New evidence for assessing tetrahydrobiopterin (BH(4)) responsiveness

To evaluate the protocol we propose for detecting BH(4)-responsive patients and the possibility of delimiting more precisely the population to be tested.

We recruited 102 phenylketonuric patients on a phenylalanine (Phe)-restricted diet. The initial stage of the protocol was a 24-h BH(4) loading test involving Phe loading and subsequent ingestion of the cofactor, a 50% fall in blood Phe levels being considered a positive response. The non-responders at this stage then completed a one-week therapeutic test combining BH(4) administration and daily protein intake meeting recommended dietary allowances, to assess whether the 24-h test had detected all responders.

The 24-h test detected almost all BH(4) responders (30.3% of the 99 patients included in the analysis), with just two patients (2.0%) subsequently responding positively to the therapeutic test. The 24-h test did not give any false positive results.

The 24-h BH(4) loading test is clinically useful for screening phenylketonuric patients. Specifically, 95% of patients with Phe levels <700 μmol/L, and none with Phe levels >1500 μmol/L were BH(4)-responsive. Given these results, we conclude that patients with Phe levels<700 μmol/L or>1500 μmol/L probably do not need to be tested, prioritising the identification of BH(4)-responsiveness among individuals with intermediate Phe concentrations, between the aforementioned values. Additionally, our results suggest that the therapeutic test only needs to be performed in cases where the reduction in blood Phe levels after cofactor administration is within the range 40%-50%.