Skip to main content
SpringerLink
Log in

Atypical cases of phenylketonuria

  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Conclusion

Neonatal HPA can be caused by deficiency of PAH or of its cofactor. At present, conventional methods are not able to delineate the molecular basis of the mutations in PKU patients. DNA analysis might in future visualize the different genotypes, but might not solve the problem of therapeutic decision.

All infants with HPA should be screened for THB deficiency. Diagnostic tools are now available for the recognition of these variants among hyperphenylalaninemic infants. The most important question-which infants can achieve normal development if treated early-remains tobe answered. Efforts have to be directed toward better characterization of individual residual capacity to synthesize THB and toward and definition of protocols for the follow-up of neurotransmitter replacement therapy.

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

PKU:

phenylketonuria

HPA:

hyperphenylalaninemia

PAH:

phenylalanine hydroxylase

DHPR:

dihydropteridine reductase

BS:

biopterin synthetase

THB:

tetrahydrobiopterin

GTP:

guanosine triphosphate

GTP-ch:

GTP-cyclohydrolase

N/B ratio:

neopterin/biopterin ratio

References

  1. Bartholomé K (1974) A new molecular defect in phenylketonuria. Lancet II:1580

    Google Scholar 

  2. Bartholomé K, Byrd DJ (1975) l-Dopa and 5-hydroxytryptophan therapy in phenylketonuria with normal phenylalanine-hydroxylase activity. Lancet II:1042–1043

    Google Scholar 

  3. Bartholomé K, Lutz P, Bickel H (1975) Determination of phenylalanine hydroxylase activity in patients with phenylketonuria and hyperphenylalaninemia. Pediatr Res 9:899–903

    Google Scholar 

  4. Bartholomé K, Olek K, Trefz F (1984) Compound heterozygotes in hyperphenylalaninemia. Hum Genet 65:405–406

    Google Scholar 

  5. Beck B, Brandt NJ, Christensen F, Niederwieser A, Pedersen PS (1983) Diagnostic and therapeutic aspects of dihydrobiopterin deficiency. Acta Paediatr Scand 72:449–454

    Google Scholar 

  6. Berry MK, Hsieh M, Bofinger MK, Schubert WK (1982) Diagnosis of phenylalanine hydroxylase deficiency (phenylketonuria). Am J Dis Child 136:111–114

    Google Scholar 

  7. Blaskovics ME, Schaeffler GE, Hack S (1974) Phenylalaninemia. Differential diagnosis. Arch Dis Child 49:835–843

    Google Scholar 

  8. Blitzer MG, Bailey-Wilson JE, Shapira E (1985) Discrimination of phenylketonurics from persistent hyperphenylalaninemia patients using a simple phenylalanine loading test. Clin Chim Acta 153:137–142

    Google Scholar 

  9. Clemens P, Gruttner R (1985) Transient defect in the synthesis of biopterin. J Pediatr 107:312–313

    Google Scholar 

  10. Cotton RGH, Jennings I, Bracco G, Ponzone A, Guardamagna O (1986) Tetrahydrobiopterin non-responsiveness in dihydropteridine reductase deficiency is associated with the presence of mutant protein. J Inherited Metab Dis 9:239–243

    Google Scholar 

  11. Curtius HC, Niederwieser A, Viscontini M, Otten A, Schaub J, Scheibenreiter S, Schmidt H (1979) Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin and sepiapterin. Clin Chim Acta 93:251–262

    Google Scholar 

  12. Danks DM, Bartholomé K, Clayton BE, Curtius H-C, Gröbe H, Kaufman S, Leeming R, Pfleiderer W, Rembold H, Rey F (1978) Malignant hyperphenylalaninaemia — current status (June 1977). J Inherited Metab Dis 1:49–53

    Google Scholar 

  13. Dhondt JL (1984) Tetrahydrobiopterin deficiencies. Preliminary analysis from an international survey J Pediatr 104:501–508

    Google Scholar 

  14. Dhondt JL (1986) Tetrahydrobiopterin deficiency. Analysis from an international survey. In: Cooper BA, Whitehead VM (eds) Chemistry and biology of pteridines. de Gruyter, New York, pp 385–390

