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PEDIATRICS Vol. 112 No. 6 December 2003, pp. 1570-1574

SUPPLEMENT ARTICLE

Future Role of Large Neutral Amino Acids in Transport of Phenylalanine Into the Brain

Reuben Matalon, MD, PhD*, Sankar Surendran, PhD*, Kimberlee Michals Matalon, PhD, RD*,{ddagger}, Stephen Tyring, MD, PhD*, Michael Quast, PhD§, Wei Jinga, PhD§, Edward Ezell, PhD§ and Sylvia Szucs, MS*

* Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas
{ddagger} Department of Human Development, University of Houston, Houston, Texas
§ Department of Anatomy and Neuroscience, University of Texas, Galveston, Texas

Objective. The treatment of phenylketonuria (PKU) in children and adults has been difficult because of erosion of dietary adherence, leading to poor school performance, impairment of executive functioning, loss of IQ, and deterioration of white matter in the brain. Mutant PKU mice produced by exposure to N-ethyl-N'-nitrosourea (ENU) were used to examine the effect of large neutral amino acid (LNAA) supplementation on brain and blood phenylalanine (Phe).

Methods. Mice with PKU, genotype ENU 2/2 with features of classical PKU, were supplemented with LNAA while on a normal diet. Two dosages of LNAA were given 0.5 g/kg and 1.0 g/kg by gavage. Blood Phe was determined in the experimental, control, and sham-treated mice. Brain Phe was determined by magnetic resonance spectroscopy after perchloric acid extraction. Branched-chain amino acid transferase (BCAT) was determined in brain as a marker for energy metabolism.

Results. Blood Phe was reduced in the LNAA-treated mice by an average of 15% (0.5 g/kg) and 50% (1.0 g/kg) in 48 hours. There was a sustained decrease in the blood Phe levels over a 6-week trial. The untreated mice and sham-treated mice maintained high blood Phe throughout the experiments. Brain Phe level determined by magnetic resonance spectroscopy showed a decline of 46% after the LNAA treatment. BCAT levels were lower (33%) in the ENU 2/2 mice compared with wild-type. The BCAT normalized in mice with PKU that were treated with LNAA.

Conclusion. The results suggest that giving LNAA lowered brain and blood Phe levels in mice with PKU. Energy metabolism generated from BCAT also improved in mice with PKU after treatment with LNAA. Data from the mice suggest that LNAA should be considered among the strategies to treat PKU in humans.

Key Words: phenylketonuria • PKU • large neutral amino acids • LNAA • blood-brain barrier

Abbreviations: PKU, phenylketonuria • Phe, phenylalanine • LNAA, large neutral amino acid • VIL, valine, isoleucine, and leucine • MRS, magnetic resonance spectroscopy • BCAT, branched-chain amino acid transferase • ENU, N-ethyl-N'-nitrosourea • NMR, nuclear magnetic resonance • GI, gastrointestinal


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