Metabolic phenotyping in phenylketonuria reveals disease clustering independently of metabolic control

Phenylketonuria (PKU, MIM #261600) is one of the most common inborn errors of metabolism (IEM) with an incidence of 1:10000 in the European population. PKU is caused by autosomal recessive mutations in phenylalanine hydroxylase (PAH) and manifests with elevation of phenylalanine (Phe) in plasma and urine. Untreated PKU manifests with intellectual disability including seizures, microcephaly and behavioral abnormalities. Early treatment and good compliance result in a normal intellectual outcome in many but not in all patients. This study examined plasma metabolites in patients with PKU (n = 27), hyperphenylalaninemia (HPA, n = 1) and healthy controls (n = 32) by LC- MS/MS. We hypothesized that PKU patients would exhibit a distinct submetabolome compared to that of healthy controls. We further hypothesized that the submetabolome of PKU patients with good metabolic control would resemble that of healthy controls. Results from this study show: (i) Distinct clustering of healthy controls and PKU patients based on polar metabolite profiling, (ii) Increased and decreased concentrations of metabolites within and afar from the Phe pathway in treated patients, and (iii) A specific PKU-submetabolome independently of metabolic control assessed by Phe in plasma. We examined the relationship between PKU metabolic control and extended metabolite profiles in plasma. The PKU submetabolome characterized in this study represents the combined effects of dietary adherence, adjustments in metabolic pathways to compensate for defective Phe processing, as well as metabolic derangements that could not be corrected with dietary management even in patients classified as having good metabolic control. New therapeutic targets may be uncovered to approximate the PKU submetabolome to that of healthy controls and prevent long-term organ damage.

Automated summary

Phenylketonuria (PKU) is a common inborn error of metabolism caused by mutations in phenylalanine hydroxylase (PAH). PKU patients have elevated levels of phenylalanine and may experience intellectual disability. This study found distinct differences in metabolite profiles between PKU patients and healthy controls, as well as altered concentrations of metabolites in treated patients. The PKU submetabolome identified in this study reflects the effects of dietary adherence, compensatory metabolic pathways, and metabolic disturbances that cannot be corrected with diet. Potential therapeutic targets may be discovered to approximate the submetabolome of PKU patients to that of healthy controls and prevent long-term organ damage.