phenylketonuria

Disorders of amino acid metabolism

Phenylketonuria (PKU) is an inherited metabolic disorder. Phenylalanine, an essential (vital) amino acid, cannot be broken down inside the body.

Amino acids are basic protein building blocks and a vital component of human metabolism. The body can produce some of the amino acids itself, but others must be supplied through food every day - they are referred to as "essential", i.e. vital. Without these indispensable amino acids, the human metabolism cannot put together proteins.

Most defects in amino acid metabolism are congenital genetic defects that are inherited. Many are rather rare and their appearance also depends on whether enzymes are malfunctioning or missing.

Most defects mean that intermediate products can no longer be converted into amino acids. As a result, such intermediate products accumulate and at the same time an amino acid deficiency develops. Organ and tissue damage or various symptoms of failure occur too soon.

Disturbed amino acid transport and amino acid breakdown lead to diseases such as albinism, homocysteinuria, maple syrup disease, alkaptonuria or phenylketonuria.

What Happens With Phenylketonuria (PKU)

In total, there are more than 40 known hereditary amino acid metabolism disorders. The most common of these is phenylketonuria, in which the conversion of the amino acid phenylalanine into tyrosine is disrupted due to an enzyme defect. The enzyme responsible for this conversion process is called phenylalanine hydroxylase.
If this conversion cannot take place in the body, phenylalanine is deposited in the tissues and in the bloodstream and the brain is damaged.
As a result, the overall physical development is negatively affected and delayed. Those affected may experience seizures and mental retardation.
There is also a special diet and nutrition therapy for this amino acid metabolism disorder, which contributes significantly to normal development, especially in the first two months of newborn children.

Physicians differentiate between different forms of phenylketonuria:

• phenylketonuria
• Mild hyperphenylalaninemia
• Atypical phenylketonuria

Mild hyperphenylalaninemia is a rare form of PKU. This disorder is inherited in an autosomal recessive manner: In concrete terms, this means that both parents must pass on the defective gene segment to their child. This is the only way the disease can break out.
The enzyme phenylalanine hydroxylase (PAH) is formed, but has only a very low activity and can only convert a small amount of phenylalanine. The symptoms of the disease are accordingly mild.

The atypical form is tetrahydrobiopterin deficiency. This form of the disease can also be inherited in an autosomal recessive manner, but the PAH enzyme is not affected here. Rather, there is a deficiency of the co-factor tetrahydrobiopterin, which is indirectly required for amino acid breakdown.
This co-factor is also involved in other metabolic processes, such as dopamine and serotonin synthesis. Atypical PKU is therefore generally more severe and is also associated with neurological symptoms.

In the ICD-10, the international index of diseases, the disorders of the amino acid metabolism can be found in the chapter "Metabolic disorders" under the numbers E70.0-E72.9.

symptoms

First of all, infants with phenylketonuria do not show any symptoms. The first problems only become noticeable between the fourth and sixth month of life if the baby's illness has not yet been recognized and adequately treated by this point in time. In particular, the disturbed brain maturation causes severe complications in the further course of the disease.

The symptoms of untreated PKU are:

• Severe spiritual retardation: Brain damage continues until puberty and then suddenly stagnates. In most cases, the affected children are mentally handicapped.

• Epileptic seizures: The brain damage means that the brain nerve cells are particularly sensitive and overexcitable. As a result, epileptic seizures can occur frequently.

• The muscles of the affected patients are also overexcitable. The muscles tense up spasmodically (spastic states) and this leads to various motor disabilities and movement disorders.

• Behavioral Disorders: Some children with phenylketonuria are hyperactive and also unusually aggressive. Anger outbursts are also common.

• Microcephaly: Head growth also retards due to improper brain development. This small head circumference is particularly noticeable in older children compared to other children of the same age.

• Striking smell: In the case of phenylketonuria, various breakdown products of the amino acid phenylalanine are produced, which are reminiscent of the smell of mouse feces. These degradation substances are primarily excreted in the urine, but also in the sweat of the skin.

• Eczema-like changes in the skin.

In phenylketonuria, melanin formation is also impaired. Melanin is a pigment that is primarily responsible for the color of the skin and eyes. To a certain extent, phenylketonuria also influences the appearance of those affected.
For this reason, those affected often have very light, highly sun-sensitive skin and blond-white hair. The iris (eye iris) is light blue to even almost transparent: the reddish background of the eyes shines through clearly in those affected.

These symptoms of phenylketonuria vary in severity. The main reason for this is above all the activity of the enzyme phenyl-alanine-hydroxylase (PAH), which is restricted to different extents in each person affected. While some people still have residual enzyme activity and thus do not accumulate too large amounts of phenylalanine in the body, other people no longer show any enzyme activity at all. Accordingly, the disease progresses faster and more severely in them.

Course

Phenylketonuria (PKU) is an incurable disease. With an early diagnosis, however, a worse course of the disease can be prevented, so that the affected patients can lead an almost normal life.
A strict low-phenylalanine diet is of central importance in childhood during the period of brain development. In adulthood, the strict dietary requirements can often be relaxed a little.
Nevertheless, those affected have to be disciplined about their diet throughout their lives.

Causes and risk factors

In the case of phenylketonuria, the activity of the enzyme phenyl alanine hydroxylase (PAH) is either absent or significantly reduced. The reason for this is an error in the enzyme genetic information.
In healthy people without PKU, the PAH enzyme can convert the dietary amino acid phenylalanine into the amino acid tyrosine. In phenylketonuria patients, this conversion process no longer works or works only to a limited extent.

