The increasing importance of LNAA supplementation in phenylketonuria at higher plasma phenylalanine concentrations

D van Vliet, E van der Goot, W G van Ginkel, H J R van Faassen, P de Blaauw, I P Kema, M R Heiner-Fokkema, E A van der Zee, F J van Spronsen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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BACKGROUND: Large neutral amino acid (LNAA) treatment has been suggested as alternative to the burdensome severe phenylalanine-restricted diet. While its working mechanisms and optimal composition have recently been further elucidated, the question whether LNAA treatment requires the natural protein-restricted diet, has still remained.

OBJECTIVE: Firstly, to determine whether an additional liberalized natural protein-restricted diet could further improve brain amino acid and monoamine concentrations in phenylketonuria mice on LNAA treatment. Secondly, to compare the effect between LNAA treatment (without natural protein) restriction and different levels of a phenylalanine-restricted diet (without LNAA treatment) on brain amino acid and monoamine concentrations in phenylketonuria mice.

DESIGN: BTBR Pah-enu2 mice were divided into two experimental groups that received LNAA treatment with either an unrestricted or semi phenylalanine-restricted diet. Control groups included Pah-enu2 mice on the AIN-93 M diet, a severe or semi phenylalanine-restricted diet without LNAA treatment, and wild-type mice receiving the AIN-93 M diet. After ten weeks, brain and plasma samples were collected to measure amino acid profiles and brain monoaminergic neurotransmitter concentrations.

RESULTS: Adding a semi phenylalanine-restricted diet to LNAA treatment resulted in lower plasma phenylalanine but comparable brain amino acid and monoamine concentrations as compared to LNAA treatment (without phenylalanine restriction). LNAA treatment (without phenylalanine restriction) resulted in comparable brain monoamine but higher brain phenylalanine concentrations compared to the severe phenylalanine-restricted diet, and significantly higher brain monoamine but comparable phenylalanine concentrations as compared to the semi phenylalanine-restricted diet.

CONCLUSIONS: Present results in PKU mice suggest that LNAA treatment in PKU patients does not need the phenylalanine-restricted diet. In PKU mice, LNAA treatment (without phenylalanine restriction) was comparable to a severe phenylalanine-restricted diet with respect to brain monoamine concentrations, notwithstanding the higher plasma and brain phenylalanine concentrations, and resulted in comparable brain phenylalanine concentrations as on a semi phenylalanine-restricted diet.

Original languageEnglish
Pages (from-to)27-34
Number of pages8
JournalMolecular Genetics and Metabolism
Issue number1
Early online date14-Dec-2021
Publication statusPublished - Jan-2022


  • Phenylketonuria
  • Inborn error of metabolism
  • Large neutral amino acids
  • Mouse model
  • Dietary treatment
  • Monoaminergic neurotransmitters
  • Brain biochemistry
  • PKU

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