phenylketonuria

Phenylketonuria: Description

Phenylketonuria (PKU) is an inherited metabolic disease that has existed since birth and interferes with the breakdown of the essential amino acid phenylalanine. Amino acids are the basic building blocks of proteins and thus vital metabolic components. Some of them can only enter the body through food, the organism can not produce them. Such amino acids are called essential.

What happens with phenylketonuria?

Normally, amino acids are subject to a balance between uptake / buildup and degradation, so there is always as much as the body needs. With different amino acids, a deficiency or excess can cause significant damage and cause various symptoms.

In classical PKU, the effect of phenylalanine hydroxylase (PAH) is limited or even completely absent. It accumulates by the PAH deficiency increasingly phenylalanine in the body. Too high a concentration of phenylalanine significantly interferes with brain development and early on leads to mental disability in the young patients.

Because in the disease of the normal degradation of phenylalanine is not possible, other degradation products, called phenyl ketones. They are excreted in the urine and are responsible for the name of the disease.

Atypical phenylketonuria

Even in atypical forms of phenylketonuria, the degradation of phenylalanine is disturbed. However, the cause is not a defect of PAH. Instead, the function of a coenzyme, the tetrahydrobiopterin (BH₄), restricted. It is indirectly involved in the degradation of phenylalanine because PAH requires BH₄ for the conversion of phenylalanine to tyrosine.

Because BH₄ also important for the production of the messengers dopamine and serotonin is an atypical phenylketonuria with BH₄Lack usually more complicated than the classical form.

Who concerns a phenylketonuria?

PKU is one of the most common congenital metabolic diseases. It is estimated that around 7,000 newborns around the world suffer from it, with no difference between girls and boys. Because it is a hereditary disease, often several members of a family are affected.

Phenyketonuria: symptoms

First, babies with phenylketonuria do not show disease symptoms. It is not until the fourth to sixth month of life that the first problems appear, unless the disease has been recognized and treated until then. Especially the disturbed brain maturation causes massive complications. Symptoms of an untreated PKU include:

• a strong intellectual developmental backlog. Brain damage progresses to puberty and then stagnates. The affected children are then mostly severely mentally handicapped.
• Seizures (epilepsy). Because of the damage, the nerve cells of the brain are particularly sensitive and over-excitable. Frequent epileptic seizures are the result.
• motor disabilities. Not only the brain cells, but also the muscles of the patients is over-excitable. Therefore, it often spasmodic (spasticity), which leads to various movement disorders.
• Behavioral disorders. Some children with phenylketonuria are hyperactive and unusually aggressive, and outbreaks of anger are more common.
• a small head (microcephaly). Because the patient’s brain does not develop properly, head growth also remains. Especially in older children, the small head circumference in comparison to the peers on.
• a noticeable smell. PKU produces certain breakdown products of phenylalanine, which smell similar to mouse droppings. These substances are excreted mainly in the urine, but sometimes also through the skin.
• eczema-like skin lesions

Because phenylketonuria also interferes with the production of the pigment pigment melanin, many sufferers have very light, sun-sensitive skin and white-blond hair. Also, the iris of the eyes is light blue to transparent and lets the reddish fundus shine through.

The PKU symptoms are individually different pronounced. Above all, the reason is that the activity of phenylalanine hydroxylase (PAH) is differently restricted in each patient. Some still have some residual activity, so less phenylalanine accumulates in the organism. Others show no enzyme activity – the disease progresses correspondingly faster and more seriously.

Phenylketonuria: causes and risk factors

Phenylketonuria is a hereditary disease. There are now numerous genetic mutations known that lead to a defect of PAH. The type of mutation determines how much phenylalanine degradation is limited.

The inheritance of a PKU is recessive, which means that a person can be carriers of an altered gene, without that he gets the disease. Likewise, people with phenylketonuria can produce healthy children.

Only if both parents have mutations in the genetic material, there is a certain probability that their offspring will develop phenylketonuria. If the parents are both sick and not only carriers, but also the PKU, all children together will also get sick.

Phenylketonuria: examinations and diagnosis

Since it is possible to prevent the serious consequences of phenylketonuria when starting treatment on time, it is particularly important to discover the disease as early as possible. In Germany, children are examined on the third day after birth as part of a general examination (neonatal screening) on ​​various congenital diseases, including the PKU.

Tandem mass spectrometry

Meanwhile, many congenital metabolic disorders diagnosed using the so-called tandem mass spectrometry. It makes it possible to examine the blood of the newborn easily and quickly. Within a few minutes, physicians can detect more than 20 other diseases besides phenylketonuria.

