Up to date knowledge on different treatment strategies for phenylketonuria

Abstract

Dietary management for phenylketonuria was established over half a century ago, and has rendered an immense success in the prevention of the severe mental retardation associated with the accumulation of phenylalanine. However, the strict low-phenylalanine diet has several shortcomings, not the least of which is the burden it imposes on the patients and their families consequently frequent dietary non-compliance. Imperfect neurological outcome of patients in comparison to non-PKU individuals and nutritional deficiencies associated to the PKU diet are other important reasons to seek alternative therapies. In the last decade there has been an impressive effort in the investigation of other ways to treat PKU that might improve the outcome and quality of life of these patients. These studies have lead to the commercialization of sapropterin dihydrochloride, but there are still many questions regarding which patients to challenge with sapropterin what is the best challenge protocol and what could be the implications of this treatment in the long-term. Current human trials of PEGylated phenylalanine ammonia lyase are underway, which might render an alternative to diet for those patients non-responsive to sapropterin dihydrochloride. Preclinical investigation of gene and cell therapies for PKU is ongoing. In this manuscript, we will review the current knowledge on novel pharmacologic approaches to the treatment of phenylketonuria.

Mapping the functional landscape of frequentphenylalanine hydroxylase(PAH) genotypes promotes personalised medicine in phenylketonuria

“…Moreover, it is well known that consequences arising from full genotypes consisting of both alleles differ from the average induced by the two mutations involved and that proteins arising from different alleles influence each other—a phenomenon termed interallelic complementation 26–28. Furthermore, although residual PAH enzyme activity assessed at fixed substrate and cofactor conditions for single mutations shows a general correlation with clinical severity and BH 4 responsiveness,29 30 there is still significant inconsistency that hampers solid phenotype prediction in clinical care. This prompted us to develop a model system that mimics the cellular situation in carriers of both homozygous and compound heterozygous genotypes.…”

A Neuropsychiatric Perspective of Phenylketonuria I: Overview of Phenylketonuria and Its Neuropsychiatric Sequelae

“…Increased levels of Phe (also a LNAA) competitively inhibit transport of other crucial LNAAs across the blood-brain barrier; therefore, LNAA supplementation may reverse this inhibition and reduce the transport of Phe into the brain. [21][22][23] Other treatment options are being actively pursued, including enzyme substitution with phenylalanine ammonia-lyase to relax dietary restrictions 24 and gene therapy (presently in a murine model). 25 …”

Micronutrients, Essential Fatty Acids and Bone Health in Phenylketonuria

“…A minority of patients is responsive to a recently available (2009) treatment with tetrahydrobiopterin (BH4), a cofactor of PAH. BH4 increases the dietary Phe tolerance and thus permits diet relaxation [9]. Deficiencies have been reported in responsive patients on a relaxed diet, who might experience difficulties making food choices after years of strict dieting [7].…”