*8.5. Tetrahydrobiopterin*

The supplementation of co-factor BH4 in some PKU patients with high residual activity reduced their Phe levels. The metabolic response to BH4 improves the stability of the misfolded PAH enzyme and increases enzyme activity by reducing proteolysis. In 2007, a synthetic form of BH4, sapropterin dihydrochloride, was approved in multiple countries as an adjuvant therapy. The treatment requires that the mutant enzyme possess some amount of residual activity, which is most commonly found in patients with milder forms of PKU. Most patients with severe forms of PKU, in which the enzyme activity is null, do not respond to sapropterin treatment. Sapropterin acts as a molecular chaperone to assist with PAH folding and stability. A reduction in blood Phe of 30% or more from baseline is considered to be a sapropterin response. Chaperone therapy is a promising new approach in the treatment of PKU and HPA [110,121].
