How does phenylketonuria affect metabolic pathways

Phenylketonuria (PKU)

Phenylketonuria (PKU) is a disorder in protein metabolism. The cause is a change in the genetic make-up - a genetic change.

To put it somewhat simply, every person has a double set of genes. He inherits each gene once from the mother and once from the father. Phenylketonuria only occurs when the corresponding genetic change has been passed on from both the mother and the father (autosomal recessive inheritance).

One in approximately 10,000 newborns is affected by PKU. This makes PKU one of the most common congenital metabolic diseases.

What happens with a PKU?

The key role in PKU is played by a specific enzyme with the complicated name of phenylalanine hydroxylase (PAH). Enzymes are protein bodies that the organism uses as a kind of tool to break down and convert substances.

Normally, the PAH enzyme breaks down a certain amino acid into another amino acid. Amino acids are the components of proteins that the body uses as building material, among other things. In healthy people, the amino acid tyrosine is created from the amino acid phenylalanine with the help of the enzyme PAH.

In phenylketonuria, this metabolic pathway does not work as it should. In most cases, the blueprint of the PAH enzyme has been changed. As a result, it cannot do its job properly.

The body cannot break down the amino acid phenylalanine sufficiently. She enriches herself. This can result in serious damage, especially in the brain. On the other hand, the body lacks the amino acid tyrosine because it is not sufficiently produced. It is a component of many important messenger substances, including the thyroid hormones.

There are different forms of PKU

There are several variants of the gene modification - and thus different manifestations of phenylketonuria. In some cases the PAH enzyme practically doesn't work at all, in others it just doesn't work as well. According to the residual activity of the PAH, doctors differentiate between classic PKU, mild PKU and mild hyperphenylalaninemia.

The cause of a PKU is seldom caused by the enzyme itself but by its "colleague", the so-called cofactor. It is called tetrahydrobiopterin (BH4). If there is a deficiency of BH4, it is a so-called "atypical PKU".

What are the symptoms of PKU?

Today, PKU is almost always discovered in the first few days of life (see diagnosis). With a suitable diet, there are usually no symptoms.

However, if PKU remains untreated, it will fail to thrive after about two to four months. Mental and motor development is delayed. The affected children suffer from agitation, overexcitability and seizures (epileptic fits). Typical is a noticeable odor of the urine, reminiscent of mouse droppings or a horse stable. The cause is the substance phenylacetic acid, which occurs to a greater extent in the urine due to the disturbed protein metabolism.

In adolescents and adults, excessively high phenylalanine levels lead to an impairment of the general condition with impaired concentration and forgetfulness.

How does the doctor make a diagnosis?

There is a newborn screening for PKU: On the second to third day of life (36th to 72nd hour of life) doctors examine all newborns for various congenital diseases. To do this, the doctor takes a drop of blood from the newborn's heel and applies it to a filter card. The blood is examined using what is known as tandem mass spectrometry.

If the screening examination reveals a suspicion of PKU, further tests are carried out in a specialized metabolism center. This includes measuring the exact levels of phenylalanine in the blood. A genetic test confirms the diagnosis of PKU and allows conclusions to be drawn about the severity of the PKU. This also makes it possible to check whether treatment with BH4 promises success (see section on new treatment methods).

Therapy of a PKU

People with PKU must follow a strict diet. Since they cannot break down phenylalanine, they are only allowed to take in a small amount of phenylalanine. Depending on the severity of the PKU, they can produce little or no tyrosine, which the body normally produces from phenylalanine. So it has to be supplemented in a targeted manner.

The problem: Phenylalanine is found in numerous foods, especially meat, fish, dairy products, eggs, grains and legumes. These foods are usually completely forbidden in the PKU diet. The diet consists mainly of fruit, vegetables and industrially produced low-protein food. The main source of protein is phenylalanine-free and tyrosine-enriched amino acid mixtures.

