The Impact of High Phenylalanine Exposure on Brain Structure in Adult Phenylketonuria Patients

Background

Phenylketonuria (PKU) is a rare hereditary metabolic disorder characterized by a deficiency of phenylalanine hydroxylase, leading to elevated levels of phenylalanine (Phe) in the blood and brain. If Phe levels are not strictly controlled during childhood and adolescence, the condition can result in severe intellectual disability. Although early diagnosis and treatment can partially mitigate these consequences, studies have shown that even early-treated PKU patients still exhibit subtle cognitive changes and brain structural abnormalities, particularly in the white matter (WM). However, further research is needed to understand the impact of high Phe exposure on the brain structure of adult PKU patients.

Source of the Study

This study was conducted collaboratively by multiple departments of Inselspital, Bern University Hospital, and the University of Bern, including the Departments of Diabetes, Endocrinology, Clinical Nutrition and Metabolism, the Support Center Advanced Neuroimaging (SCAN), and the Swiss Institute for Translational and Entrepreneurial Medicine (Translational Imaging Center). The research was published in the Brain journal by Oxford University Press.

Research Methods

The study employed a double-blind, randomized, placebo-controlled crossover trial design to evaluate the impact of four weeks of high Phe exposure on the brain structure of early-treated adult PKU patients. It also examined the relationship between these structural changes and cognitive performance and metabolic parameters. The specific study procedures are as follows:

1. Participant Selection: 28 early-treated classical PKU patients aged 19-48 years were selected. Participants had to meet certain exclusion criteria, such as no high Phe diet within the past six months and no other conditions or medications that could affect the study results.

2. Randomization and Intervention: Subjects were randomly divided into two groups. One group received the high Phe intervention first (1500-3000mg Phe daily), followed by the placebo; the other group had the reverse order. Each intervention period lasted four weeks, with a four-week washout period in between.

3. Data Collection: MRI scans were performed at four time points (before intervention and after four weeks of intervention) to collect T1-weighted images for structural analysis using the DL+Direct deep learning tool. ^1H MRS was used to measure brain Phe levels, and blood samples were taken at each time point to measure Phe, tyrosine, and tryptophan levels. Cognitive performance tests for attention and executive functions were also conducted.

Study Results

The study found key results as follows:

1. Elevated Phe Levels: Blood Phe levels significantly increased after the high Phe intervention period (from 873µmol/l before intervention to 1441µmol/l).

2. Brain Structural Changes: Compared to the placebo period, the high Phe period resulted in significant reductions in cortical thickness in 17 regions out of 60 brain areas (such as the right frontal lobe and the left lingual gyrus). Additionally, there was a significant increase in both left and right brain white matter and ventricular volumes.

3. Effects on Cognitive Performance: Although most correlations between cortical thickness changes and cognitive functions did not pass strict FDR correction, the overall trend indicated that cortical thinning was associated with cognitive decline.

4. Relationship Between Metabolic Parameters and Brain Structure: Blood and brain Phe levels were significantly correlated with increases in white matter volume (rs=0.43-0.51, p≤0.036). Furthermore, reductions in cortical thickness were also associated with elevated Phe levels.

Conclusion and Significance

This study provides important evidence that four weeks of high Phe exposure can lead to decreased cortical gray matter and increased white matter volume in adult PKU patients. However, these structural changes revert to baseline levels during the washout period, suggesting they may be reversible when Phe levels are reduced. This finding underscores the importance of controlling Phe levels in PKU patients to maintain brain health and cognitive function.

Study Highlights

1. Unique Methodology: For the first time, a randomized, placebo-controlled crossover trial design was used, combined with advanced MRI analysis techniques, to scientifically validate the short-term effects of high Phe exposure on the brain structure of adult PKU patients.

2. Evidence of Structural Changes: Although deemed temporary, the study revealed significant brain structural changes due to high Phe exposure, particularly reductions in cortical gray matter and increases in white matter volume.

3. Potential for Recovery: The finding of brain structural changes reverting upon lowering Phe levels provides hope for developing new treatment strategies to protect brain health in PKU patients.

Future Research Directions

Future research should further explore the long-term impact of high Phe exposure on brain and cognitive function in PKU patients, especially those who have difficulty controlling Phe levels effectively. Additionally, studies involving pharmacological interventions, such as tetrahydrobiopterin (BH4), can help understand brain structural changes under extremely low Phe levels.