    Google Scholar 

  15. Dhondt JL, Farriaux JP (1981) Hepatic phenylalanine hydroxylase activity in hyperphenylalaninemia. J Inherited Metab Dis 5: 59–60

    Google Scholar 

  16. Dhondt JL, Delcroix M, Farriaux JP (1981) Unconjugated pteridines in human milk. Clin Chim Acta 121:33–35

    Google Scholar 

  17. Dhondt JL, Largillière C, Farriaux JP (1983) Essai de classification des hyperphénylalaninémies. A propos de 62 malades. Arch Fr Pédiat 40:243–246

    Google Scholar 

  18. Dhondt JL, Farriaux JP Leroux B, Lyon ICT (1983) Dihydrobiopterin-synthetase deficiency. In: Curtius HC, Pfleiderer W, Wachter H (eds) Biochemical and clinical aspects of pteridines. de Gruyter, Berlin, pp 318–324

    Google Scholar 

  19. Dhondt JL, Leroux B, Farriaux JP, Largillière C, Leeming RJ (1983) Dihydrobiopterin biosynthesis deficiency. Eur J Pediatr 141:92–95

    Google Scholar 

  20. Firgaira FA Choo KH, Cotton RGH, Danks DM (1981) Heterogeneity of the molecular defect in human dihydropteridine reductase deficiency. Biochem J 198:677–682

    Google Scholar 

  21. Güttler F (1980) Hyperphenylalaninemia. Diagnosis and classification of the various types of phenylalanine hydroxylase deficiency in childhood. Acta Paediatr Scand 280:1–80

    Google Scholar 

  22. Güttler F, Lou H, Lykkelund C, Niederwieser A (1984) Combined tetrahydrobiopterin-phenylalanine loading test in the detection of partially defective biopterin synthesis. Eur J Pediatr 142: 126–129

    Google Scholar 

  23. Hoganson G, Berlow S, Kaufman S, Milstien S, Schuett V, Matalon R, Naylor E, Seifert W (1984) Biopterin synthesis defects: problems in diagnosis. Pediatrics 74:1004–1011

    Google Scholar 

  24. Hreidarsson S, Valle D, Holtzman N, Coyle J, Singer H, Kapatos G, Kaufman S (1982) A peripheral defect in biopterin synthesis: a new mutant? Pediatr Res 16:192A

    Google Scholar 

  25. Kaufman S, Kapatos G, McInnes RR, Schulman JD, Rizzo WB (1982) Use of tetrahydropterins in the treatment of hyperphenylalaninemia due to defective synthesis of tetrahydrobiopterin: evidence that peripherally administered tetrahydropterins enter the brain. Pediatrics 70:376–380

    Google Scholar 

  26. Largillière C, Dhondt JL, Farriaux JP (1986) Hepatic phenylalanine hydroxylase and dietary tolerance in hyperphenylalaninemic patients. J Inherited Metab Dis 9 [Suppl 2]:209–211

    Google Scholar 

  27. Lehman WD, Heinrich HC (1985) Oral versus intravenous l-phenylalanine loading compared by simultaneous application of l-[-2H5] and l-[-15N]phenylalanine. Clin Chim Acta 147:261–266

    Google Scholar 

  28. Leupold D, Wang M, Niederwieser A (1982) Tetrahydrobiopterin monotherapy in two siblings with dihydrobiopterin deficiency. In: Wachter H, Curtius H-C, Pfleiderer W (eds) Biochemical and clinical aspects of pteridines, de Gruyter, Berlin, pp 307–317

    Google Scholar 

  29. Lutz P, Schmidt H, Frey G, Bickel H (1982) Standardized loading test with protein for the differentiation of phenylketonuria from hyperphenylalaninaemia. J Inherited Metab Dis 5:29–35

    Google Scholar 

  30. Matalon R (1984) Current status of biopterin screening. J Pediatr 104:579–581

    Google Scholar 

  31. Matalon R, Matthews DE, Michals K, Bier D (1982) The use of deuterated phenylalanine for the in vivo assay of phenylalanine hydroxylase activity in children J Inherited Metab Dis 5:17–19

