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

  • ICIEM 2006
  • Published:
Journal of Inherited Metabolic Disease

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.

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Abbreviations

BBB:

blood–brain barrier

LNAA:

large neutral amino acids

Phe:

phenylalanine

PKU:

phenylketonuria

VIL:

valine, isoleucine and leucine

References

  • 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.

    PubMed  CAS  Google Scholar 

  • Blau N, Scriver CR (1997) New approaches to treat PKU: How far are we? Mol Genet Metab 81: 1–2.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Bickel H, Gernrard J, Hickmans EM (1953) Influence of phenylalanine intake on phenylketonuria. Lancet 2: 812–813.

    Article  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Choi TB, Pardridge WM (1986) Phenylalanine transport at the human blood–brain barrier. J Biol Chem 261: 6536–6541.

    PubMed  CAS  Google Scholar 

  • 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.

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • 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.

    Article  Google Scholar 

  • 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 

  • Hargreaves KM, Pardridge WM (1988) Neutral amino acid transport at the human blood–brain barrier. J Biol Chem 263(19): 392–397.

    Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Jervis GA (1953) Phenylpyruvic oligophrenia: deficiency of phenylalanine oxidising system. Proc Soc Exp Biol Med 82: 514–515.

    PubMed  CAS  Google Scholar 

  • Kaufman S (1971) The phenylalanine hydroxylating system from mammalian liver. Adv Enzymol 35: 245–319.

    PubMed  CAS  Google Scholar 

  • Kure S, Hou DC, Ohura T, et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency: a novel clinical entity. J Pediatr 135: 375–378.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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 

  • Matalon R, Koch R, Michals-Matalon K, et al (2004) Biopterin responsive phenylalanine hydroxylase deficiency. Genet Med 6(1): 27–32.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • MRC Working Party on Phenylketonuria (1993) Recommendation on the dietary management of phenylketonuria. Arch Dis Child 68: 426–427.

    Google Scholar 

  • Muntau AC, Roschinger W, Habich M, et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347: 2122–2132.

    Article  PubMed  CAS  Google Scholar 

  • Michals K, Dominick M, Schuett V, Brown E, Matalon R (1985) Return to diet therapy in patients with phenylketonuria. J Pediatr 106: 933–936.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

  • Oldendorf WH, Szabo J (1976) Amino acid assignment to one of three blood–brain barrier amino acid carriers. Am J Physiol 230: 94–98.

    PubMed  CAS  Google Scholar 

  • Pardridge WM (1977) Kinetics of competitive inhibition of neutral amino acid transport across the blood–brain barrier. J Neurochem 28: 103–108.

    Article  PubMed  CAS  Google Scholar 

  • 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.

  • Pardridge WM, Oldendrof WH (1975) Kinetic analysis of blood–brain barrier transport of amino acids. Biochim Biophys Acta 401: 128–136.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Pietz J, Dunckelmann R, Rupp A, et al (1998) Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 157: 824–830.

    Article  PubMed  CAS  Google Scholar 

  • Ris MD, Williams SE, Hunt MM, Berry HK, Leslie N (1994) Early-treated phenylketonuria: adult neuropsychological outcome. J Pediatr 124: 388–392.

    Article  PubMed  CAS  Google Scholar 

  • SAS Institute (2004) SAS/STAT 9.1 User’s Guide. Cary, NC: SAS Institute Inc.

  • 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.

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Thompson AJ, Smith IL, Brenton D, et al (1990) Neurological deterioration in young adults with phenylketonuria. Lancet 336: 602–605.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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 

  • Trefz F, Aulehla-Scholz C, Blau N (2001) Successful treatment of phenylketonuria with tetrahydrobiopterin. Eur J Pediatr 160: 315.

    Article  PubMed  CAS  Google Scholar 

  • Walter JH, White FJ, Hall SK, et al (2002) How practical are recommendations for dietary control in phenylketonuria? Lancet 360: 55–57.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of Texas Medical Branch, Children’s Hospital, Galveston, Texas, USA

    R. Matalon, G. Bhatia & J. Grady

  2. University of Houston, Houston, Texas, USA

    K. Michals-Matalon

  3. Inherited Metabolic Disease Unit and Department of Neuroscience, Neurological Clinic, University Hospital of Padua, Italy

    A. B. Burlina & A. P. Burlina

  4. Diagnósticos Laboratoriais Especializados and Centro Ambulatorial de Prevenção/APAE-Rio de Janeiro, Brazil

    C. Braga

  5. Department of Pediatrics, San Paolo Hospital, University of Milan, Italy

    L. Fiori & M. Giovannini

  6. Institute of Clinical Genetics, Kharkiv State Medical University, Kharkiv, Ukraine

    E. Grechanina

  7. Department of Clinical Genetics, Institute of Pediatrics and Child Surgery, Moscow, Russia

    P. Novikov

  8. University of Texas-Health Science Centre, Houston, Texas, USA

    S. K. Tyring

  9. Kennedy Institute, Glostrup, Denmark

    F. Guttler

Authors
  1. R. Matalon
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  2. K. Michals-Matalon
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  3. G. Bhatia
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  4. A. B. Burlina
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  5. A. P. Burlina
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  6. C. Braga
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  7. L. Fiori
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  8. M. Giovannini
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  9. E. Grechanina
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  10. P. Novikov
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  11. J. Grady
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  12. S. K. Tyring
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  13. F. Guttler
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Corresponding author

Correspondence to R. Matalon.

Additional information

Communicating editor: Verena Peters

Competing interests: None declared

References to electronic databases: Phenylketonuria (PKU; OMIM 261600)

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Matalon, R., Michals-Matalon, K., Bhatia, G. et al. Double blind placebo control trial of large neutral amino acids in treatment of PKU: Effect on blood phenylalanine. J Inherit Metab Dis 30, 153–158 (2007). https://doi.org/10.1007/s10545-007-0556-4

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  • DOI: https://doi.org/10.1007/s10545-007-0556-4

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