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J Nutr Biochem. 2018 Mar;53:20-27. doi: 10.1016/j.jnutbio.2017.09.020. Epub 2017 Oct 12.

Large neutral amino acid supplementation as an alternative to the phenylalanine-restricted diet in adults with phenylketonuria: evidence from adult Pah-enu2 mice.

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University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, the Netherlands.
University of Groningen, Groningen Institute for Evolutionary Life Sciences (GELIFES), Department of Molecular Neurobiology, Groningen, the Netherlands.
University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, the Netherlands.
University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, the Netherlands. Electronic address:


Phenylketonuria treatment mainly consists of a phenylalanine-restricted diet but still results in suboptimal neuropsychological outcome, which is at least partly based on cerebral monoamine deficiencies, while, after childhood, treatment compliance decreases. Supplementation of large neutral amino acids (LNAAs) was previously demonstrated in young phenylketonuria mice to target all three biochemical disturbances underlying brain dysfunction in phenylketonuria. However, both its potential in adult phenylketonuria and the comparison with the phenylalanine-restricted diet remain to be established. To this purpose, several LNAA supplements were compared with a severe phenylalanine-restricted diet with respect to brain monoamine and amino acid concentrations in adult C57Bl/6 Pah-enu2 mice. Adult phenylketonuria mice received a phenylalanine-restricted diet, unrestricted diet supplemented with several combinations of LNAAs or AIN-93M control diet for 6 weeks. In addition, adult wild-type mice on AIN-93M diet served as controls. The severe phenylalanine-restricted diet in adult phenylketonuria mice significantly reduced plasma and brain phenylalanine and restored brain monoamine concentrations, while brain concentrations of most nonphenylalanine LNAAs remained subnormal. Supplementation of eight LNAAs was similarly effective as the severe phenylalanine-restricted diet to restore brain monoamines, while brain and plasma phenylalanine concentrations remained markedly elevated. These results provide biochemical support for the effectiveness of the severe phenylalanine-restricted diet and showed the possibilities of LNAA supplementation being equally effective to restore brain monoamines in adult phenylketonuria mice. Therefore, LNAA supplementation is a promising alternative treatment to phenylalanine restriction in adult phenylketonuria patients to further optimize neuropsychological functioning.


Adults; Inborn error of metabolism; Large neutral amino acids; Mouse model; Neurotransmitters; Phenylketonuria

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