High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002.

Tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia (HPA) is a recently described variant of phenylalanine hydroxylase deficiency. In contrast to patients with classical phenylketonuria, these patients respond to BH(4) loading tests (20mg/kg) with decrease of plasma phenylalanine levels 4 and 8 h after administration and they can be treated with BH(4) monotherapy. We retrospectively evaluated 1,919 loading tests from 33 different countries performed in our laboratory between 1988 and 2002 of which 278 loading tests were performed with 6R-BH(4), which is about 33% more active than the formerly used 6R,S-BH(4). The loading tests were performed between the ages of one week and 4.6 years, using 2.6-30.0 mg 6R,S- or 6R-BH(4)/kg. Plasma phenylalanine levels before the test ranged from 121 to 4,705 micromol/L. We calculated the phenylalanine "hydroxylation rate" 4 and 8 h after BH(4) administration and plotted the slope of the hydroxylation rate against the phenylalanine levels at time 0. The slope was greater than 3.75 in 65, 74, 33, 17, 0, and 10% of patients with basal phenylalanine levels of 120-400, 400-800, 800-1,200, 1,200-1,600, 1,600-2,200, and >2,200 micromol/L, respectively, when loaded with 20 mg 6R-BH(4)/kg (p>0.0001). This is 5-20 times higher compared with tests using 6R,S-BH(4) or lower doses of BH(4). More than 70% of patients with mild HPA (<800 micromol/L) are found to be BH(4) responders. Therapy with BH(4) (approximately 10mg/kg/day) was initiated in several patients instead of a low-phenylalanine diet, resulting in much better treatment compliance. Our data further demonstrate that BH(4) loading tests can only distinguish between BH(4) responders and non-responders. To differentiate between BH(4) and phenylalanine hydroxylase deficiencies additional tests are essential.