5th June 2025

Phenylketonuria

This is an inherited error in amino acid metabolism caused by deficiency in phenylalanine hydroxylase enzyme activity. The enzyme is responsible for converting dietary phenylalanine to tyrosine. The products of this metabolic pathway are key in the creation of catecholamines, neurotransmitters and melanin. In phenylketonuria due to decreased phenylalanine hydroxylase activity there is elevated blood phenylalanine. The phenotypes range from mild increases in blood phenylalanine concentrations to severe hyperphenylalaninemia.

Classification

PKU can be divided into two main types:

• Classical PKU: higher elevation of blood phenylalanine, usually >1211 micromol/L, accumulation of phenyl ketones and a profound deficiency of phenylalanine hydroxylase activity  
• Non-PKU hyper-phenylalaninaemia: Lower elevation of blood phenylalanine without the accumulation of phenyl ketones

Presentation

Most patients with PKU appear normal at birth and are identified through neonatal screening.  

If this condition is left untreated it can lead to epilepsy, eczema, Parkinson-like features, musty body odour, defects in executive functioning and decreased skin/hair pigmentation. They will also have varying levels of intellectual impairment and behavioural problems.

Diagnosis

Diagnosis is done through UK newborn screening which suggests PKU if there is elevated phenylalanine concentration (>120 mmol/L)

Blood and urinary pterin evaluation or tetrahydrobiopterin (BH4) loading test can also be performed to differentiate between classic PKU from BH4- sensitive PKU and other forms of hyperphenylalaninemia. 

An MRI scan may reveal demyelination in older children who were non-compliant to dietary manipulation.

Treatment 

Patients with PKU should be carefully managed by a specialist metabolic/ paediatric team to avoid consequences of untreated disorders and nutritional deficiencies. 

Mainstay of treatment is dietary changes for life involving restricting dietary protein and phenylalanine intake. The type of diet is dependent on severity and classification of PKU. In classical PKU meat, dairy, rice, pasta and commercial baked goods are restricted. 

These diets are monitored through food diaries, growth measurements and regular assay of phenylalanine levels to ensure patients are receiving adequate calories, protein, and trace minerals. 

In some patients sapropterin (tetrahydrobiopterin) therapy can be used as blood phenylalanine is reduced and protein tolerance is increased.