Skip to main content
SpringerLink
Log in

Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria

  • BH4 and PKU
  • Published:
Journal of Inherited Metabolic Disease

Summary

Background

The value of genotyping to identify tetrahydrobiopterin-responsive (BH4-responsive) patients with phenylalanine hydroxylase (PAH) deficiency is a matter of debate.

Methods

We reviewed 250 cases of patients with PAH deficiency, using published data from 198 cases and unpublished data from 52 cases of patients attending our own clinic. Patients underwent analyses for BH4 load and genetic mutations. Partial and full BH4 responses were defined as a 10–29% decrease and a ≥30% decrease from baseline in blood phenylalanine levels, respectively. BH4-responsive alleles were identified from BH4-responsive patients as either homozygous for a specific allele or compound heterozygous for that allele with a null mutation.

Results

Most inconsistencies between observed genotype and BH4 response were associated with mutations in the regulatory domain of PAH (p.R68S, p.I65T, p.L48S and p.F39C), where 20/62 alleles (32.2%) were non-responsive. In the catalytic domain (mutations p.Y414C, p.R261Q, p.E390G, p.A300S, p.R241C, p.A403V and p.V388M), only 8/125 alleles (6.4%) were non-responsive. Seven patients had a genotype with two BH4-responsive alleles resulting in no response or only a partial response to BH4. Ten patients had identical genotypes but inconsistent responses in BH4 load.

Conclusions

These results show that BH4 non-responsiveness is associated with genotype. However, patients with mutations in the regulatory domain show inconsistent results. In patients with two responsive alleles, non-responsiveness may be related to negative inter-allelic complementation. In patients with the same genotype and inconsistent results for BH4 load, external factors such as intestinal absorption of BH4, catabolic conditions or other genetic factors may be responsible. Further in vitro studies are necessary to clarify the genotype–phenotype correlation in patients with BH4-responsive PKU.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BH4 :

tetrahydrobiopterin

PAH:

phenylalanine hydroxylase

Phe:

phenylalanine

PKU:

phenylketonuria

References

  • Blau N, Bernegger C, Trefz FK (Mar 2003) Tetrahydrobiopterin-responsive hyperphenylalaninaemia due to homozygous mutations in the phenylalanine hydroxylase gene. Eur J Pediatr 162(3): 196.

    PubMed  Google Scholar 

  • Baldellou-Vázquez A, Salazar García-Blanco MI, Ruiz-Echarri Zalaya MP, et al (2006) Tetrahydrobiopterin therapy for hyperphenylalaninemia due to phenylalanine hydroxylase deficiency. When and how? An Pediatr (Barc) 64: 146–152. doi:10.1157/13084174.

    Article  Google Scholar 

  • Bardelli T, Donati MA, Gasperini S, et al (2002) Two novel genetic lesions and a common BH4-responsive mutation of the PAH gene in Italian patients with hyperphenylalaninemia. Mol Genet Metab 77(3): 260–266. doi:10.1016/S1096-7192(02)00166-X.

    Article  PubMed  CAS  Google Scholar 

  • Desviat LR, Pérez B, Bèlanger-Quintana A, et al (2004) Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype. Mol Genet Metab 83: 157–162. doi:10.1016/j.ymgme.2004.06.007.

    Article  PubMed  CAS  Google Scholar 

  • Dipple KM, McCabe ER (2000) Modifier genes convert “simple” Mendelian disorders to complex traits. Mol Genet Metab 71: 43–50. doi:10.1006/mgme.2000.3052.

    Article  PubMed  CAS  Google Scholar 

  • Erlandsen H, Pey AL, Gámez A, et al (2004) Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc Natl Acad Sci U S A 101(48): 16903–16908. doi:10.1073/pnas.0407256101.

    Article  PubMed  CAS  Google Scholar 

  • Fiege B, Ballhausen D, Kierat L, et al (2004) Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration. Mol Genet Metab 81(1): 45–51. doi:10.1016/j.ymgme.2003.09.014.

    Article  PubMed  CAS  Google Scholar 

  • Fiege B, Bonafé L, Ballhausen D, et al (2005) Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria: a pilot study. Mol Genet Metab 86(Supplement 1): S91–95. doi:10.1016/j.ymgme.2005.09.014.

    Article  PubMed  CAS  Google Scholar 

  • Hennermann JB, Bührer C, Blau N, et al (2005) Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab 86(Supplement 1): S86–90. doi:10.1016/j.ymgme.2005.05.013.

    Article  PubMed  CAS  Google Scholar 

  • Kaufman S (1976) Phenylketonuria: biochemical mechanisms. Adv Neurochem 2: 1–132.

    Google Scholar 

  • Kure S, Hou DC, Ohura T, et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135(3): 375–378. doi:10.1016/S0022-3476(99)70138-1.

    Article  PubMed  CAS  Google Scholar 

  • Lässker U, Zschocke J, Blau N, et al (2002) Tetrahydrobiopterin responsiveness in phenylketonuria. Two new cases and a review of molecular genetic findings. J Inherit Metab Dis 25(1): 65–70. doi:10.1023/A:1015194002487.

