Reduction of Cerebrospinal Fluid Phenylalanine after Oral Administration of Valine, Isoleucine, and Leucine

Abstract

SummaryA supplement of the branched chain amino acids, valine, isoleucine, and leucine (VIL) was administered orally to patients with phenylketonuria, either together with unrestricted diet of natural protein or with a low phenylalanine diet. The VIL supplement brought about a significant reduction of the cerebrospinal fluidserum ratio of phenylalanine from a mean value of 0.254 without VIL to 0.204 with VIL. The reduction varied from 15-40% (mean 21%). Concentrations of glycine, lysine, methionine, threonine, tryptophan, and tyrosine were within normal limits in serum and cerebrospinal fluid of infants with phenylketonuria. No amino acid imbalance was created by the supplement and no adverse effects from VIL were observed. SpeculationThe branched chain amino acids and phenylalanine share a common transport system. High levels of phenylalanine in brain of children with phenylketonuria may be reduced by administration of a supplement of valine, isoleucine and leucine (VIL). Supplementation of the low-phenylalanine diet with VIL during the first 2 years of life may add a measure of protection to the developing brain beyond that which can be achieved by diet alone. In older children, VIL supplementation may permit liberalization of the diet without unfavorable behavioral consequences.Treatment for phenylketonuria (PKU) by means of a lowphenylalanine diet has become common practice since its first use in affected newborn infants (3). The treatment partially corrects the abnormal amino acid pattern, including the high concentration of phenylalanine and its metabolites, and allows relatively normal intellectual and physical development if the treatment is begun early enough (10). Initially it was assumed that treatment would be terminated when major phases of brain growth were completed. Evidence has accumulated which suggests that termination of treatment for the patient with classic PKU, at least during the school years, is unwise (13,15,16) and it may be prudent to continue the diet into adult years for women with PKU in order to avoid the teratogenic effects of phenylalanine (6).An animal model developed in this laboratory was used to demonstrate the effects of experimental hyperphenylalaninemia (PKU) (12). Methods to inhibit the deleterious effects of phenylalanine on the central nervous system were studied in the model. Administration of branched chain amino acids, valine, isoleucine, and leucine (VIL), to pregnant rats with experimentally induced PKU prevented the decrease in fetal brain weight characteristic of PKU animals (7). A striking finding was that phenylalanine levels in brain of PKU fetuses whose mothers received VIL supplement were lower than in PKU fetuses not exposed to VIL, although fetal blood phenylalanine levels were similar. Subsequent studies suggested that isoleucine was more effective than other amino acids in exerting a beneficial effect on fetal rat brain growth (1 1).Human trials followed. VIL was first used as a supplement to the low-phenylalanine diet of several older PKU children in w...

Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine

“…This supplement may be especially important for PKU mothers since in addition to the maternal intestine, the endothelial cells of the capillaries in the fetal brain and the neuronal cell membrane, the amino acids must pass one more barrier (the placenta) before reaching the sites of biosynthesis in the developing fetal brain. Besides their properties as essential amino acids, valine, leucine and isoleucine are also beneficial since they competitively exclude phenylalanine from the brain resulting in decreased CSF concentration of phenylalanine [2,3]. A case of maternal PKU with increased dietary tyrosine during pregnancy has been reported.…”

Significant phenylalanine hydroxylation in vivo in patients with classical phenylketonuria.

“…A number of alternative approaches to treatment of PKU have been proposed previously, including the administration ofbranched-chain amino acids to reduce the entry ofphenylalanine into the central nervous system (38), the administration of beta-2-thienylamine to promote renal excretion and inhibit intestinal absorption of phenylalanine (39) in this study indicates a possible benefit of therapies aimed at inducing alternate pathway activity. Such therapy could be directed towards induction of tyrosine hydroxylase or other hydroxylases.…”

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria

“…Although plasma concentrations of Phe remained unchanged, an ∼20% decrease of Phe concentrations in CSF seemed to confirm the hypothesis. In addition, improvements on a neuropsychologic task were shown for VIL treatment (5,39). The VIL approach was also used in an animal model of maternal PKU (40).…”