Phenylketonuria

Synonyms: phenylalanine hydroxylase deficiency, oligophrenia/idiotica/imbecilitas phenylpyruvica, Folling's disease,¹ type I hyperphenylalaninaemia

Phenylketonuria (PKU) is an inborn error of amino acid metabolism (the most common in the UK) caused by absent or virtually absent phenylalanine hydroxylase (PAH) enzyme activity. This enzyme converts dietary phenylalanine to tyrosine. The products of 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.

• Type I or classical PKU:
  • Inherited in an autosomally recessive fashion. The gene locus is on the long arm of chromosome 12.²
  • There are multiple allelic forms of the dysfunctional gene and many patients are compound heterozygotes for two of these.
• Type II:
  • There are cases of hyperphenylalaninaemia (HPA) where up to 5% of enzyme activity is retained, due to less critical mutations in the enzyme's sequence, or differing phenotypic expression.
  • These patients tend to suffer less serious disease that presents later in life and their optimal treatment is less clear-cut.
• Malignant PKU:
  • There is a variety of PKU due to a deficiency in the synthesis or metabolism of the enzyme's co-factor tetrahydrobiopterin (THB), important for the hydroxylation of tyrosine and tryptophan.
  • Such patients tend to develop more severe neurological disease that is not fully responsive to dietary manipulation.

• Classical PKU 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 programmes have largely eliminated the burden of neurological dysfunction caused by the disease, screening programmes of those in long-term residential care for mental impairment have found a prevalence of up to 1% in this group.⁴
• Therefore the disease should still form part of the differential diagnosis of developmental delay or mental retardation in children presenting 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 or general family colouring.
• In undetected cases children often give off a musty or 'mousey' 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/'mousey' 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 HPA
• Malignant PKU or THB deficiency
• Tyrosinaemia types I and II
• Any cause of liver disease in infants/children
• Other causes of mental retardation

• 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 THB 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 scan may be used to detect demyelination and other abnormalities in older, treated children who become unwell after stopping, or complying poorly with, dietary manipulation.

• Sufferers should be managed in a speciality 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.
• The degree to which dietary phenylalanine must be restricted remains controversial.⁴ The optimal duration of dietary restriction necessary to avoid the adverse effects of HPA is also unclear.⁵ Some authorities consider that the diet (which is difficult to adhere to and often not popular with older children) can be discontinued in later childhood but 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.⁵
• There are currently insufficient data to draw conclusions regarding the short-term or long-term use of protein substitutes in PKU.⁶
• Regular assay of plasma phenylalanine level, along with levels of its metabolites, are used to assess and monitor response to therapy.
• Definitive evidence of benefit for tyrosine supplementation is lacking, but it is widely used and biochemically plausible as a potentially beneficial intervention.⁷
• 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.⁸
• Treatment is still thought to bring benefits in children or adults with mental impairment who were not diagnosed in infancy.
• 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

• 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.
• Agoraphobia, low self-esteem and other psychological disturbance can affect some patients, usually if not on a special diet.

• Worsening mental impairment and developmental delay in infancy and childhood if untreated.
• 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 programme for newborns.
• 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.
• Careful management of pregnant women with PKU protects against disease in the newborn.

1. Whonamedit.com; Details of the disease's discoverer and its eponymous alternative name and other synonyms.
2. Phenylketonuria, Online Mendelian Inheritance in Man (OMIM)
3. Hutchesson AC, Bundey S, Preece MA, et al; A comparison of disease and gene frequencies of inborn errors of metabolism among different ethnic groups in the West Midlands, UK.; J Med Genet. 1998 May;35(5):366-70. [abstract]
4. Arnold G; Phenylketonuria; eMedicine, February 2009.
5. Poustie VJ, Rutherford P; Dietary interventions for phenylketonuria. Cochrane Database Syst Rev. 2000;(2):CD001304. [abstract]
6. Yi SH, Singh RH; Protein substitute for children and adults with phenylketonuria. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD004731. [abstract]
7. Poustie VJ, Rutherford P; Tyrosine supplementation for phenylketonuria.; Cochrane Database Syst Rev. 2000;(2):CD001507. [abstract]
8. Cleary MA, Feillet F, White FJ, et al; Randomised controlled trial of essential fatty acid supplementation in phenylketonuria.; Eur J Clin Nutr. 2006 Jul;60(7):915-20. Epub 2006 Mar 8. [abstract]
9. Magee AC, Ryan K, Moore A, et al; Follow up of fetal outcome in cases of maternal phenylketonuria in Northern Ireland. Arch Dis Child Fetal Neonatal Ed. 2002 Sep;87(2):F141-3. [abstract]

• Arnold G; Hyperphenylalaninaemia; eMedicine, February 2009.
• Scheinfeld N, Jones EL; Tetrahydrobiopterin Deficiency; eMedicine, June 2008.
• Management of PKU (Phenylketonuria), National Society for Phenylketonuria UK (2004)
• UK National Screening Committee; Homepage
• Lucaks Z, Santer R; Evaluation of electrospray-tandem mass spectrometry for the detection of phenylketonuria and other rare disorders.; Mol Nutr Food Res 2006 Apr;50(4-5):443-50.
• National Society for Phenylketonuria; Homepage. Patient/medical resources, dietary information etc.