Effect of tetrahydrobiopterin on Phe/Tyr ratios and variation in Phe levels in tetrahydrobiopterin responsive PKU patients

Background: Whilst a reduction in blood phenylalanine (Phe) levels is essential in patients with PKU, a decrease in Phe/Tyrosine (Tyr) ratio and fluctuations in blood Phe levels over time have been recently associated with improved neuropsychological outcome. The aim of this study was to identify if Tetrahydrobiopterin (BH(4)) offers additional benefit based on the assumption that these 2 factors are beneficial.

Method: Since 2002, 9 patients identified through NBS as BH(4) responsive (BH(4) group) and 25 non-responsive patients (non-BH(4) group) produced a total of 1384 and 4415 samples, respectively, for analysis. Statistical analysis was performed to compare mean and median Phe levels, Tyr levels and Phe/Tyr ratios in BH(4) and non BH(4) responsive patients.

Results: Variations in blood Phe levels were greater in the non-BH(4) group (BH(4): median 338 μmol/L, 95% Confidence Interval (CI) 329-346, mean: 358 μmol/L, CI 350-366; non-BH(4): median 338 μmol/L CI 332-344, mean: 370 μmol/L CI 364-376). Variations in blood Tyr levels were slightly greater in the non-BH(4) group: (BH(4): median 59 μmol/L CI 58-61, mean 67 CI 66-69; non-BH(4): median 62 μmol/L CI 61-63, mean 70 CI 69-71). The variation in Phe/Tyr ratios was greater in the non-BH(4) group (mean 6.12, CI 5.9-6.3) than in the BH(4) group (Mean 5.44, CI 5.3-5.6), particularly at blood Phe levels >600 μmol/L.

Conclusion: BH(4) responsive patients have smaller variations in blood Phe levels and tighter Phe/Tyr ratios than non-BH(4) responsive patients, particularly at high blood Phe levels. If decreased fluctuations in Phe levels and a decreased Phe/Tyr ratio are indeed neuro-protective, then BH(4) responsiveness is advantageous over diet alone in PKU. Neuropsychological testing in patients who have been treated with BH(4) long term may be able to ascertain the clinical benefit of these biochemical findings.