What is the Phenylketonuria (PKU)?

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  2. Phenylketonuria (PKU)
  3. What is the Phenylketonuria (PKU)?

Phenylketonuria (PKU; OMIM 261600) is an inborn error of metabolism caused predominantly by  mutations in the phenylalanine hydroxylase (PAH) gene.

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Mutations in the PAH gene result in decreased catalytic activity affecting the catabolic pathway of phenylalanine (Phe).
PAH is a hepatic enzyme that requires the cofactor tetrahydrobiopterin (BH4) to convert Phe to tyrosine  (Tyr). A deficiency in PAH or its cofactor BH4, results in the accumulation of excess phenylalanine, whose toxic effects can cause severe and irreversible intellectual disability if untreated.


Diagnosis is initially undertaken through newborn screening programs in the first weeks of life.
PKU has been described in all ethnic groups and its incidence varies widely around the world, affecting of one in every 10,000 births in Caucasians, and with the highest incidence being in Northern Europe. Finland has the lowest incidence in Europe with one case in every 100,000 live births, while Turkey has the highest incidence with one in every 4000 births due to high consanguinity within the population. In Australia, approximately 25 babies are diagnosed with PKU each year (based on the recorded incidence of new cases).


Currently, there is no cure for PKU, however, the prevailing treatment is predominantly through dietary restriction of Phe to the minimum required for normal growth, supplemented with specifically designed medical foods. The establishment of newborn screening programs along with the prompt institution of dietary treatment has prevented intellectual disability. Patients with PKU must strictly limit their intake of foods rich in protein, such as meats, fish, eggs and dairy products. Due to the severe restriction of protein intake, PKU patients must be supplemented with medical food substitutes containing the right mix of essential amino acids, vitamins, minerals and trace nutrients. Normally, about 90% of the dietary phenylalanine intake is converted into tyrosine; therefore a crucial part of the treatment is tyrosine supplementation.  Furthermore, there are often problems associated with dietary therapy, including nutritional deficiencies as well as non-compliance due to poor palatability. Early treated PKU patients with well-controlled Phe levels have normal  development and were thought to have a generally normal IQ. The discontinuation of dietary control is correlated with a decline in school performance in children and an increase in behavioural and psychosocial problems in adults. Furthermore, females with PKU are at high risk of having a child with the so-called maternal PKU syndrome, causing microcephaly, intra-uterine growth restriction, congenital heart defects, a characteristic facial appearance and cognitive impairment in the affected infant. As a result of several studies, the recommendation is to continue life-long diet therapy.
In recent years, a synthetic analogue to BH4, sapropterin, has been developed, which can also be used to treat a specific group of patients that results responsive. The BH4 loading test was first used to differentiate between patients with elevated Phe levels either due to PAH deficiency or BH4 deficiency. However this response is noted predominantly in mild to moderate cases of PKU. Treatment with the cofactor BH4 or sapropterin in BH4 responsive PKU patients has proven successful in significantly increasing Phe tolerance allowing patients to relax their diet. However, for 90% of patients with classical PKU, who comprise about 50-80% of patients detected by newborn screening, BH4 therapy has no beneficial effects. Other alternative treatment are under investigation.


Phenylketonuria: a review of current and future treatments. Naz Al Hafid & John Christodoulou. Translational Pediatrics, Vol 4, No 4 October 2015