Abstract
Four neonates with a positive phenylalanine screening test (Phe concentrations between 258 and 1250 μmol/L) were investigated further to differentiate between phenylalanine hydroxylase (PAH) deficiency and variant hyperphenylalaninaemia (HPA) forms. In patients 1 and 2 a tetrahydrobiopterin (BH4) load caused a significant decrease of the plasma Phe levels. A combined phenylalanine/BH4 loading test was performed in patients 2, 3 and 4. In the latter two patients, plasma Phe concentrations completely normalized within 8 h after the BH4 load (20 mg/kg). Basal urinary pterins were normal in all four patients. The activity of dihydropteridine reductase (DHPR) was normal in patients 1, 2 and 3 and 50% of control values in patient 4 (not in the range of DHPR-deficient patients). In patient 3 a subsequent phenylalanine loading test with concomitant analysis of plasma biopterins revealed a normal increase of biopterin, excluding a BH4 biosynthesis defect. Pterins and neurotransmitter metabolites in CSF of patients 1, 3 and 4 were normal. DNA mutations detected in the PAH gene of patients 1–4 were A313T, and L367fsinsC; V190A and R243X; A300S and A403V; R241C and A403V. The results are suggestive for mutant PAH enzymes with decreased affinity for the cofactor BH4.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
Blau N, Blaskovics ME (1996) Hyperphenylalaninemia. In Blau N, Duran M, Blaskovics ME, eds. Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases. London: Chapman and Hall Medical, 65-78.
Blau N, Thöny B, Renneberg A, et al (1999) Variant of dihydropteridine reductase deficiency without hyperphenylalaninemia: effect of oral phenylalanine loading. J Inherit Metab Dis 22: 216-220.
Bonafé L, Thöny B, Leimbacher W, Kierat L, Blau N. (2001) Diagnosis of Dopa-responsive dystonia and other tetrahydrobiopterin disorders by the study of biopterin metabolism in fibroblasts. Clin Chem 47: 477-485.
Fukushima T, Nixon JC (1980) Analysis of reduced forms of biopterin in biological tissues and fluids. Anal Biochem 102: 176-188.
Kure S, Hou D-C, Ohura T, et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135: 375-378.
Mallolas J, Vilaseca MA, Campistol J, et al (1999) Mutational spectrum of phenylalanine hydroxlase deficiency in the population resident in Catalonia: genotype-phenotype correlation. Hum Genet 105: 468-473.
Nixon JC, Lee Ch-L, Milstien S, Kaufman S, Bartholome K. (1980). Neopterin and biopterin levels in patients with atypical forms of phenylketonuria. J Neurochem 35: 898-904.
Ponzone A, Guardamagna O, Spada M, et al (1993) Differential diagnosis of hyperphenylalaninaemia by a combined phenylalanine-tetrabiopterin loading test. Eur J Pediatr 152: 655-661.
Scriver CR, Kaufman S, Eisensmith RC, Woo SLC (1995) The hyperphenylalaninemias. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th edn. New York: McGraw-Hill, 1015-1075.
Surplice IM, Griffiths PD, Green A, Leeming RJ (1990). Dihydropteridine reductase activity in eluates from dried blood spots: automation of an assay for a national screening service. J Inherit Metab Dis 13: 169-177.
van der Sijs-Bos CJ, Diepstraten CM, Juyn JA, et al 1996. Phenylketonuria in the Netherlands: 93% of the mutations are detected by single-strand conformational analysis. Hum Hered 46: 185-190.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Spaapen, L.J.M., Bakker, J.A., Velter, C. et al. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates. J Inherit Metab Dis 24, 352–358 (2001). https://doi.org/10.1023/A:1010596317296
Issue Date:
DOI: https://doi.org/10.1023/A:1010596317296