Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates

L.J.M. Spaapen*, J.A. Bakker, C. Velter, W. Loots, M.E. Rubio-Gozalbo, Ph. Forget, L. Dorland, T.J. de Koning, B.T. the Poll, H.K. van Ploos Amstel, J. Bekhof, N. Blau, M. Duran

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates.

Spaapen LJ, Bakker JA, Velter C, Loots W, Rubio-Gonzalbo ME, Forget PP, Dorland L, De Koning TJ, Poll-The BT, Ploos van Amstel HK, Bekhof J, Blau N, Duran M.

Department of Biochemical Genetics, Stichting Klinische Genetica Zuid-Oost Nederland, Maastricht. leo.spaapen@gen.unimaas.nl

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 - 1 Jan 2001

Cite this