    Google Scholar 

  32. Nakabayashi H, Owada M, Kitigawa I (194) A mild case of dihydropteridine reductase deficiency with residual activity in erythrocytes. J Inherited Metab Dis 7:135–136

    Google Scholar 

  33. Niederwieser A, Curtius H-C, Wang M, Leupold D (1982) Atypical phenylketonuria with defective biopterin metabolism. Monotherapy with tetrahydrobiopterin or sepiapterin, screening and study of biosynthesis in man. Eur J Pediatr 138:110–112

    Google Scholar 

  34. Niederwieser A, Leimbacher W, Curtius H-C, Ponzone A, Rey F, Leupold D (1985) Atypical phenylketonuria with “dihydrobiopterin synthetase” deficiency: absence of phosphate-eliminating enzyme activity demonstrated in liver. Eur J Pediatr 144:13–16

    Google Scholar 

  35. Rampini S, Völlmin JA, Bosshard HR, Müller M, Curtius H-C (1974) Aromatic acids in urine of healthy infants, persistent hyperphenylalaninemia, and phenylketonuria, before and after phenylalanine load. Pediatr Res 8:704–709

    Google Scholar 

  36. Rey F, Blandin-Sajova F, Rey J (1979) Kinetics of phenylalanine disappearance after intravenous load in phenylketonuria and its genetic variants. Pediatr Res 13:21–25

    Google Scholar 

  37. Rey F, Saudubray JM, Leeming RJ, Nierderwieser A, Curtius H-C, Rey J (1983) Les déficits partiels en tétrahydrobioptérine. Arch Fr Pediatr 40:237–241

    Google Scholar 

  38. Sawada Y, Shintaku H, Isshiki G, Hase Y, Tsuruhara T, Oura T (1984) Transient neonatal hyperphenylalaninemia due to immature development of 7,8-dihydrobiopterin synthesis. Acta Paediatr Jpn 26:561–564

    Google Scholar 

  39. Scriver CR, Clow CL, Kaplan P, Watters GV, Laberge C, Mohyuddin F, Milstien S (1986) Defective biopterin synthesis in a Chinese infant. In: Cooper BA, Whitehead VM (eds) Chemistry and biology of pteridines. de Gruyter, New York, pp 403–406

    Google Scholar 

  40. Smith I, Dhondt JL (1985) Birthweight in patients with defective biopterin synthesis. Lancet I:818

    Google Scholar 

  41. Smith I, Clayton BE, Wolff OH (1975) New variant of phenylketonuria with progressive neurological illness unresponsive to phenylalanine restriction. Lancet I:1108–1111

    Google Scholar 

  42. Smith I, Leeming RJ, Cavanagh NPC, Hyland K (1986) Neurological aspects of biopterin metabolism. Arch Dis Child 61:130–137

    Google Scholar 

  43. Takahashi T, Kodama S, Nishio H, Takumi T, Matsuo T, Hase Y, Sawada Y (1985) Transient hyperphenylalaninemia with a high neopterin to biopterin ratio in urine. J Inherited Metab Dis 8:105–108

    Google Scholar 

  44. Trefz FK, Bartholomé K, Bickel H, Lutz P, Schmidt H, Seyberth HW (1981) In vivo residual activities of the phenylalanine hydroxylating system in phenylketonuria and variants. J Inherited Metab Dis 4:101–102

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratoire de Biochimie, Faculté Libre de Médecine, 56 rue du Port, F-59046, Lille Cédex, France

    J. -L. Dhondt

  2. Service de Génétique et Maladies Héréditaires de Métabolisme, Lille, France

    J. -P. Farriaux

Authors
  1. J. -L. Dhondt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. -P. Farriaux
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dhondt, J.L., Farriaux, J.P. Atypical cases of phenylketonuria. Eur J Pediatr 146, A38–A43 (1987). https://doi.org/10.1007/BF00442055

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00442055

Key words

Search

Navigation