    Article  PubMed  Google Scholar 

  • Leandro J, Nascimento C, de Almeida IT, et al (2006) Co-expression of different subunits of human phenylalanine hydroxylase: evidence of negative interallelic complementation. Biochim Biophys Acta 1762: 544–550.

    PubMed  CAS  Google Scholar 

  • Lee DH, Koo SK, Lee KS, et al (2004) The molecular basis of phenylketonuria in Koreans. J Hum Genet 49(11): 617–621. doi:10.1007/s10038-004-0197-5.

    Article  PubMed  CAS  Google Scholar 

  • Leuzzi V, Carducci C, Carducci C, et al (2006) The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency. J Inherit Metab Dis 29: 38–46. doi:10.1007/s10545-006-0096-3.

    Article  PubMed  CAS  Google Scholar 

  • Levy HL, Milanowski A, Chakrapani A, et al (2007a) Sapropterin Research Group. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 370: 504–510. doi:10.1016/S0140-6736(07)61234-3.

    Article  PubMed  CAS  Google Scholar 

  • Levy H, Burton B, Cederbaum S, et al (2007b) Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria and its use in treatment. Mol Genet Metab 92: 287–291. doi:10.1016/j.ymgme.2007.09.017.

    Article  PubMed  CAS  Google Scholar 

  • Lindner M, Steinfeld R, Burgard P, et al (2003) Tetrahydrobiopterin sensitivity in German patients with mild phenylalanine hydroxylase deficiency. Hum Mutat 21: 400. doi:10.1002/humu.9117.

    Article  PubMed  CAS  Google Scholar 

  • Martinez MA. PAH as misfolding disease. International Conference on tetrahydrobiopterin, PKU and NOS. March 23–28 2008, St. Moritz-Champfer, Switzerland.

  • Matalon R, Michals-Matalon K, Koch R, et al (2005) Response of patients with phenylketonuria in the US to tetrahydrobiopterin. Mol Genet Metab 86(Supplement 1): S17–21. doi:10.1016/j.ymgme.2005.06.024.

    Article  PubMed  CAS  Google Scholar 

  • Milstien S, Kaufman S (1975) Studies on the phenylalanine hydroxylase system in liver slices. J Biol Chem 250(12): 4777–4781.

    PubMed  CAS  Google Scholar 

  • Muntau AC, Röschinger W, Habich M, et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347: 2122–2132. doi:10.1056/NEJMoa021654.

    Article  PubMed  CAS  Google Scholar 

  • Pérez-Dueñas B, Vilaseca MA, Mas A, et al (2004) Tetrahydrobiopterin responsiveness in patients with phenylketonuria. Clin Biochem 37: 1083–1090. doi:10.1016/j.clinbiochem.2004.09.005.

    Article  PubMed  Google Scholar 

  • Pey AL, Desviat LR, Gámez A, et al (2003) Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum Mutat 21(4): 370–378. doi:10.1002/humu.10198.

    Article  PubMed  CAS  Google Scholar 

  • Pey AL, Pérez B, Desviat LR, et al (2004) Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations. Hum Mutat 24(5): 388–399. doi:10.1002/humu.20097.

    Article  PubMed  CAS  Google Scholar 

  • Scriver CR, Kaufman S (2001) Hyperphenylalaninemia: 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 

  • Shintaku H, Kure S, Ohura T, et al (2004) Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene. Pediatr Res 55: 425–430. doi:10.1203/01.PDR.0000111283.91564.7E.

    Article  PubMed  CAS  Google Scholar 

  • Shintaku H, Fujioka H, Sawada Y, et al (2005) Plasma biopterin levels and tetrahydrobiopterin responsiveness. Mol Genet Metab 86(Supplement 1): S104–106. doi:10.1016/j.ymgme.2005.06.018.

    Article  PubMed  CAS  Google Scholar 

  • Töpel T, Scholz U, Mischke U, et al (2002) Supporting genotype–phenotype correlation with the rare metabolic diseases database Ramedis. Silico Biol 2(3): 407–414.

    Article  Google Scholar 

  • Trefz FK, Scheible D, Frauendienst-Egger G, et al (2005) Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin. Mol Genet Metab 86(Supplement 1): S75–80. doi:10.1016/j.ymgme.2005.06.026.

    Article  PubMed  CAS  Google Scholar 

  • Zurflüh MR, Zschocke J, Lindner M, et al (2008) Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat 29(1): 167–175. doi:10.1002/humu.20637.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik für Kinder und Jugendmedizin Kreiskliniken Reutlingen GmbH, Steinenbergstrasse 31, 72764, Reutlingen, Germany

    F. K. Trefz, D. Scheible & G. Frauendienst-Egger

  2. Software Service GmbH, Schwabach, Germany

    H. Götz

Authors
  1. F. K. Trefz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Scheible
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Götz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Frauendienst-Egger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F. K. Trefz.

Additional information

Communicating editor: Nenad Blau

Competing interests: F. K. Trefz is a member of the scientific advisory board for PKU supported by Merck Serono International S.A., Geneva, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trefz, F.K., Scheible, D., Götz, H. et al. Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria. J Inherit Metab Dis 32, 22–26 (2009). https://doi.org/10.1007/s10545-008-0940-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-008-0940-8

Keywords

Search

Navigation