Phenylalanine-restricted diet with phenylalanine-free amino acid substitution[1][2][5]

Phenylalanine restriction via dietary substitution with Phe-free amino acids is the foundational medical nutrition therapy for phenylketonuria (PKU), an inherited deficiency of phenylalanine hydroxylase leading to hyperphenylalaninemia and risk of neurotoxicity[2][4][5]. The diet severely limits natural protein to reduce Phe intake and replaces it with phenylalanine-free L-amino acid “protein substitutes,” typically taken in divided doses throughout the day, often alongside low-protein specialty foods and close biochemical monitoring[1][2][5]. Protein substitutes also help balance competitive transport of large neutral amino acids at the blood–brain barrier to limit brain Phe entry[1][3]. Adjunct or alternative pharmacotherapies include sapropterin for responsive patients, large neutral amino acid formulations to reduce brain Phe via LAT1 competition, and pegvaliase to enzymatically degrade Phe, each used to improve metabolic control and dietary flexibility where appropriate[1][2][3][5].

Other names

Phenylalanine-restricted diet[2][6]Phe-restricted diet[2]Low-phenylalanine diet[5]Phe-free amino acid supplements (protein substitutes)[1][2][5]Medical nutrition therapy for PKU[2][5]

Dietary Phe restriction reduces systemic and brain phenylalanine accumulation by limiting intake from natural protein sources[1][2][5]. Phe-free amino acid mixtures provide essential amino acids without Phe, supporting growth/nitrogen balance while minimizing blood Phe[1][2][5]. LNAA supplementation competes with Phe at LAT1 (L-type amino acid transporter 1) at the blood–brain barrier, lowering brain Phe and helping normalize neurotransmitter precursors[1][3]. Sapropterin (BH4) acts as a pharmacologic chaperone/cofactor to enhance residual PAH activity in responsive patients, increasing Phe tolerance and lowering blood Phe[1][2]. Pegvaliase (PEGylated phenylalanine ammonia-lyase) degrades Phe to trans-cinnamate and ammonia, reducing blood Phe independently of PAH[2].