Summary
Background:
Tetrahydrobiopterin (BH4) is a potential new orphan drug for the treatment of some patients with phenylketonuria (PKU), mostly mild forms. Numerous studies have confirmed this finding and BH4-responsiveness may be predicted to some extent from the corresponding genotype.
Aim:
To investigate the response to BH4 loading test, the phenylalanine hydroxylase (PAH) mutations and the long-term therapeutic efficacy of BH4 in patients with PKU, and to better define BH4-responsive patients according to phenylalanine (Phe) levels and dietary phenylalanine tolerance.
Methods:
30 Italian PKU patients (age range: 6 months–24 years; 12 female, 18 male) were included in this retrospective study. Eleven out of 30 patients presented with Phe levels below 450 μmol/L and 19 patients with Phe levels between 450 and 900 μmol/L. In the second group, we investigated the effect of long-term (6 months–7 years) oral administration of BH4 on blood Phe levels and daily Phe tolerance.
Results:
In all patients with initial blood Phe levels <450 μmol/L (n = 11), BH4 loading test was positive, but no treatment was introduced. In 12 out of 19 patients with blood Phe levels >450 μmol/L and positive at BH4 loading, the treatment with BH4 (10 mg/kg per day) was initiated. Before BH4 treatment, Phe tolerance was less than 700 mg/day in all patients except for one (patient no. 9), increasing to 2–3-fold (from 498 ± 49 to 1475 ± 155 mg/day) on BH4 treatment. In these patients the amino acid mixture supplementation was stopped and the diet was a combination of low-protein foods and natural proteins, mostly from animal sources.
Conclusion:
Long-term BH4 substitution (up to 7 years) in a group of moderate PKU patients allowed a substantial relaxation of the dietary restrictions or even replacement of the diet with BH4 without any adverse effects.
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Abbreviations
- 6RBH4 :
-
(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin
- BH4:
-
tetrahydrobiopterin
- HPA:
-
hyperphenylalaninaemia
- PAH:
-
phenylalanine hydroxylase
- Phe:
-
phenylalanine
- PKU:
-
phenylketonuria
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Acknowledgements
Supported by Centro Regionale Malattie Metaboliche Ereditarie, Regione Veneto and COMETA-ASMME, Italy and in part by the Swiss National Science Foundation Grant.
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Communicating editor: John Walter
Competing interests: None declared
References to electronic databases: Phenylalanine-4-hydroxylase: EC 1.14.16.1.
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Burlina, A., Blau, N. Effect of BH4 supplementation on phenylalanine tolerance. J Inherit Metab Dis 32, 40–45 (2009). https://doi.org/10.1007/s10545-008-0947-1
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DOI: https://doi.org/10.1007/s10545-008-0947-1