Journal of Inherited Metabolic Disease

, Volume 30, Issue 2, pp 153–158 | Cite as

Double blind placebo control trial of large neutral amino acids in treatment of PKU: Effect on blood phenylalanine

  • R. Matalon
  • K. Michals-Matalon
  • G. Bhatia
  • A. B. Burlina
  • A. P. Burlina
  • C. Braga
  • L. Fiori
  • M. Giovannini
  • E. Grechanina
  • P. Novikov
  • J. Grady
  • S. K. Tyring
  • F. Guttler
ICIEM 2006

Summary

Large neutral amino acids (LNAA) have been used on a limited number of patients with phenylketonuria (PKU) with the purpose of decreasing the influx of phenylalanine (Phe) to the brain. In an open-label study using LNAA, a surprising decline of blood Phe concentration was found in patients with PKU in metabolic treatment centres in Russia, the Ukraine, and the United States. To validate the data obtained from this trial, a short-term double-blind placebo control study was done using LNAA in patients with PKU, with the participation of three additional metabolic centres – Milan, Padua and Rio de Janeiro. The results of the short trial showed significant lowering of blood Phe concentration by an average of 39% from baseline. The data from the double-blind placebo control are encouraging, establishing proof of principle of the role of orally administered LNAA in lowering blood Phe concentrations in patients with PKU. Long-term studies will be needed to validate the acceptability, efficacy and safety of such treatment.