As a result, there is an excessive accumulation of phenylalanine in the brain as well as in the bloodstream. The amino acid phenylalanine is also increasingly excreted in the urine. However, excessive amounts have harmful effects on the human body. Without appropriate therapy, this amino acid metabolism disorder leads to severe impairment of brain development.

Phenylketonuria is a congenital amino acid metabolism disorder, specifically a hereditary disease. Around one in every 10,000 newborn babies in Germany suffers from this amino acid metabolism disorder. Overall, however, PKU is rare.

Affected persons can in turn pass on the defective genetic information, i.e. the defective PAH gene, to their children. In the child, however, the metabolic disease is only triggered when both parents carry the defective gene and pass it on to the baby. This type of inheritance is known in medicine as autosomal recessive.

If only one of the parents passes on the enzyme defect, the child will not show any symptoms later. In such a case, the child itself is a carrier of genetic information and can later transmit the genetic defect to its own children.

In principle, however, there is also the possibility that the child inherits the healthy, undamaged gene variant from both parents.
In such a case, there are no symptoms and the child itself is not a carrier of the genetic defect.

therapy

A strict low-protein diet is the most important therapeutic measure for phenylketonuria.

The essential amino acid phenylalanine cannot be produced by the body itself, but must be supplied through food. When consuming phenylalanine, however, it is very important that there is no excess, because in such a case the organism is not able to break it down again. So only the amounts of the essential amino acid should be ingested that the body needs.

This amino acid is found in almost every protein, so intake should be monitored throughout life to avoid excess.

The following foods are forbidden during the low-protein diet:

• Meat
• cured meats
• Fish
• seafood
• Legumes such as chickpeas, beans, peas, lentils or soy
• Grain products such as pasta, rice or bread
• Milk and dairy products (particularly with infants, care must be taken to ensure that breast milk - if at all - may only be fed in very small quantities)

The sweetener aspartame is also found in numerous light products and sugar-free drinks. This is also taboo for people suffering from PKU because it consists largely of phenylalanine.

However, in order to prevent a deficiency of phenylalanine, the patients should take a mixture of amino acids every day that also contains minerals and vitamins.

BH4 administration in phenylketonuria

If there is still residual enzyme activity in the affected patient, there is the possibility of promoting this PAH activity by administering BH4. This is intended to increase tolerance for the ingested phenylalanine in the affected patients. Under certain circumstances, the dietary requirements can even be relaxed a little. However, this drug for the treatment of phenylketonuria is only approved from the age of four.

In the case of atypical phenylketonuria, the missing coenzyme BH4 is artificially replaced, as are certain messenger substances such as serotonin and dopamine. In some cases, sufferers must remain on a low-phenylalanine diet for life.

Phenylketonuria in pregnant women

Pregnant women who suffer from PKU should observe the following rules:

• A low-protein diet must be strictly adhered to, otherwise the unborn child can be damaged and, in the worst case, a miscarriage can occur.

• Blood values ​​should be checked regularly by a doctor. In such a case, the European guidelines recommend two weekly measurements of the phenylalanine blood values. Not only the baby's brain can be damaged by an excess of phenylalanine, but also the heart and the eyes. Malformations of the skeleton are also possible.

• Women who want to have children should plan their pregnancy thoroughly and also attend all important examinations regularly.

• For a smooth pregnancy, it is important that the expectant mothers allow themselves to be guided by the doctor treating them.

You can do that yourself

Since this amino acid metabolism disorder is a hereditary disease, there are no options for prevention. Anyone suffering from PKU can, however, prevent unwanted complications and symptoms by following a strict diet consisting of foods low in phenylalanine.

In the case of classic phenylketonuria, the focus is on a lifelong vegan diet without the phenylalanine source aspartame. Newborn babies are fed exclusively phenylalanine-free formula. Vegetable and fruit meals are suitable as supplementary food. Parents of affected babies must precisely calculate the phenylalanine content of all food and consistently comply with the limit values ​​specified by the treating doctor.

Later, the baby food is then replaced by a protein powder that was specially developed for this metabolic disease. Patients must add this amino acid mixture to every meal. It is the main component of the medically required low-phenylalanine diet for life.
It is also very advisable to get the toddler used to the smell and taste of the powder in a playful way.

Nowadays there is a wide range of training and cooking courses for sufferers of all ages. Above all, these pedagogical measures address the patient's personal responsibility. At the same time, a positive approach to diet-related restrictions is supported.
Low-phenylalanine finished products are also available, which enable small patients in particular to take part in school trips and excursions.

Parents of sick children are exposed to great organizational and psychological stress. In order to process this psychological strain, participation and exchange with other affected people in self-help groups can be very helpful.
Adult patients must approach family planning with particular care. Especially during pregnancy, strict dietary requirements must be observed to ensure normal phenylalanine levels. However, normal values ​​are already mandatory at the time of conception in order to avoid serious prenatal damage.

Sources

https://flexikon.doccheck.com/de/Phenylketonurie
https://www.msdmanuals.com/de/heim/gesundheitsproblemen-von-kinder/herbliche-metabolic-disorders/phenylketonuria-pku
https://www.medical-genetics.de/diagnostics/humangenetics/diseases/syndrome/stoffabolic-diseases/phenylketonurie-pku
https://lexikon.stangl.eu/11364/phenylketonurie
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