For many decades, a special low-protein (low-phenylalanine) diet has been the only way of treating children suffering from phenylketonuria (PKU) that effectively prevents them from developing severe impairments in mental function. However, this type of diet is not very tasty and it is often difficult to get children to cooperate. A paediatrician from Reutlingen, Prof. Dr. Friedrich Trefz, has now been able to show that the substance sapropterin is able to reactivate the defective metabolic pathway to a degree that means that some sufferers can return to a normal diet.
A slight prick in the heel in order to withdraw and collect a few droplets of blood on a piece of filter paper is the routine screening test that has been used to screen newborn babies for the presence of PKU, a costly procedure considering that the disease is very rare, affecting only one in approximately 10,000 newborns. Phenylketonuria is a genetic disorder characterised by a deficiency in the enzyme that is needed to metabolise the amino acid phenylalanine. Professor Dr. Friedrich Trefz, chief physician in the Children's Hospital in Reutlingen, knows that the dramatic consequences of PKU can only be avoided if the newborn is put on a medically supervised low-phenylalanine diet within a few days of birth. "If this does not happen, the child will develop severe neurological disorders during their first months of life, which will lead to severe mental dysfunction.
Until recently, a low-phenylalanine diet was the only way to counteract the development of PKU. The German paediatrician Professor Dr. Horst Bickel developed the diet back in 1953. He was able to show that children who were put on a low-phenylalanine diet as quickly as possible after birth often developed normally, both physically and mentally. "Together with the routine PKU newborn screening test, the introduction of this special diet was a milestone in preventive medicine," said Trefz who worked with Bickel at the University of Heidelberg for many years. "This diet helped to save thousands of children from severe impairments."
PKU is characterised by mutations in the phenylalanine hydroxylase (PAH) gene which encodes an enzyme that is taken up with food and that metabolises the amino acid phenylalanine to the amino acid tyrosine in the liver. The defect leads to a strong increase in phenylalanine levels in the blood of PKU sufferers, which has a dramatic effect on the maturation of the children’s brains. In addition, PAH deficiency also leads to lower levels of neurotransmitter substances in the brain and to lower levels of melanin, which is why children who are affected are often very blond, pale and have blue eyes. The severe neurological symptoms can be greatly reduced if the uptake of phenylalanine is kept to a minimum immediately after birth. Phenylalanine is taken up with food and is found in high concentrations in meat, fish and dairy products. However, the diet has its price: it is very expensive because the patients require industrially produced amino acid mixtures as dietary supplements, which, in addition, are anything but tasty. “As the children get older, it becomes more and more difficult for them to have the willpower to follow this diet,” said Trefz speaking from his long-standing experience with PKU patients.
Although elevated phenylalanine concentrations do not have a direct effect on the intelligence quotient of children once the brain is fully developed, experts nevertheless recommend that PKU sufferers continue eating a low-phenylalanine diet for the rest of their lives. "We have seen that the processing of information in the brain can be impaired in many ways," said the physician, who points out that PKU patients often complain about headaches and poor concentration. "However, as the patients get older it is no longer necessary to meticulously maintain phenylalanine levels at the same low concentrations as in small children," said Trefz.
Pregnant women suffering from PKU must stick to a strict low-phenylalanine diet, as the mother's elevated phenylalanine levels might have dramatic effects on the development of the unborn child. The clinical symptoms of PKU are similar to those of alcohol embryopathy and include abnormalities in behaviour and mental impairments. Trefz has supervised many patients in this critical phase of life, an experience that has left him with lasting impressions. "The prevention of maternal PKU has become a kind of life task for me," said Trefz who established a special consultation hour in Reutlingen many years ago, providing help and advice to people suffering from genetic metabolic diseases.
By treating PKU patients with the substance sapropterin (tetrahydrobiopterin, BH4), Trefz and his colleagues have now achieved important therapeutic progress in the treatment of PKU patients. BH4 is an essential co-factor for the enzyme phenylalanine hydroxylase (PAH) and has long been of central importance in the treatment of a rare type of PKU. “It is known that a small percentage of people with elevated phenylalanine levels have a genetic deficiency of BH4 rather than a PAH defect,” said Trefz. Patients treated with sapropterin, i.e. synthetic BH4, very quickly develop normal phenylalanine levels.
The fact that BH4 is also effective in the treatment of classical, autosomal recessive genetic PKU has only recently become known. “It appears that high BH4 dosages lead to a considerable stabilisation of the mutated phenylalanine hydroxylase in the cells,” said Trefz adding that this so-called chaperone effect does not work in all patients, but only in those whose PAH still has a residual enzymatic activity.
The majority of the more than 400 different mutations in the phenylalanine hydroxylase gene lead to changes in the resulting protein that are so profound that the enzyme, and hence also BH4, has no effect whatsoever. “However, in at least 30 per cent of patients a considerable effect on PAH activity, and hence also the phenylalanine levels, can be achieved with sapropterin,” said Trefz adding that in such cases, the patients can either follow a less strict diet or can drop the special diet altogether.”Sapropterin therefore helps people to enjoy their daily meals once again. In addition, concrete clinical advantages are associated with sapropterin treatment: a low-phenylalanine diet is associated with side effects, particularly as far as bone metabolism is concerned. “Many PKU sufferers on a low-phenylalanine diet develop osteoporosis at quite a young age,” said Trefz, “or they reveal other deficiencies that could be prevented with normal nutrition.”
Despite its advantages, not all patients are equally enthusiastic about the new therapy. Many patients regard the diet as a natural treatment method and see BH4 as a chemical solution. “Therefore, some patients take a lot of convincing,” said Trefz pointing out that most usually tolerate BH4 very well. However, Trefz also sees some light at the end of the tunnel for patients suffering from a classical, severe type of PKU that does not respond to BH4 treatment. “Enzyme replacement therapy involving phenylalanine ammonia-lyase is currently being tested in a clinical trial,” said Trefz explaining that “the recombinant enzyme can degrade the surplus phenylalanine and turn it into cinnamic acid and ammoniac, thereby rendering it harmless to the human body.”
Prof. Dr. med. Friedrich K. TrefzDistrict Clinics ReutlingenChildren's HospitalSteinebergstraße 3172764 ReutlingenTel.: 07121 200-3412Fax: 07121 200-3571E-mail: trefz_f(at)kreiskliniken-reutlingen.de