Affiliation:
1. Division of Metabolic Diseases University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital The Netherlands
2. Department of Laboratory Medicine Laboratory of Metabolic Diseases, University of Groningen, University Medical Centre Groningen The Netherlands
3. Department of Human Genetics Translational Metabolic Laboratory, Radboud University Medical Center Nijmegen The Netherlands
4. Laboratory of Clinical Chemistry and Hematology, Máxima Medical Centre Veldhoven The Netherlands
5. Department of Internal Medicine University of Groningen, University Medical Center Groningen The Netherlands
6. Department of Clinical Child and Adolescent Studies‐Neurodevelopmental Disorders Faculty of Social Sciences, Leiden University Leiden The Netherlands
Abstract
AbstractRecent studies in PKU patients identified alternative biomarkers in blood using untargeted metabolomics. To test the added clinical value of these novel biomarkers, targeted metabolomics of 11 PKU biomarkers (phenylalanine, glutamyl‐phenylalanine, glutamyl‐glutamyl‐phenylalanine, N‐lactoyl‐phenylalanine, N‐acetyl‐phenylalanine, the dipeptides phenylalanyl‐phenylalanine and phenylalanyl‐leucine, phenylalanine–hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate) was performed in stored serum samples of the well‐defined PKU patient‐COBESO cohort and a healthy control group. Serum samples of 35 PKU adults and 20 healthy age‐ and sex‐matched controls were analyzed using ultra‐high performance liquid chromatography quadrupole time‐of‐flight mass spectrometry. Group differences were tested using the Mann–Whitney U test. Multiple linear regression analyses were performed with these biomarkers as predictors of (neuro‐)cognitive functions working memory, sustained attention, inhibitory control, and mental health. Compared to healthy controls, phenylalanine, glutamyl‐phenylalanine, N‐lactoyl‐phenylalanine, N‐acetyl‐phenylalanine, phenylalanine–hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate were significant elevated in PKU adults (p < 0.001). The remaining three were below limit of detection in PKU and controls. Both phenylalanine and N‐lactoyl‐phenylalanine were associated with DSM‐VI Attention deficit/hyperactivity (R2 = 0.195, p = 0.039 and R2 = 0.335, p = 0.002, respectively) of the ASR questionnaire. In addition, N‐lactoyl‐phenylalanine showed significant associations with ASR DSM‐VI avoidant personality (R2 = 0.265, p = 0.010), internalizing (R2 = 0.192, p = 0.046) and externalizing problems (R2 = 0.217, p = 0.029) of the ASR questionnaire and multiple aspects of the MS2D and FI tests, reflecting working memory with R2 between 0.178 (p = 0.048) and 0.204 (p = 0.033). Even though the strength of the models was not considered strong, N‐lactoyl‐phenylalanine outperformed phenylalanine in its association with working memory and mental health outcomes.
Funder
Nutricia Research Foundation