Abbreviations

BBB

blood–brain barrier

LNAA

large neutral amino acids

Phe

phenylalanine

PKU

phenylketonuria

VIL

valine, isoleucine and leucine

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References

  1. Azen C, Koch R, Friedman EG, et al (1991) Intellectual development in 12-year-old children treated for phenylketonuria. Am J Dis Child 145: 35–39.PubMedGoogle Scholar
  2. Blau N, Scriver CR (1997) New approaches to treat PKU: How far are we? Mol Genet Metab 81: 1–2.CrossRefGoogle Scholar
  3. Blau N, Trefz F (2002) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency: possible regulation of gene expression in a patient with the homozygous L48S mutation. Mol Genet Metab 75: 186–187.PubMedCrossRefGoogle Scholar
  4. Bickel H, Gernrard J, Hickmans EM (1953) Influence of phenylalanine intake on phenylketonuria. Lancet 2: 812–813.CrossRefGoogle Scholar
  5. Burgard P, Rey F, Rupp A, Abadie V, Rey J (1997) Neuropsychologic functions of early treated patients with phenylketonuria, on and off diet: results of a cross-national and cross-sectional study. Pediatr Res 41: 368–374.PubMedGoogle Scholar
  6. Choi TB, Pardridge WM (1986) Phenylalanine transport at the human blood–brain barrier. J Biol Chem 261: 6536–6541.PubMedGoogle Scholar
  7. Diamond A (2001) A model system for studying the role of dopamine in the prefrontal cortex during early development in humans: early and continuously treated phenylketonuria. In Nelson CA, Luciana M, eds. Handbook of Cognitive Neuroscience. Cambridge, MA: MIT Press, 433–472.Google Scholar
  8. Dotremont H, Francois B, Diels M, Gillis P (1995) Nutritional value of essential amino acids in the treatment of adults with phenylketonuria. J Inherit Metab Dis 18: 127–130.PubMedCrossRefGoogle Scholar
  9. Erlandsen H, Pey AL, Gamez A, et al (2004) Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc Natl Acad Sci USA 101(48): 16903–16908.PubMedCrossRefGoogle Scholar
  10. Fisch RO, Chang PN, Weisberg S, Guldberg P, Guttler F, Tsai MY (1995) Phenylketonuria patients decades after diet. J Inherit Metab Dis 18: 426–427.CrossRefGoogle Scholar
  11. Fisch R, Matalon R, Weisberg S, Michals K (1997) Phenylketonuria: current dietary treatment practices in the United States and Canada. Am J Coll Nutr 16: 147–151.Google Scholar
  12. Folling A (1934) Uber Ausscheidung von Phenylbrenztraubensaure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillitat. Hoppe-Seylers Z Physiol Chem 277: 169.Google Scholar
  13. Griffiths P, Paterson L, Harvie A (1995) Neuropsychological effects of subsequent exposure to phenylalanine in adolescents and young adults with early-treated phenylketonuria. J Intellec Dis Res 39: 365–372.CrossRefGoogle Scholar
  14. Gleason LA, Michals K, Matalon R, Langenberg P, Kamath S (1992) A treatment program for adolescents with phenylketonuria. Clin Pediatr 6: 331–335.Google Scholar
  15. Hargreaves KM, Pardridge WM (1988) Neutral amino acid transport at the human blood–brain barrier. J Biol Chem 263(19): 392–397.Google Scholar
  16. Hidalgo IJ, Borchardt RT (1990) Transport of a large neutral amino acid (phenylalanine) in a human intestinal epithelial cell line: Caco-2. Biochim Biophys Acta 1028(1): 25–30.PubMedCrossRefGoogle Scholar
  17. Jervis GA (1953) Phenylpyruvic oligophrenia: deficiency of phenylalanine oxidising system. Proc Soc Exp Biol Med 82: 514–515.PubMedGoogle Scholar
  18. Kaufman S (1971) The phenylalanine hydroxylating system from mammalian liver. Adv Enzymol 35: 245–319.PubMedGoogle Scholar
  19. Kure S, Hou DC, Ohura T, et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency: a novel clinical entity. J Pediatr 135: 375–378.PubMedCrossRefGoogle Scholar
  20. Larsen PR, Ross JE, Tapley DF (1964) Transport of neutral, dibasic and N-methyl substituted amino acids by rat intestine. Biochim Biophys Acta 88: 570–577.PubMedGoogle Scholar
  21. Lassker U, Zschocke J, Blau N, Santer R (2002) Tetrahydrobiopterin responsiveness in phenylketonuria. Two new cases and a review of molecular genetic findings. J Inherit Metab Dis 25: 65.PubMedCrossRefGoogle Scholar
  22. Lindner M, Hass D, Zschocke J, Burgard P (2003a) Tetrahydrobiopterin responsiveness in phenylketonuria differs between patients with the same genotype. Mol Genet Metab 73: 104–106.CrossRefGoogle Scholar
  23. Lindner M, Steinfeld R, Burgard P, Schulze A, Mayatepek E, Zschocke J (2003b) Tetrahydrobiopterin sensitivity in German patients with mild phenylalanine hydroxylase deficiency. Hum Mutat 21: 400.CrossRefGoogle Scholar
  24. Lou H, Guttler F, Lykkelund C, Bruhn P, Niewieser A (1985) A decreased vigilance and neurotransmitter synthesis after discontinuation of dietary treatment for phenylketonuria in adolescents. Eur J Pediatr 144: 17–20.PubMedCrossRefGoogle Scholar
  25. Matalon R, Koch R, Michals-Matalon K, Moseley K, Stevens RC (2002) Tetrahydrobiopterin-responsive phenylalanine hydroxylase mutation. J Inherit Metab Dis 25(Supplement): 23.Google Scholar
  26. Matalon R, Surendran S, Michals-Matalon K, et al. (2003) Future role of large neutral amino acids in transport of phenylalanine into the brain. Pediatrics 122: 1570–1574.Google Scholar
  27. Matalon R, Koch R, Michals-Matalon K, et al (2004) Biopterin responsive phenylalanine hydroxylase deficiency. Genet Med 6(1): 27–32.PubMedCrossRefGoogle Scholar
  28. Matalon R, Michals-Matalon K, Bhatia G, et al (2006) Large neutral amino acids in the treatment of phenylketonuria (PKU) J Inherit Metab Dis 29: 732–738.PubMedCrossRefGoogle Scholar
  29. MRC Working Party on Phenylketonuria (1993) Recommendation on the dietary management of phenylketonuria. Arch Dis Child 68: 426–427.Google Scholar
  30. Muntau AC, Roschinger W, Habich M, et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347: 2122–2132.PubMedCrossRefGoogle Scholar
  31. Michals K, Dominick M, Schuett V, Brown E, Matalon R (1985) Return to diet therapy in patients with phenylketonuria. J Pediatr 106: 933–936.PubMedCrossRefGoogle Scholar
  32. Michals K, Azen C, Acosta PB, Koch R, Matalon R (1988) Blood phenylalanine and intelligence of ten-year-old children with phenylketonuria in the national collaborative study. J Am Diet Assoc 88: 1226–1229.PubMedGoogle Scholar
  33. NIH Consensus Report on Phenylketonuria (2001) Phenylketonuria: screening and management of PKU. US Department of Health and Human Services, Public Health Services, National Institutes of Health, National Institute of Child Health and Human Services.Google Scholar
  34. Oldendorf WH, Szabo J (1976) Amino acid assignment to one of three blood–brain barrier amino acid carriers. Am J Physiol 230: 94–98.PubMedGoogle Scholar
  35. Pardridge WM (1977) Kinetics of competitive inhibition of neutral amino acid transport across the blood–brain barrier. J Neurochem 28: 103–108.PubMedCrossRefGoogle Scholar
  36. Pardridge WM (1982) Blood–brain barrier amino-acid transport: clinical implications. In: Cockburn F, Gitzelmenn R, eds. Inborn Errors of Metabolism in Humans. Lancaster, UK: MTP Press, 87–99.Google Scholar
  37. Pardridge WM, Oldendrof WH (1975) Kinetic analysis of blood–brain barrier transport of amino acids. Biochim Biophys Acta 401: 128–136.PubMedCrossRefGoogle Scholar
  38. Pietz J, Landwehr R, Kutscha A, Schmidt H, de Sonneville L, Trefz FK (1995) Effect of high-dose tyrosine supplementation on brain function in adults with phenylketonuria. J Pediatr 127: 936–943.PubMedCrossRefGoogle Scholar
  39. Pietz J, Dunckelmann R, Rupp A, et al (1998) Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 157: 824–830.PubMedCrossRefGoogle Scholar
  40. Ris MD, Williams SE, Hunt MM, Berry HK, Leslie N (1994) Early-treated phenylketonuria: adult neuropsychological outcome. J Pediatr 124: 388–392.PubMedCrossRefGoogle Scholar
  41. SAS Institute (2004) SAS/STAT 9.1 User’s Guide. Cary, NC: SAS Institute Inc.Google Scholar
  42. Scriver CR, Kaufman S (2001) Hyperphenylalaninemias: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 1667–1724.Google Scholar
  43. Schmidt E, Rupp A, Burgard P, Pietz J, Weglage J, de Sonneville L (1994) Sustained attention in adult phenylketonuria: the influence of the concurrent phenylalanine blood-level. J Clin Exp Neuropsychol 16: 681–688.PubMedGoogle Scholar
  44. Seashore MR, Friedman E, Novelly RA, Bapat V (1985) Loss of intellectual function in children with phenylketonuria after relaxation of dietary phenylalanine restriction. Pediatrics 75: 226–232.PubMedGoogle Scholar
  45. Smith I, Lobascher M, Stevenson J, et al (1978) Effect of stopping the low phenylalanine diet on the intellectual progress of children with phenylketonuria. Br Med J 2: 723–726.PubMedGoogle Scholar
  46. Smith I, Beasley MG, Ades AE (1991) Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 66(3): 311–316.PubMedCrossRefGoogle Scholar
  47. Spaapen LJM, Bakker JA, Velter C, et al (2000) Tetrahydrobiopterin-responsive hyperphenylalaninemia (HPA) in Dutch neonates. J Inherit Metab Dis 23(Supplement 1): 45.Google Scholar
  48. Thompson AJ, Smith IL, Brenton D, et al (1990) Neurological deterioration in young adults with phenylketonuria. Lancet 336: 602–605.PubMedCrossRefGoogle Scholar
  49. Thompson AJ, Tillotson A, Smith I, Kendall B, Moore SG, Brenton DP (1994) Brain MRI changes in phenylketonuria. Associations with dietary status. Brain 344: 87–90.Google Scholar
  50. Trefz F, Blau N, Aulehla-Scholz C, Korall H, Frauendienst-Egger G (2000) Treatment of mild phenylaketonuria (PKU) by tetrahydrobiopterin (BH4) J Inherit Metab Dis 23(Supplement 1): 47.Google Scholar
  51. Trefz F, Aulehla-Scholz C, Blau N (2001) Successful treatment of phenylketonuria with tetrahydrobiopterin. Eur J Pediatr 160: 315.PubMedCrossRefGoogle Scholar
  52. Walter JH, White FJ, Hall SK, et al (2002) How practical are recommendations for dietary control in phenylketonuria? Lancet 360: 55–57.PubMedCrossRefGoogle Scholar
  53. Weglage J, Grenzebach M, Teeffelen-Heithoff T, et al (2002) Tetrahydrobiopterin responsiveness in a large series of phenylketonuria patients. J Inherit Metab Dis 25: 321–322.PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2007

