For example, high protein weight loss diets may be contraindicated for heterozygous carriers of PKU. The present study would also increase our scientific understanding of PKU as well as foster the emergence of several lines of related research (e.g., elucidation of the precise neurophysiologic mechanisms by which non-PKU variants of PAH have an impact on behavior and cognition). Project Number: 1R21HD115129-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Shawn Christ | Institution: UNIVERSITY OF MISSOURI-COLUMBIA, COLUMBIA, MO | Award Amount: $255,343 | Activity Code: R21 | Study Section: Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section[NPAS] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HD11512901A1