Phenylketonuria: Symptoms and Treatment

Phenylketonuria (phenyl pyruvic oligophrenia, Felling disease) is a hereditary disease associated with impaired amino acid exchange of phenylalanine. As a result of the accumulation of toxic products due to improper metabolism, lag in mental and physical development develops. And the emerged violations in the state of health are irreversible, but timely diagnosis of the disease can prevent all pathological changes. Treatment consists in the exclusion of foods containing phenylalanine. If such an elimination diet is used almost from birth, a person grows healthy. Let's find out in more detail what kind of disease it is, how it manifests itself, how it is diagnosed and treated.

First described in 1934. Dr. Felling, from where it got its second name. It occurs at an average frequency of 1: 1, 00, but in different countries of the world there are fluctuations from: 600 (in Turkey) to: 00 000 (in Finland and Japan), in Russia from: 000 to: 0 000.

Causes of phenylketonuria

At the heart of the disease is a genetic defect - a mutation of the gene of the 12th chromosome (98% of all cases of phenylketonuria). This is the so-called classical phenylketonuria. The gene encodes the amount of the enzyme phenylalanine-4-hydroxylase. The enzyme is responsible for the conversion of the amino acid phenylalanine in the human body to tyrosine in the liver cells. Phenylalanine is an amino acid that is found in protein products (meat, fish, milk, eggs and others).

When the gene is mutated, the amount of the enzyme decreases, which leads to the accumulation of phenylalanine and intermediate metabolic products in the tissues of the body. The body tries to get rid of phenylalanine and the products of its disintegration, removing them with urine.

Such metabolic disorders lead to a breakdown in the structure of nerve wires, a decrease in the formation of neurotransmitters. All this, along with the direct toxic effect of excess phenylalanine, leads to the development of mental disorders, which are the main manifestation of the disease.

Phenylketonuria is inherited in an autosomal recessive manner, that is, it does not depend on sex, and arises when two pathological genes from the father and mother coincide.

The remaining 2% of cases of phenylketonuria are associated with other genetic defects and depend on the concentration of other enzymes (dihydropteridine reductase, etc.). They have the same clinical manifestations, but can not be treated with a diet. Such variants are referred to as atypical course of the disease. Among them, it is customary to isolate phenylketonuria II and III. Genetic defect in phenylketonuria II is located in the 4 th chromosome, with III - in the 11 th chromosome.

Symptoms

Children with phenylketonuria have blonde hair, pale skin, and blue eyes.

A child with phenylketonuria is born apparently healthy, that is, it does not differ from other children. With the arrival of food in the body begins to hit the protein, and hence the phenylalanine. The latter gradually accumulates, and usually to 2 months of life there are the first symptoms: lethargy or anxiety, lack of interest in the world around, regurgitation, changes in muscle tone. Sometimes, regurgitation is so frequent and abundant that there is a suspicion of the pathology of the gastrointestinal tract (pyloric stenosis). The child because of regurgitation can badly gain weight.

By 4-6 months, mental retardation becomes evident. The child does not follow the toy, does not react to the sound, does not recognize the parents. The longer the flow of phenylalanine into the body with food continues, the more pronounced are the disturbances in the mental and mental spheres. The development of speech is abruptly delayed. Sometimes vocabulary can be limited to a few words. If the diagnosis is not made and treatment is not initiated, then by the age of 3-4 years, mental disorders will reach the degree of idiocy (the most severe degree of oligophrenia).

The peculiarity of the clinical course of phenylketonuria is the irreversibility of the arising mental and intellectual changes. That is, with late detection, it is no longer possible to help such babies - they remain mentally retarded for life.

Physical development also lags behind: children later start to hold their heads, turn over, sit. When such children begin to walk, then they spread their legs widely, bending them simultaneously in the knee and hip joints. The walk is swaying, in small steps. In the sitting position, the children take the "tailor's pose" - they bend both hands and feet, pushing the latter under him. Usually the volume of the head is smaller than normal. There may be pronounced microcephaly: a small head.

