Phenylketonuria

Synonyms: PKU, phenylalanine hydroxylase (PAH) deficiency, oligophrenia/idiotica/imbecilitas phenylpyruvica, Folling's disease,¹ Type I hyperphenylalaninaemia.

This is an inborn error of amino acid metabolism (the commonest in the UK) caused by absent, or virtually absent phenylalanine hydroxylase enzyme activity. This enzyme converts dietary phenylalanine to tyrosine. Products further downstream on this metabolic pathway are important in the formation of catecholamines, neurotransmitters and melanin.

High plasma concentrations of phenylalanine lead to the formation of the by-products phenylpyruvic acid and phenylethylamine, which are thought to be neurotoxic above a threshold concentration. If untreated, the condition leads to mental retardation usually developing in the first year of life. The condition is eminently treatable through dietary manipulation and is screened for by heel-prick blood taken from all babies born in the UK. The condition can cause damage to the unborn children of mothers affected by the condition and must be carefully managed during pregnancy to avoid this complication.

Affects about 1 in 14,000 live births in Northern Ireland,³ with US rates about 1 in 15,000.⁴ Carriage frequency of dysfunctional alleles is about 1 in 50. There is marked variation between different ethnic groups. Turkey is the country with the highest incidence at around 1 in 2,600 live births. High incidence of the disease is also found in the Yemenite Jewish population, as well as in parts of northern and eastern Europe, Italy, and China.⁴ Although screening programs have largely eliminated the burden of neurological dysfunction caused by the disease, screening programs of those in long-term residential care for mental impairment have found a prevalence of up to 1% in this group.⁴ This indicates that some cases slip through screening, so the disease should still form part of the differential diagnosis of developmental delay or mental retardation in children presenting/being investigated at any age.

• Most children appear normal at birth and diagnosis usually occurs through an abnormal result in the heel-prick blood assay.
• Children tend to be very fair with pale blue eyes, if compared to siblings/general family colouring.
• In undetected cases children often give off a musty or 'mousy' odour.
• Progressive developmental delay and mental retardation are the usual modes of presentation in those not detected by screening.
• Diagnosed children who cease dietary manipulation may show deterioration in motor skills and cognitive function (IQ falling by about 10 points); there may be MRI evidence of demyelination.
• Other presentations in infancy or later childhood include:
  • Recurrent vomiting
  • Unusual musty/'mousy' odour
  • Eczematous skin eruptions, scleroderma-like skin lesions and other dermatological abnormalities.
  • Seizures
  • Self-mutilation
  • Severe behavioural disturbance
  • Untreated older children may be hyperactive with rhythmic rocking and writhing movements classically affecting the hands, face and tongue.

• Type II PKU or hyperphenylalaninaemia
• Malignant PKU or tetrahydrobiopterin deficiency
• Tyrosinaemia types I and II
• Any cause of liver disease in infants/children
• A myriad of other causes of mental retardation due to other organic acidurias, other metabolic disorders and diseases of non-metabolic aetiology

• Heel-prick blood should be assayed for phenylalanine (or subjected to indirect Guthrie assay) in all UK-born newborns.
• This test should be carried out at >12 hours after birth.
• Blood levels of phenylalanine above a threshold value (usually around 120 μmol/l) suggest the diagnosis and prompt re-testing and/or formal assay by a specialist laboratory and assessment by a metabolic disease service.
• Tyrosine and tetrahydrobiopterin assay may form part of specialist investigations.
• The disease may be detected during aminoaciduria screening for older children with developmental delay or mental retardation.
• Children being treated for the condition may be prone to nutritional deficiencies due to the special diet. Those who are ill or have other blood test abnormalities may need assay/assessment of iron, vitamins, selenium, protein, essential fatty acids and other nutrient levels.
• MRI may be used to detect demyelination and other abnormalities in older, treated children who become unwell after stopping or complying poorly with dietary manipulation.

Hyperphenylalaninaemia (sub-critical impairment of phenylalanine hydroxylase deficiency, a.k.a. Type II PKU); Malignant PKU (tetrahydrobiopterin deficiency).

• Sufferers should be managed in a specialty metabolic/paediatric clinic.
• The cornerstones of therapy are dietary protein restriction, combined with dietary substitution of proteins containing a balanced mixture of amino acids, including a generous supply of tyrosine.
• Definitive evidence of benefit for tyrosine supplementation is lacking, but it is widely used and biochemically plausible as a potentially beneficial intervention.⁵
• The degree to which dietary phenylalanine must be restricted remains controversial.⁴
• Optimal dose regimens for protein substitutes are not fully elucidated.⁶
• Regular assay of plasma phenylalanine level, along with levels of its metabolites, are used to assess and monitor response to therapy.
• Aspartame, a common sweetening agent, should be avoided as it is a rich source of phenylalanine.
• Supplementation of iron, vitamins and minerals may be necessary for those on the diet.
• There is some evidence that the diet causes deficiency of essential fatty acids and supplementation has been shown to have an improving effect on lipid profile without affecting phenylalanine levels.⁷
• The optimal duration of dietary restriction necessary to avoid the adverse effects of hyperphenylalaninaemia is unclear.⁸
• Some consider that the diet (which is somewhat onerous to adhere to and often not popular with older children) can be discontinued in later childhood; others advocate lifelong dietary adjustment.
• There is some limited evidence that there are subtle differences in IQ between those who stop the diet after childhood and those who maintain it.⁸
• It is very important that pregnant PKU patients who are not strictly adherent to their diet should resume it; one study found a prevalence of 44% of congenital anomaly and/or developmental delay in offspring of PKU mothers who were not strictly adherent to the regimen, particularly in the first and second trimesters.⁹
• Treatment is still thought to bring benefits in children or adults with mental impairment who were not diagnosed in infancy.

• Worsening mental impairment and developmental delay in infancy and childhood if untreated.
• Developmental delay or mental impairment developing in later life due to non-adherence to diet
• Epilepsy
• Severe behavioural disturbance
• Congenital anomaly and mental impairment in offspring of untreated PKU mothers
• Skin lesions (eczematous or scleroderma-like)
• Subtle deficiencies in attention and organisational planning abilities may affect some treated sufferers. This is thought to be due to poorly controlled phenylalanine levels. Can cause academic difficulties.
• Agoraphobia, low self-esteem and other psychological disturbance can affect some patients, usually if not on special diet. Phenylalanine may act by competing at CNS receptors with the serotonin precursor tryptophan and a trial of dietary intervention is worthwhile for psychological problems.

Long-term outlook is excellent in those who adhere to dietary and other therapies. Overall intelligence is normal or near-normal although some sufferers may encounter significant educational challenges.

Vigilance in heel-prick blood testing program for newborns. Careful management of pregnant women with PKU protects against disease in the newborn. adherence to dietary and other manipulations prevents serious complications of the disease; it should be instituted and supported by healthcare staff and family from an early age.