title: Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates.
abstract: 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.
authors.affiliation: Department of Biochemical Genetics, Stichting Klinische Genetica Zuid-Oost Nederland, Maastricht. leo.spaapen@gen.unimaas.nl
authors.forename: L J
authors.initials: LJ
authors.lastname: Spaapen
authors.forename: J A
authors.initials: JA
authors.lastname: Bakker
authors.forename: C
authors.initials: C
authors.lastname: Velter
authors.forename: W
authors.initials: W
authors.lastname: Loots
authors.forename: M E
authors.initials: ME
authors.lastname: Rubio-Gozalbo
authors.forename: P P
authors.initials: PP
authors.lastname: Forget
authors.forename: L
authors.initials: L
authors.lastname: Dorland
authors.forename: T J
authors.initials: TJ
authors.lastname: De Koning
authors.forename: B T
authors.initials: BT
authors.lastname: Poll-The
authors.forename: H K
authors.initials: HK
authors.lastname: Ploos van Amstel
authors.forename: J
authors.initials: J
authors.lastname: Bekhof
authors.forename: N
authors.initials: N
authors.lastname: Blau
authors.forename: M
authors.initials: M
authors.lastname: Duran
authors.forename: M E
authors.initials: ME
authors.lastname: Rubio-Gonzalbo
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D004093:Dihydropteridine Reductase / Q000378:metabolism; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007700:Kinetics; D009154:Mutation; D009426:Netherlands; D010649:Phenylalanine / Q000097:blood; D010651:Phenylalanine Hydroxylase / Q000172:deficiency* / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011622:Pterins / Q000134:cerebrospinal fluid / Q000652:urine
chemical_list: D011622:Pterins; D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; D004093:Dihydropteridine Reductase; C003402:sapropterin