Genetic etiology and clinical challenges of phenylketonuria

Abstract

This review discusses the epidemiology, pathophysiology, genetic etiology, and management of phenylketonuria (PKU). PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. The prevalence of PKU varies widely among ethnicities and geographic regions, affecting approximately 1 in 24,000 individuals worldwide. Deficiency in the PAH enzyme or, in rare cases, the cofactor tetrahydrobiopterin results in high blood Phe concentrations, causing brain dysfunction. Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). Severe phenotypes are classic PKU, and less severe forms of PAH deficiency are moderate PKU, mild PKU, mild hyperphenylalaninaemia (HPA), or benign HPA. Early diagnosis and intervention must start shortly after birth to prevent major cognitive and neurological effects. Dietary treatment, including natural protein restriction and Phe-free supplements, must be used to maintain blood Phe concentrations of 120-360 μmol/L throughout the life span. Additional treatments include the casein glycomacropeptide (GMP), which contains very limited aromatic amino acids and may improve immunological function, and large neutral amino acid (LNAA) supplementation to prevent plasma Phe transport into the brain. The synthetic BH4 analog, sapropterin hydrochloride (i.e., Kuvan®, BioMarin), is another potential treatment that activates residual PAH, thus decreasing Phe concentrations in the blood of PKU patients. Moreover, daily subcutaneous injection of pegylated Phe ammonia-lyase (i.e., pegvaliase; PALYNZIQ®, BioMarin) has promised gene therapy in recent clinical trials, and mRNA approaches are also being studied.

Keywords: Epidemiology; Genetic etiology; PKU management; Pathophysiology; Phenylalanine hydroxylase; Phenylketonuria; Tetrahydrobiopterin.

Fig. 1

Prevalence of PKU in five world regions (prevalence, 1:X)

Fig. 2

Phenylalanine metabolism in PKU. Phenylalanine hydroxylase (PAH) catalyzes the hydroxylation of L-phenylalanine to L-tyrosine

Fig. 3

Protein network interactions contained the PAH and 10 related genes examined in this review created with STRING (https://string-db.org/), where there are strong interactions between the PAH gene and associated BH4 genes. Each node represents all the proteins (n = 11) produced by a single, protein-coding gene locus. Colored nodes describe proteins and the first shell of interactors. Edges represent protein–protein associations (n = 20) that are meant to be specific and meaningful, i.e., proteins jointly contribute to a shared function; this does not necessarily mean they are physically binding each other

Fig. 4

Role of sapropterin as a synthetic form of BH4. Fully active BH4 is regenerated through the sequential action of pterin-4a-carbinolamine dehydratase and dihydropteridine reductase (DHPR) or may be synthesized de novo from guanosine triphosphate (GTP) [50]