Using Large Neutral Amino Acids for PKU: A View from "Down Under"

by Prof. John Christodoulou, Head, Genetic Metabolic Disorders Service and Director, Western Sydney Genetics Program, The Children’s Hospital at Westmead, Sydney, Australia

From the Winter 2008 issue of National PKU News

There have been great improvements in the range of low-phe formulas and food products available over the years since newborn screening for PKU started in the 1960’s. Still, there are a proportion of individuals with PKU, particularly adolescents and adults, who struggle with the diet. Could a newly available therapy, large neutral amino acids, offer an alternative for such individuals?

Large Neutral Amino Acids and Brain Phenylalanine

There is the occasional individual with PKU, who despite poor control of the diet and chronic marked elevations of blood phe seems to escape any significant neurological impairment. It is suspected that such individuals may be protected at the level of the “blood-brain barrier.” The blood-brain barrier serves to protect the brain from exposure to potentially toxic chemicals in the bloodstream. However, the blood-brain barrier is so effective that it can potentially restrict the entry of most substances, including essential nutrients (like phe), which would have a disastrous effect on brain growth and development. To overcome this problem specific transporter proteins act as "gateways", allowing the controlled entry of these essential nutrients.

The blood-brain barrier “phe transporter” also can transport a number of other amino acids, so-called large neutral amino acids (LNAA); these amino acids compete with each other and with phe to be transported into the brain. This has led to the theory that if extra amounts of LNAAs were provided in the diet, these could block the passage of phe into the brain, lowering brain levels and thereby offering an extra measure of protection to the brain.

To examine this question we undertook a research study which was very generously supported by SHS International. Our aims were to examine whether LNAA supplementation would alter brain and blood phe levels and to examine the effects of LNAAs on brain function in a number of individuals with PKU. (Schindeler S, et al. The Effects of Large Neutral Amino Acid Supplements in PKU: an MRS and Neuropsychological Study. Molecular Genetics and Metabolism 91: 48-54, 2007).

What We Did

We undertook a study in 16 individuals with “classical” PKU, ranging from 11 to 45 years of age. All were still on diet, and most were judged to have good metabolic control (blood phe levels under 750 micromol/L or 12.5 mg/dl most of the time). For our study we used a product from SHS International called LanaflexTM, at a dose of 250 mg/kg/day (divided into three equal doses during the day). There were four phases to the study:

Phase 1: PKU diet, usual medical food + LNAA
Phase 2: PKU diet, usual medical food + placebo
Phase 3: PKU diet, no medical food + LNAA
Phase 4: PKU diet, no medical food + placebo

Each phase lasted two weeks, with a minimum four week “washout” period between phases. Throughout this time, neither the investigators nor the subjects knew whether the subjects were on the placebo or LNAA product (a so-called “double-blind study”). Blood and brain phe were measured at the end of each phase (the latter using a technique called magnetic resonance spectroscopy or MRS), as was a battery of neuropsychological studies lasting several hours.

What We Found

We were unable to obtain reliable brain measurements of phe, because for the majority of measurements, the blood phe level was less than 1200 micromol/L (20 mg/dl) at the time of the brain measurement. It has been shown that when blood levels are less than 1200, brain levels are unreliably measured by MRS.

However, interestingly, we found that the blood phe level varied significantly depending on the total intake of LNAA (that is, as the LNAA intake increased the blood phe level fell). Don’t forget the phe-free medical product contributes considerably to LNAA intake, with some LNAAs coming from natural protein as well.

Our results suggested that LNAA supplementation had some beneficial effect on specific brain function, including verbal abilities, the ability to control impulsive behavior, and short term memory, although there was considerable individual variation. However, our neuropsychological studies also indicated that anxiety levels were higher when participants were on LNAA supplementation, regardless of whether they were taking the phe-free medical product or not.

What We Concluded

Our studies have shown that there was a trend to a lowering of plasma phe levels with a higher intake of LNAA. Recently other researchers have found similar results (Matalon, et al. J Inher Metab Dis 29: 732 –738, 2006). There is a LNAA transporter in the gut as well, and so it is likely that LNAA supplements are partially blocking the uptake of phe from the gut into the bloodstream, thereby leading to a reduction in the blood phe level; this in turn would be likely to result in brain levels also being lower. However, we also found that if an individual with PKU is already complying with the PKU diet and taking the low-phenylalanine formula, there is little to be gained by taking extra LNAA supplements.

So, although still controversial, LNAA may be of benefit to patients who find it difficult to take their phe-free medical product. One word of caution: in our study, being on LNAA supplements was associated with increased anxiety on neuropsychological testing, so one needs to consider their use very carefully.

Acknowledgements:

We would especially like to thank the individuals with PKU who were part of this study. We are also grateful to SHS International for provision of the LNAA powder (Lanaflex) and for funding this research project. I would also like to thank Sue Thompson, Dept of Nutrition and Dietetics, Children’s Hospital at Westmead, for many valuable discussions, and for her help in preparing this report.

Last update: February 2008
National PKU News: www.pkunews.org
E-mail: schuett@pkunews.org