Tetrahydrobiopterin treatment in phenylketonuria: A repurposing approach

Abstract

In phenylketonuria (PKU) patients, early diagnosis by neonatal screening and immediate institution of a phenylalanine‐restricted diet can prevent severe intellectual impairment. Nevertheless, outcome remains suboptimal in some patients asking for additional treatment strategies. Tetrahydrobiopterin (BH4) could be one of those treatment options, as it may not only increase residual phenylalanine hydroxylase activity in BH4‐responsive PKU patients, but possibly also directly improves neurocognitive functioning in both BH4‐responsive and BH4‐unresponsive PKU patients. In the present review, we aim to further define the theoretical working mechanisms by which BH4 might directly influence neurocognitive functioning in PKU having passed the blood‐brain barrier. Further research should investigate which of these mechanisms are actually involved, and should contribute to the development of an optimal BH4 treatment regimen to directly improve neurocognitive functioning in PKU. Such possible repurposing approach of BH4 treatment in PKU may improve neuropsychological outcome and mental health in both BH4‐responsive and BH4‐unresponsive PKU patients.

Influencing Factors on the Use of Tetrahydrobiopterin in Patients with Phenylketonuria

“…In 1999, Kure et al [ 10 ] found a reduced blood Phe concentration after the oral administration of BH4. BH4-responsive PAH deficiency is divided into complete responders and partial responders [ 11 ]. The complete responder means that the blood Phe concentration of patients can reach normal levels after BH4 medication, whereas the partial responder fails to reach the normal range.…”

Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock‐in mouse model

“…19 Indeed, it has been proposed that in addition to increasing residual PAH activity in BH 4 -responsive PKU patients, BH 4 may also improve neurocognitive functioning and thus also be given to BH 4 unresponsive PKU patients who do not show any effect on their hyperphenylalaninemia. 49 In addition to the enzyme stabilizing effect, there are several mechanisms underlying responsiveness to BH 4 for some PAH variants, such as the hyperbolic relationship between the activity and the concentration of the cofactor/ co-substrate BH 4 , as well as the protection of the enzyme from rapid oxidative inactivation. 50 Altogether, our results may indicate a similar multifactorial effect of BH 4 supplementation on TH and THD-associated mutants.…”

Chemical Chaperones Modulate the Formation of Metabolite Assemblies

“…Chemical and pharmacological chaperones emerge as promising therapeutics that stabilize and reactivate the mutant enzyme, hence delaying or curing disease phenotypes [64,65]. For instance, the pharmacological chaperone sapropterin (Kuvan) has already been approved as the first nondietary treatment for patients suffering from phenylketonuria which results from a single amino acid alteration in phenylalanine hydroxylase (PHA) [66]. Furthermore, chemical chaperones have been demonstrated to enhance the activity of mutated PHA, mutated cystathionine beta-synthase known to be associated with homocystinuria, and mutated branched-chain alpha-ketoacid decarboxylase which is associated with maple syrup urine disease [67][68][69].…”