Rare diseases
The incidence of phenylketonuria (PKU) is approximately 1 in 10,000 in European populations. The disease is less common in the African-American population, with an incidence of approximately 1 in 50,000. Rare in Finland and Japan, the incidence can vary considerably between different regions.
Phenylketonuria (PKU) is caused by a deficiency of a liver enzyme, Phenylalanine Hydroxylase (PAH), which catalyzes the transformation of phenylalanine (Phe) into tyrosine. The activity of PAH is conditioned by the presence of a cofactor, tetrahydrobiopterin.
If untreated, symptoms begin in the first few months of life and may range from very severe to mild. Clinical manifestations include irreversible intellectual disability, growth retardation, microcephaly, seizures, tremor, vomiting, and typical odor (mouse). These patients often have light skin and hair, resulting from tyrosine deficiency.
In addition, a more severe form of hyperphenylalaninemia exists, malignant PKU. This abnormality is not caused directly by PAH deficiency, but by a synthesis defect of its cofactor, tetrahydrobiopterin. With approximately 1-2% of cases of phenylketonuria, malignant PKU is characterized by both hyperphenylalaninemia and neurotransmitter deficiency (serotonin and dopamine). Clinical signs include psychomotor retardation, microcephaly, myoclonic epilepsy, hyperthermia, swallowing difficulties, and hypersalivation.
The diagnosis of PKU is based on measuring the increase in phenylalanine in the blood. Three forms are mostly distinguished, depending on the level of PAH activity impairment and the resulting plasma phenylalanine level:
The diagnosis is confirmed by monitoring plasma phenylalanine concentrations, taking a new sample, and by molecular analysis of the PAH gene.
In order to exclude any possible DHPR deficiency (malignant UPC), urine biopterin and blood dihydropterine reductase (DHPR) measurements should also be systematically considered. If this test is positive, a QDPR gene test should be considered.
The treatment will be adapted to the enzymatic deficiency identified. Phenylketonuria, classic or moderate, is treated with a diet depleted of phenylalanine. The more severe the form of PKU, the more restrictive the regimen will be. This diet must be very strict during the first 10 years of life, then it may be somewhat relaxed. Women who plan to become pregnant should also follow a strict diet to avoid fetal poisoning.
Some patients (15 to 30%) respond to treatment with tetrahydrobiopterin (sapropterin), which lowers plasma phenylalanine concentrations. These patients may therefore be on a less restrictive phenylalanine-depleted diet.
Patients with hyperphenylalaninemia usually do not follow a diet, but should be monitored regularly, especially if it is a female as future pregnancies should be monitored.
Malignant PKU is also managed by dietary monitoring of phenylalanine, supplemented by sapropterin supplementation and drug treatment to restore neurotransmitter levels (L-Dopa/carbidopa and 5-hydroxy-tryptophane). Progressive cerebral folate deficiency is prevented by folinic acid supplementation.
Phenylketonuria is inherited in an autosomal recessive manner.
NEONATAL PKU Screening Assay is a quantitative enzyme assay used in phenylketonuria (PKU) newborn screening. It's a PKU test for newborns that quantifies an abnormal concentration of phenylalanine in dried blood samples on 903® or 226 blotting paper.