Advances in the nutritional and pharmacological management of phenylketonuria

Abstract

Purpose of review: The purpose is to discuss advances in the nutritional and pharmacological management of phenylketonuria (PKU).

Recent findings: Glycomacropeptide (GMP), a whey protein produced during cheese production, is a low-phenylalanine (phe) intact protein that represents a new dietary alternative to synthetic amino acids for people with PKU. Skeletal fragility is a long-term complication of PKU that based on murine research, appears to result from both genetic and nutritional factors. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an amino acid diet, allowing greater radial bone growth. Pharmacologic therapy with tetrahydrobiopterin, acting as a molecular chaperone for phenylalanine hydroxylase, increases tolerance to dietary phe in some individuals. Large neutral amino acids inhibit phe transport across the intestinal mucosa and blood-brain barrier, and are most effective for individuals unable to comply with the low-phe diet.

Summary: Although a low-phe synthetic amino acid diet remains the mainstay of PKU management, new nutritional and pharmacological treatment options offer alternative approaches to maintain lifelong low phe concentrations. GMP medical foods provide an alternative to amino acid formula that may improve bone health, and tetrahydrobiopterin permits some individuals with PKU to increase tolerance to dietary phe. Further research is needed to characterize the long-term efficacy of these new approaches for PKU management.

Figure 1

Phenylalanine (phe) metabolism in phenylketonuria (PKU). As indicated by the “X”, PKU results from mutations (over 800 have been identified) that affect the hepatic phe hydroxylase (PAH) enzyme needed for the hydroxylation of the indispensable amino acid phe to tyrosine. PKU may also result from mutations in genes involved in recycling the essential PAH cofactor tetrahydrobiopterin. Due to these mutations which reduce the conversion of phe to tyrosine, phe accumulates in blood and is transaminated and decarboxylated into many compounds which appear in blood and urine; three of the compounds which are measured clinically are shown. Tyrosine, a precursor for multiple biological products, becomes an indispensable AA and must be provided by the diet for those with PKU. Under physiological conditions PAH catalyzes about 75% of the phe input from the diet and protein catabolism.

Figure 2

Probability of intelligence quotient (IQ) <85 at varying blood phenylalanine (phe) levels and phe measurement times. Blood phe levels were historical, that is measured more than one year prior to IQ testing, in children before age 6 or at or after age 6. There is moderate evidence for a threshold effect of a phe level of 400 μmole/L associated with IQs of <85. The probability of having an IQ <85 does not increase considerably above a blood phe level of 2,000 μmole/L. Adapted with permission from [3].

Figure 3

PKU genotype decreases femoral strength (maximum load) and ductility (post yield displacement) compared with WT genotype (A). Provision of dietary protein from AAs decreases femoral size (cross sectional area) and strength (maximum load) in both PKU and WT mice compared with casein and GMP diets (B). Schematic of a load displacement curve generated from the three-point bending test is shown in A and representative photographs of femoral cross-sectional geometry in PKU mice fed casein, AA and GMP diets is shown in B. Adapted with permission from [23].