A hypothesis on the biochemical mechanism of BH4-responsiveness in phenylalanine hydroxylase deficiency

We describe six children with tetrahydrobiopterin (BH4) responsive phenylalanine hydroxylase (PAH) deficiency. All patients carry two mutant alleles in the PAH gene. Cofactor deficiency was excluded. The effect of BH4 administration was studied by correlating different oral BH4 doses with plasma phenylalanine levels under defined protein intake. Our results indicate that oral BH4 supplementation may be used as long-term treatment for individuals with BH4-responsive PAH deficiency, either without or in combination with a less restrictive diet. Previous in vitro studies have demonstrated that BH4 inhibits PAH tetramers but activates PAH dimers. This may indicate, that BH4-responsiveness results from BH4 induced stabilization of mutant PAH dimers. In addition, interindividual differences in the cellular folding apparatus may determine the tertiary structure and the amount of mutant PAH dimers and hence may account for divergent BH4-responsiveness reported for the same PAH genotype.