Multicompartment analysis of protein‐restricted phenylketonuric mice reveals amino acid imbalances in brain

Background The mainstay of therapy for phenylketonuria (PKU) remains dietary protein restriction. Developmental and neurocognitive outcomes for patients, however, remain suboptimal. We tested the hypothesis that mice with PKU receiving protein‐restricted diets would reveal disruptions of brain amino acids that shed light on these neurocognitive deficits. Method Phenylalanine hydroxylase‐deficient (PKU) mice and parallel controls (both wild‐type and heterozygous) were fed custom diets containing 18, 6, and 4 % protein for 3 weeks, after which tissues (brain, liver, sera) were collected for amino acid analysis profiling. Results Phenylalanine (phe) was increased in all tissues ( p  < 0.0001) of PKU mice and improved with protein restriction. In sera, decreased tyrosine ( p  < 0.01) was corrected (defined as not significantly different from the level in control mice receiving 18 % chow) with protein restriction, whereas protein restriction significantly increased many other amino acids. A similar trend for increased amino acid levels with protein restriction was also observed in liver. In brain, the effects of protein restriction on large neutral amino acids (LNAAs) were variable, with some deficit correction (threonine, methionine, glutamine) and no correction of tyrosine under any dietary paradigm. Protein restriction (4 % diet) in PKU mice significantly decreased lysine, arginine, taurine, glutamate, asparagine, and serine which had been comparable to control mice under 18 % protein intake. Conclusion Depletion of taurine, glutamate, and serine in the brain of PKU mice with dietary protein restriction may provide new insight into neurocognitive deficits of PKU.