Authors and Affiliations

  • R. Matalon
    • 1
  • K. Michals-Matalon
    • 2
  • G. Bhatia
    • 1
  • A. B. Burlina
    • 3
  • A. P. Burlina
    • 3
  • C. Braga
    • 4
  • L. Fiori
    • 5
  • M. Giovannini
    • 5
  • E. Grechanina
    • 6
  • P. Novikov
    • 7
  • J. Grady
    • 1
  • S. K. Tyring
    • 8
  • F. Guttler
    • 9
  1. 1.Department of PediatricsUniversity of Texas Medical Branch, Children’s HospitalGalvestonUSA
  2. 2.University of HoustonHoustonUSA
  3. 3.Inherited Metabolic Disease Unit and Department of Neuroscience, Neurological ClinicUniversity Hospital of PaduaItaly
  4. 4.Diagnósticos Laboratoriais Especializados and Centro Ambulatorial de Prevenção/APAE-Rio de JaneiroBrazil
  5. 5.Department of PediatricsSan Paolo Hospital, University of MilanItaly
  6. 6.Institute of Clinical GeneticsKharkiv State Medical UniversityKharkivUkraine
  7. 7.Department of Clinical GeneticsInstitute of Pediatrics and Child SurgeryMoscowRussia
  8. 8.University of Texas-Health Science CentreHoustonUSA
  9. 9.Kennedy InstituteGlostrupDenmark

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