Background: The outcome in phenylketonuria is related to the early diagnosis and management due to neonatal screening.
Aims: To assess the interest of tetrahydrobiopterin (BH4) loading test and phenylalanine hydroxylase (PAH) genotyping in the management of neonates with hyperphenylalaninemia (HPA).
Study design: We evaluate the effectiveness of a BH4 loading test (20 mg/kg) in ten neonates screened for HPA. We evaluated the time required to reach a target plasma Phenylalanine (Phe) level below 300 micromol/l. We compared these ten BH4-loaded patients to the 10 previous neonates non-loaded with BH4. In all these patients, the PAH genotype was determined.
Results: One loaded patient had biopterin synthesis deficiency and has been retrieved from statistical analysis. All others patients have PAH deficiency. Between the BH4 loaded group (L) and the BH4 non-loaded group (NL), a statistically significant difference was observed in the average time required to reached the target Phe level (13.56 +/- 4.30 (L) vs. 20.6 +/- 7.59 days (NL) [p < 0.02]). Results of the genotyping from all but one of these 19 patients indicated that among all mutations present in this patient population, there were 4 known PAH mutations associated with BH4 responsiveness (p.R261Q, the p.V388 M, the p.E390G and the p.Y414C). These mutations were found in 4 non-loaded and 6 loaded patients. Two patients had a more than 90% reduction in their plasma Phe level within 24 h after the load. One of these patients had a PTPS deficiency. The other fully responsive patient (p.Y414C and IVS10-11G>A) has been treated with BH4 from birth with an excellent metabolic control for three years now.
Conclusion: BH4 loading test improves the management of HPA. It allows an immediate identification of the children fully responsive to BH4. Our results therefore suggest the incorporation of BH4 loading test in the management of neonates screened for HPA.