Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates

L J Spaapen, J A Bakker, C Velter, W Loots, M E Rubio-Gozalbo, P P Forget, L Dorland, T J De Koning, B T Poll-The, H K Ploos van Amstel, J Bekhof, N Blau, M Duran, M E Rubio-Gonzalbo

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Four neonates with a positive phenylalanine screening test (Phe concentrations between 258 and 1250 micromol/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.

Original languageEnglish
Pages (from-to)352-358
Number of pages7
JournalJournal of Inherited Metabolic Disease
Issue number3
Publication statusPublished - Jun-2001
Externally publishedYes


  • Biopterin
  • DNA Mutational Analysis
  • Diagnosis, Differential
  • Dihydropteridine Reductase
  • Female
  • Humans
  • Infant, Newborn
  • Kinetics
  • Mutation
  • Netherlands
  • Phenylalanine
  • Phenylalanine Hydroxylase
  • Polymorphism, Single-Stranded Conformational
  • Pterins
  • Case Reports
  • Journal Article
  • Research Support, Non-U.S. Gov't

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