Guthrie test

Also named after its inventor Guthrie test allows the diagnosis of a PKU. To do this, remove a small amount of blood from the heel of children and apply it to a piece of filter paper. In the laboratory, one can then determine whether the concentration of phenylalanine is increased.

The Guthrie test was introduced in the 1960s and has long been the standard method for detecting phenylketonuria. However, it has disadvantages compared to tandem mass spectrometry. Thus, the Guthrie test delivers only after five days, a result that is also error-prone. Factors such as diet or possible antibiotic therapy of the child, for example, distort the results. In some countries, the Guthrie test is still in use, in Germany it is usually no longer used.

Other tests

If neonatal screening leads to the suspicion of phenylketonuria, another investigation will follow. With this one can determine at the same time the exact concentration of phenylalanine in the blood.

Finally, it remains to be distinguished whether it is a typical (classical) or atypical PKU. Special tests such as the tetrahydrobiopterin stress test are also available. The distinction is important because an atypical phenylketonuria is treated differently than the classical form.

Amniocentesis

A phenylketonuria can already be detected during pregnancy (prenatal diagnosis). A small amount of amniotic fluid is taken from the mother’s amniotic sac and the cells of the unborn child are examined. Any genetic defects that cause a PKU can thus be determined.

With neonatal screening, phenylketonuria is usually discovered early enough to be treated. Because an amniocentesis examination always involves a certain risk, its use to diagnose a PKU usually does not make sense.

Phenylketonuria: treatment

There is only one way to counteract the excess of phenylalanine in a PKU: The affected children must follow a special diet to take as little phenylalanine with the food. In addition, they need certain dietary supplements to replace substances that would be produced in healthy children from phenylalanine.

The therapy must begin before the first symptoms of a developmental disorder occur, ie within the first two months of life. Already occurred brain damage can not be undone.

Nutritional therapy with the PKU diet

All natural proteins consist of about five percent of the amino acid phenylalanine. So most foods contain far more than the body needs. For a healthy person this is not a problem because it breaks down and excretes the excess amount of phenylalanine.

Patients with phenylketonuria, on the other hand, have to do without natural proteins for the most part. Industrially manufactured special products replace the missing food components. On the one hand, it is intended to prevent excess phenylalanine and, on the other hand, to supply patients with those substances that would otherwise be lacking, such as tyrosine, which is formed from phenylalanine.

The goal of the PKU diet, however, is not to completely stop the intake of phenylalanine. Because a certain amount of amino acid needs the organism for important metabolic processes. Achieving the right concentration poses a great challenge to physicians and patients and requires a lot of discipline.

The diet must therefore be maintained for a lifetime, but especially strictly until the age of six. Because the brain develops very strongly up to this age and is therefore particularly susceptible to damage. In adulthood, high levels of phenylalanine do not cause brain damage, as in children. But they can be the trigger for other neurological disorders such as concentration disorders or a slowing of the reaction.

Phenylketonuria diet treatment should begin in a Metabolic Disease Center. Because not in every hospital it is possible to instruct the parents in the diet. This is best done with the help of diet advice that shows how to do the diet and regularly monitor phenylalanine blood levels.

Treatment of atypical phenylketonuria

Atypical forms of PKU artificially replace the missing coenzyme BH₄ as well as certain messenger substances such as dopamine and serotonin. In some cases, the patient must additionally follow a diet low in phenylalanine.

Phenylketonuria during pregnancy

If you are pregnant and you yourself suffer from phenylketonuria, you should consider the following:

• Keep your diet particularly strict!
• Get your phenylalanine blood levels determined at short intervals. For the concentrations of phenylalanine in the unborn child are about twice as high as in pregnant women. In addition to the brain, they can also harm the heart and eyes of the unborn child. Abnormalities of the child’s skeleton can also arise from a high level of phenylalanine during pregnancy.
• To prevent brain damage to the baby in early pregnancy, women with phenylketonuria should plan a pregnancy well and provide it from the beginning.
• In pregnant women with phenylketonuria, a diet that is not strictly followed may sometimes lead to a miscarriage (spontaneous abortion).
• In any case, pregnant women with a phenylketonuria should be advised and instructed by a doctor.

Phenylketonuria: disease course and prognosis

With an early diagnosis of phenylketonuria, if possible already in the newborn, and if the specific PKU diet is followed, the prognosis is usually good. The children develop mentally normal and have an average life expectancy.

In contrast, brain damage leads to severe mental development disorders that can not be compensated later. Although those affected have a normal life expectancy, their intelligence quotient is almost always well below the norm.

A special case is the rare atypical form of phenylketonuria, in which aBH₄Lack exists. This variant of phenylketonuria despite diet can lead to progressive neurological damage with severe cramps.