6th February 2024

Phenylketonuria

Phenylketonuria is the most well-known amino acid metabolism disorder, affecting around 1 in 10,000 babies born in the UK. It is characterised by the inability to break down the amino acid phenylalanine due to a deficiency or complete absence of phenylalanine hydroxylase. This enzyme catabolises phenylalanine to form another amino acid, tyrosine (see pathway). Without this pathway, phenylalanine accumulates in the blood and other tissues, whilst tyrosine levels become deficient, leading to intellectual disability, seizures, behavioural problems and other neurological issues.

Clinical features

Clinical features of Phenylketonuria often appear shortly after birth when the baby consumes phenylalanine in breast milk or formula. They include:

• Intellectual disability
  • High levels of phenylalanine are toxic to the brain and interfere with its development, causing intellectual disability and cognitive impairment if left untreated. Other neurological features can include tremors, epilepsy and clonus.
• Behavioural problems
  • Children with PKU may exhibit behavioural issues such as hyperactivity, attention deficit disorder, and poor impulse control. This can present as behavioural difficulties and even self-harm.
• Skin and hair changes:
  • Some individuals with PKU have lighter skin and hair pigmentation than unaffected individuals. This is due to the role of phenylalanine in melanin production.
  • If phenylalanine levels are high, affected individuals may have a characteristic “musty odour” to their breath, skin and urine.

Diagnosis

PKU is usually diagnosed through the newborn screening programme, where a small blood sample is taken from a heel prick shortly after birth and tested for elevated phenylalanine levels (amongst other things – see later). In those with elevated levels, confirmatory tests are then performed, as well as genetic testing.

Management

Treatment involves strict dietary management with a lifelong low phenylalanine diet. Foods that are high in phenylalanine, such as meat, fish, eggs, dairy products and aspartame (which is converted to phenylalanine), must be restricted in favour of special medical formulas and low protein foods that have low or zero phenylalanine content. This helps to maintain levels within the normal range, preventing neurological damage.

Individuals with PKU require lifelong monitoring of blood phenylalanine levels to ensure they remain within a target range, with dietary adjustments indicated where levels are high. Initially, blood tests are frequent. However, they are reduced over time as the individual ages and their diet becomes stable. 

Women of childbearing age with PKU must adhere very strictly to a low phenylalanine diet to prevent pregnancy complications; elevated phenylalanine levels during pregnancy can cause harm to the developing foetus, in particular, causing developmental issues.

Whilst PKU is a lifelong disease requiring close monitoring, early diagnosis and strict dietary control ensure individuals with this condition can lead healthy and fulfilling lives, minimising the risk of intellectual disability and other associated complications.

A small proportion of patients with a mild form of PKU called hyperphenylalaninaemia may be suitable for treatment with sapropterin. This medication reduces the level of phenylalanine within the body, improving symptoms and offering neuroprotection. It allows better control of phenylalanine levels and affords patients greater dietary flexibility. However, it is not a magic bullet; patients will still require regular monitoring, and its long-term efficacy is still being determined.