Phenylketonurie

Synonyms: phenylalanine hydroxylase deficiency, oligophrenia/idiotica/imbecilitas phenylpyruvica, Følling's disease, 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 byproducts phenylpyruvic acid and phenylethylamine, which are thought to be neurotoxic above a threshold concentration. If untreated, the condition leads to general learning disability, 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, to avoid this complication, must be carefully managed during pregnancy.

Classification of phenylketonuria

Type I, or classical, PKU

• Inherited in an autosomally recessive fashion. The gene locus is on the long arm of chromosome 12¹ .

• 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 phenotypical expression.

• These patients tend to have 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.

• One study estimated the prevalence per 10,000 live births in South East England was 1.14 among white, 0.11 among black and 0.29 among Asian ethnic groups⁴ .

• 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 population⁵ as well as in parts of Northern and Eastern Europe, Italy and China⁶ .

• Although screening programmes have largely eliminated the burden of neurological dysfunction caused by the disease,a study in 2008 suggested that there were likely to be a large number of people with PUK living in the UK who were born before the national screening scheme was instituted⁷ .

• The disease should therefore still form part of the differential diagnosis of developmental delay or general learning disability 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 general learning disability 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.

  • Anfälle.

  • 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.

• Andere Ursachen für general learning disability.

• 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 general learning disability.

• 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.

• Genetic testing may be appropriate where genetic counselling is required, to determine the status of at-risk relatives and for prenatal testing⁸ .

Children with PKU should be managed in a specialist 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. Regular assay of plasma phenylalanine level, along with levels of its metabolites, are used to assess and monitor response to therapy.

• Careful weaning is very important in PKU. Dietary phenylalanine intake is severely restricted and the diet is supplemented with phenylalanine-free amino acids and special low-protein foods⁹ .

• The degree to which dietary phenylalanine must be restricted remains controversial. The diet should be monitored to ensure that growth and nutritional status are not affected and deficiency of phenylalanine or tyrosine does not develop. The diet should also be adjusted to allow for illness and activity⁸ . The optimal duration of dietary restriction necessary to avoid the adverse effects of HPA is unclear¹⁰ .

• 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 it¹⁰ .

• There are currently insufficient data to draw conclusions regarding the short-term or long-term use of protein substitutes in PKU¹¹ .

• There is evidence of short-term benefit from using sapropterin in some patients with sapropterin-responsive forms of PKU; blood phenylalanine concentration is lowered and protein tolerance increased¹² . See further details in the editor's note below.

• Definitive evidence of benefit for tyrosine supplementation is lacking but it is widely used and biochemically plausible as a potentially beneficial intervention¹³ .

• 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, which can have an adverse effect on bone mineral density¹⁴ .

• Treatment is still thought to bring benefits in children or adults with intellectual disability 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. Studies suggest that untreated PKU in pregnancy is associated with microcephaly, intellectual disability and attention deficit hyperactivity disorder¹⁵ .

• Developmental delay or intellectual disability developing in later life due to non-adherence to diet.

• Epilepsie.

• Severe behavioural disturbance.

• Congenital anomaly and intellectual disability 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 intellectual disability 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 of those affected may encounter significant educational challenges.

• Vigilance in the 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.