Of the other neurologic symptoms, there may be disturbances in the muscle tone, convulsive seizures. Epileptic seizures usually appear at the age, years, and lead to an even greater progression of intellectual disorders.

Some of the patients with phenylketonuria appear involuntary movements in the limbs, trembling (hyperkinesis). In the movements there is no smoothness and consistency, the equilibrium is disturbed.

In addition to a number of mental and intellectual changes, phenylketonuria is characterized by the following symptoms:

• a specific "mouse" smell (or the smell of mold) from the child: this symptom is characteristic only of phenylketonuria. The smell appears as a result of the release of metabolic products of phenylalanine (phenylpyruvic, phenyl-milk, phenylacetic acids) through the skin and urine;
• skin manifestations: dermatitis, eczema, just peeling (arise for the same reason as the "mouse" smell);
• later teething: in such children, the first teeth can appear after 18 months, the enamel is underdeveloped;
• Pigmentation disorder: these children usually have blue eyes, very light skin and hair as a result of a decrease in the amount of melanin (its content depends on the metabolism of phenylalanine). Because of this, these children have increased sensitivity to sunlight;
• vegetative symptoms: low blood pressure, excessive sweating, constipation, acrocyanosis (cyanotic brushes and feet);
• often phenylketonuria is accompanied by congenital heart defects.

Atypical cases of phenylketonuria associated with impaired activity of other enzymes involved in the metabolism of phenylalanine, except for mental changes are characterized by the development of muscle weakness in all limbs with a simultaneous increase in muscle tone, spastic tetraparesis. Also, with these forms develop salivation, bouts of fever.

In adults suffering from phenylketonuria, there may be convulsions, coordination disorders, trembling in the limbs, memory and attention impairment, the onset of depression. Usually, these symptoms occur when the elimination diet is not observed.

Diagnostics

Screening tests for the content of phenylalanine by all newborns are carried out in the hospital.

In connection with the fact that phenylketonuria is accompanied by the development of irreversible mental disorders, in many countries of the world, including in Russia, it is customary to use screening methods for diagnosis. What does this mean? All without exception, newborn babies in the hospital are subjected to rapid tests for the content of phenylalanine. To do this, take the capillary blood (from the heel) on the 4th-5th day of the life of the baby (in premature babies on the 7th), apply to a special paper form and sent to the laboratory, where, for certain changes, the laboratory doctor makes conclusions about the content of phenylalanine in blood. A negative test indicates the absence of phenylketonuria.

If the test is positive, then additional studies are performed to determine the phenylalanine content in blood and urine (chromatography, fluorimetry). The concentration of phenylalanine in the blood and urine is regularly checked during treatment to monitor the effectiveness of the diet and correct it when necessary.

It is possible to conduct a genetic study to confirm the mutation in the gene responsible for phenylalanine-4-hydroxylase. Such a study is possible as a prenatal diagnosis, that is, during the pregnancy (take amniotic fluid by puncture). This invasive examination is done according to strict indications (for example, the presence of a patient with phenylketonuria in a family). The detection of a genetic defect in the fetus allows the termination of pregnancy.

Treatment of phenylketonuria

To date, the most effective and common way to treat phenylketonuria is the elimination diet: a diet with the exception of foods containing phenylalanine. If you strictly adhere to it in the first years of your child's life, when the development of the nervous system is still going on, you can grow a healthy and full-fledged person. It is very important to exclude phenylalanine in the first year of life, when the nervous system develops most actively. If the elimination diet is prescribed after a year, mental disorders are not cured. Each month of the first year of life without dieting, the child will be irrevocably lost about 4 IQ points. It is usually sufficient to adhere to a diet of 16-18 years, after this age the body becomes less sensitive to the toxic effect of phenylalanine, and it is possible to expand the diet. Inclusion of new products should be carried out under the control of the content of phenylalanine in the blood. Sometimes lifelong strict adherence to a diet is required. Pregnant women and women planning pregnancy, and with the patient phenylketonuria, for the birth of a healthy child must strictly adhere to the diet.

