Tetrahydrobiopterin responsiveness in phenylketonuria.: Two new cases and a review of molecular genetic findings

We report two new patients with tetrahydrobiopterin (BH4)-responsive phenylketonuria and compare their phenylalanine hydroxylase (PAH) genotypes (A395P/IVS12+1g>a and R261Q/I65T, respectively) to those of previous cases from the literature. These case observations confirm earlier reports stating that BH4-responsive patients are frequently carriers of a missense mutation within the DNA region coding for the catalytic domain of the enzyme. Interestingly, many of the PAH gene mutations detected in BH4-responsive patients have been associated with an inconsistent phenotype in the past. Our case reports confirm that it is necessary to thoroughly examine individuals with increased phenylalanine levels, not only to detect BH4 deficiency, but also to identify patients with PAH deficiency who may benefit from BH4 treatment. In both of our patients, however, an effect of BH4 (7.5 mg/kg) on plasma phenylalanine levels was not seen in the newborn period. We therefore conclude that a normal neonatal BH4 test does not necessarily exclude BH4 responsiveness in all such patients.