Parents of affected children receive comprehensive nutritional advice and training. In the first few years of life in particular, it is extremely important to adhere to the recommended dietary rules. As the brain develops during this time, excessively high phenylalanine levels can cause serious damage. Despite the strict requirements, there must of course be no shortage of vital nutrients.

The amount of phenylalanine that can be contained in food varies from patient to patient and also according to age. It's called phenylalanine tolerance.

Regular checks, a lot of discipline

To check the treatment, the doctor will measure the level of phenylalanine in the blood at regular intervals. The capillary blood collection for small children can be carried out by parents and, from school age, usually the patients themselves after appropriate training. In Germany, specialists recommend phenylalanine levels between 0.7 and 4 milligrams per deciliter of blood.

From adolescence, higher limit values ​​actually apply. In the meantime, however, studies have shown that consistent continuation of the diet with continued low phenylalanine concentrations in the blood leads to a better quality of life for those affected. Experts therefore strongly advise adhering to such a diet for life.

It is essential for pregnant women with PKU. High levels of phenylalanine during pregnancy can cause serious harm to the unborn child.

Adhering to the PKU diet is time-consuming and requires a great deal of discipline from those affected, their parents and families. Many need psychological support in order to be able to stick to the diet measures better. Adults in particular often no longer have this stamina. The exchange with other affected persons, for example in self-help groups, can be very helpful here (see link below).

New treatments for PKU

For a long time, a diet with a special protein composition was the only possible treatment. The new active ingredient tetrahydrobiopterin (BH4) has been approved for the treatment of PKU since 2009. Some of those affected can benefit from this new drug.

BH4 is an important cofactor for the PAH enzyme (see above) and can cause increased enzyme activity. A certain amount of residual activity of the PAH enzyme is a prerequisite for successful treatment with BH4. According to expert estimates, this is present in around 30 percent of those affected. With them, BH4 can significantly increase their phenylalanine tolerance. This allows you to relax the diet noticeably and in some cases even stop it completely. However, since BH4 is very expensive, doctors must carefully check whether treatment can be expected to be successful before prescribing it permanently.

In addition, there are research activities on other treatment approaches such as enzyme replacement therapy or gene therapy. Such treatment methods could one day also benefit those affected, for whom BH4 is not effective.

What is the prognosis for PKU?

If the diet begins in the neonatal period and is followed consistently, harm can be completely avoided. The good prognosis of the disease with early diagnosis and treatment has given the PKU a model character for the successful management of congenital metabolic diseases.

The complex and sometimes debilitating diet remains a challenge. It is also very important that adolescents and adult patients continue to receive qualified care. Appropriate training and treatment offers are also necessary for them.

Advisory experts:

This text was created with the kind support of the metabolic outpatient department of Dr. from Hauner's Children's Hospital in Munich.


Koletzko B :, Pediatric and Adolescent Medicine, greeted by Harnack G-H, 14th edition, Berlin, Heidelberg, Springer Verlag, 2013

Bald M, Biberthaler P, Blattmann C, short textbook pediatrics, Stuttgart, Thiemeverlag 2012

Classical Phelylketonuria and Tetrahydrobiopterin (BH4) -responsive Hyperphenylalaninemia, An Overview, in Pediatric and Adolescent Medicine 5/11. Online: (accessed on February 11. 2014)

Guidelines of the Society for Pediatrics and Adolescent Medicine. Confirmation diagnostics for suspected congenital metabolic diseases from newborn screening as of October 2010, AWMF registration number 027/021. Online: (accessed on August 10, 2013)

Explain PKU well! Guideline, status 2005. Online: (accessed on August 12, 2013)

German Phenylketonuria Interest Group: Basic food for thought for a catalog of requirements. Online: (accessed on August 12, 2013)

Important NOTE:
This article contains general information only and should not be used for self-diagnosis or self-treatment. He can not substitute a visit at the doctor. Unfortunately, our experts cannot answer individual questions.