The degree of severity of a diet depends on the concentration of phenylalanine in the blood of a child. At its level up to 2-6 mg% (120-360 μmol / l) diet is not prescribed, higher than this indicator - is mandatory.

The essence of the diet is the exclusion of protein products.

Refusal of breastfeeding is not necessary, but in this case the nursing mother must strictly adhere to an elimination diet, because breast milk contains protein (respectively, phenylalanine). The question of the possibility of breastfeeding is solved individually!

To replenish protein reserves, special mixtures are prescribed that do not contain phenylalanine - Afenylac, Lofenalak, Nofemix. After a year, this is Phenilfrey, Nofelan, Bigrefen, Tetrafen, MD Mil PKU-3 and others. As complementary foods, vegetable and fruit purees, fruit jelly, protein-free cereals (rice, corn) are prescribed. After 6 months, you can use special drinks Loprofin, Nutrigen and others, eat pasta, protein-free bread.

In Russia, the provision of nutritional food for children with phenylketonuria is free by law.

The following products are contraindicated in patients with phenylketonuria: meat, fish (and seafood), nuts, cottage cheese, hard cheese, legumes, eggs, wheat flour, buckwheat and semolina, oat flakes.

During the appointment of the elimination diet, strict control of the phenylalanine content in the blood is necessary: ​​the first 3 month of life - every week, from 3 months to a year - at least once a month, from year to 3 years - 1 time in 2 month. Aspiration to the content of phenylalanine 2-6 mg% in younger children, after 10 years - up to 10 mg%. Be sure to observe the child's psychoneurologist.

In addition to the elimination diet, the complexes of vitamins and minerals are periodically prescribed. If there are convulsive seizures, it is necessary to use anticonvulsants (Depakin, Clonazepam and others). Many of these children show massage, exercise therapy. It is possible to use physiotherapy to correct muscle tone.

Atypical forms of phenylketonuria are not amenable to treatment with an elimination diet. In this case, the use of hepatoprotectors, anticonvulsants, drugs with levodopa (for the correction of hyperkinesia), 5-hydroxytryptophan, tetrahydrobiopterin (BH 4) is indicated. These forms of phenylketonuria have a worse prognosis for life and even more so of intellectual development.

To date, new directions in the treatment of phenylketonuria are being developed. Among them is worth noting the following:

• use of phenylalanine lase (PAL) substitution therapy, a plant enzyme that cleaves phenylalanine to non-toxic compounds;
• genetic engineering (introduction of an artificially created normal gene responsible for phenylalanine-4-hydroxylase);
• the method of "large neutral amino acids" is a reduction in the absorption of phenylalanine from food and intake into the brain with the help of special preparations.

While these modern developments are not widely used, some studies confirming their effectiveness are already underway.

Maternal phenylketonuria

If a woman suffering from phenylketonuria does not adhere to the diet when planning a pregnancy and when she is onset, this affects the development of her child. The offspring of such women has a delay in intrauterine development and congenital malformations: malformations heart, brain development abnormalities, bladder, microcephaly, facial skeletal anomalies (crevices).

To prevent pathological changes in the child, such women should adhere to the elimination diet prior to conception and the entire pregnancy. Deficiency of protein is compensated for by special protein mixtures without phenylalanine.

Thus, phenylketonuria is a genetic disorder of the amino acid metabolism, which in late diagnosis leads to the development of severe intellectual disorders in the child. Screening of this disease in maternity homes allows you to diagnose it in the first weeks of life and in time to prescribe treatment. The main method at present is the appointment of an elimination diet, which allows you to save intellect to a small man, and therefore, to maintain health, which will ensure a full-fledged existence for all life.