The cornerstone of nutrition therapy for Phenylketonuria has been limiting the consumption of Phenylalanine to avoid accumulation in the blood.

This concept of limiting phenylalanine in the diet was first demonstrated in early 1950’s, as it had a positive impact on the behaviour in a young patient with PKU. Specialized amino acid based formula with low phenylalanine made dietary treatment for these patients possible. Although earlier it was believed that formula should be given only for 6 years, later data indicated that diet for life is the optimal mode of treatment.

Despite these significant results in behaviour, cognitive deficits were found in poorly managed individuals going to adulthood. Compliance for strict regimen among PKU individuals was found to be difficult which led to undesirable clinical outcomes.

Different approaches in nutrition management were  explored  such as glycomacropeptide protein-based medical foods and large neutral amino acids. Here we elaborate on Large Neutral Amino Acids.

 

What are Large Neutral Amino Acids?

PKU: UNDERSTANDING LARGE NEUTRAL AMINO ACIDS


LAT-1 transporter
helps these amino acids pass the blood brain barrier.

In an individual with PKU due to the absence of enzyme Phenylalanine hydroxylase (PAH) & tetra hydrobiopterin (BH4), phenylalanine does not get metabolised to tyrosine, which thus gets accumulated in the liver and results in increased levels in the blood. Phenylalanine passes the blood-brain barrier with the help of LAT 1 transporter which leads to cognitive deficits, neurophysiological & neuropsychological dysfunction.

PKU: UNDERSTANDING LARGE NEUTRAL AMINO ACIDS

 

Supplementation of LNAA increases the levels in the brain and reduces the concentration of Phenylalanine as they compete with LAT1 transporter for crossing the blood-brain barrier. This was suggested 40 years ago while experimenting on artificially induced hyperphenylalaninemic rats. The successful lowering of phenylalanine levels in the brain led to further research in this area. Data suggests that various combinations of LNAA were tried depending upon the treatment goal.

LNAA treatment goal –  to decrease cerebral Phenylalanine concentration

  • LNAA supplementation:
  • Increases the levels in the plasma thus competing with Phe for uptake at the blood-brain barrier. The concentration of Phe in the brain was decreased by 20 % when studied in humans. (Moats, 2003)
  • Increases branched amino acids like isoleucine, valine and leucine concentration in the brain showing improvement in verbal ability, cognitive functions and protein synthesis in the brain (Moats, 2003)
  • Improves neurotransmitter synthesis serotonin and dopamine known as feel good chemicals depending upon the concentration of tyrosine and tryptophan in the brain. Although, reports find deficiency of tyrosine in the brain, thus indicating higher concentration of the tyrosine in LNAA supplementation (van Spronsen FJ, 2010)

LNAA supplementation to decrease blood phenylalanine concentration

  • LNAA supplementation in PKU mice had shown reduction of Phe by 47-63.5 % (Matalon, 2006).
  • It is hypothesized that due to supplementation of LNAA there is competition of Phe for uptake from GI tract into the blood (van Spronsen FJ, 2010)
  • Reports suggest that, the availability of high concentration of essential amino acid in the blood results in Phe utilization for protein synthesis. This leads to decrease in Phe in the blood (Danique van Vilet, 2015)

 

LNAA is seen as an alternative to conventional dietary therapy in PKU treatment especially for individuals, like adolescents and adults, who have uncontrolled phenylalanine levels. The concentration of LNAA supplementation depends upon different treatment strategies.