Work-Influenced Circadian Disruption Connected to Disease Risk but Not Microbiomes in a Cohort of Philadelphia Nurses.

Phenylketonuria (PKU; OMIM 261600), a rare metabolic disorder first identified by Asbjørn Følling (1934), results from a biallelic mutation in the autosomal recessive gene encoding the enzyme phenylalanine hydroxylase (PAH, EC 1.14.16.1) [, ]. PAH, which is primarily located in the liver and to a lesser extent in the kidneys, catalyzes the conversion of the amino acid phenylalanine (Phe) into tyrosine (Tyr) [, ]. When PAH is dysfunctional, Phe accumulates in blood and brain [, ]. Elevated plasma levels of Phe can competitively inhibit the transport of other large neutral amino acids, leading to reduced availability of neurotransmitter precursors including those for dopamine and serotonin, which subsequently can impair brain function [, ]. Moreover, high Phe levels are considered to be toxic to brain cells [, ]. Hence, unmanaged PKU can lead to a range of brain‐related problems, including developmental delay, microcephaly, seizures, and various functional deficits [, ] (Figure ). Schematic overview of phenylalanine metabolism, neurotransmitter deficits, and behavioral phenotypes in phenylketonuria (PKU) mice. Phenylalanine (Phe) is normally converted to tyrosine (Tyr) by phenylalanine hydroxylase (PAH) using tetrahydrobiopterin (BH4) as a cofactor. In PKU, impaired enzyme activity causes Phe accumulation and reduced Tyr availability (left panel). Elevated blood Phe also competes with Tyr and tryptophan (Trp) for transport across the blood–brain barrier via the large neutral amino acid transporter 1 (LAT1), thereby reducing brain Tyr and Trp availability and limiting downstream synthesis of dopamine, norepinephrine, and serotonin (5‐HT) (middle panel). These neurochemical changes are associated with behavioral deficits in PKU mice, including impaired cognitive functions, increased anxiety‐like behavior, locomotor abnormalities, and changes in other behavioral functions such as general activity and nest‐building (right panel). For each behavioral domain, a single representative paradigm is illustrated; additional established tasks/assays as can be found in Tables , , , within each category are omitted for clarity (denoted by “...”). The most prevalent and well‐documented symptom of untreated PKU is intellectual disability, alongside other behavioral disturbances such as social deficits [, ], emotional functioning [, ], and restlessness [, ]. These impairments can be prevented to a large extent by a Phe‐restricted dietary treatment, to be implemented as soon as possible after birth. Neonatal screening programs are therefore critical, lifelong management []. However, it has become increasingly clear that not all functional problems are solved by dietary interventions; slight reductions in cognitive performance and psychosocial deficits remain present [, , , ]. To improve the situation, and to improving the dietary intervention itself, a further understanding of the impact of high Phe on the brain using preclinical research remains crucial [, ].