Phenyl pyruvic oligophrenia or phenylketonuria

According to statistics, one of 10-15 thousand newborns reveals a genetically conditioned neurocognitive pathology - phenylpyrovine oligophrenia, which develops due to a congenital metabolic disorder of the essential amino acid phenylalanine.

The disease was first diagnosed in the 30s of the last century in Norway by a physician Ivar Foelling, who called it hyperphenylalaninemia. Now pathology is usually called phenylketonuria, its code for ICD 10 is E70.0.

[1], [2], [3], [4], [5], [6], [7]

Causes of phenylpyruvic oligophrenia

Genetic causes of phenylpyruvic oligophrenia are a recessive inheritance by the child of two mutated alleles of the enzyme phenylalanine hydroxylase (phenylalanine-4-monooxygenase) from the carrier parents. Consequently, the child completely or partially lacks this enzyme, which is necessary for cleavage of phenylalanine (proteinogenic α-amino-β-phenylpropionic acid) to tyrosine [2-amino-3- (4-hydroxyphenyl) propanoic acid].

Genetics have established that the pathogenesis of this disease is associated with more than 500 different homozygous or heterozygous structural mutations in the chromosome 12 - in the genes of the hepatic enzyme phenylalanine hydroxylase 12q23.2 or 12q22-q24.1. A gene mutation leads to the fact that the level of this enzyme, which is necessary for oxidation of phenylalanine, contained in protein food, decreases by 4 or more times.

As a result, on the one hand, the accumulation of excess phenylalanine in the blood is toxic to the development of the brain. In this case, phenylalanine, which can not be converted to tyrosine, decomposes by deamination to give phenylpyruvic acid (2-oxo-3-phenylpropionic acid or phenylpyruvate). This acid, in turn, turns into phenylacetic acid (phenylacetate) and phenyl-milk (phenyl-lactate), which have a negative effect on brain cells and CNS.

On the other hand, the primary causes of phenylpyruvic oligophrenia (congenital deficiency of phenylalanine hydroxylase and its consequence - an excess of phenylalanine) lead to a decrease in the levels of other amino acids (tryptophan, threonine, methionine, valine, isoleucine, leucine) in the brain, which completely disrupts the process of biosynthesis impulses of neurotransmitters - dopamine and norepinephrine - and causes a progressive impairment of children's mental and physical development.

[8], [9], [10], [11]

Symptoms of phenylpyruvic oligophrenia

Excess phenylalanine in the body manifests itself in infants, and its first signs: lethargy and drowsiness; problems with sucking; convulsions; vomiting; defeat epidermis eczematous nature; musty (mouse) body odor, urine and respiration (due to the high content of phenylacetate oxidizing to phenylketones).

There are typical symptoms of phenylpyruvic oligophrenia, such as growth retardation; Muscular hyperkinesis, tremor or decreased muscle tone; psychotic seizures, accompanied by unmotivated irritability and bitterness; decreased intellectual capacity or mental retardation.

Also in children with phenylketonuria hypopigmentation is expressed - much lighter and thin skin, hair and eye color in comparison with parents. The immediate cause of this symptom is a lack of tyrosine, in the oxidation of which in melanocytes of the epidermis a pigment melanin is formed.

As experts in the field of child psychiatry say, the clinical picture of phenylpyruvic oligophrenia depends on the degree of damage to the brain cells, and a baby with a pathology may seem normal during the first few months of life. If the disease was not detected immediately after birth, and the child has not received treatment for a long time, the consequences follow: irreversible brain damage and its complications in the form of severe or deep mental retardation (imbecility or idiocy).

And then there may be the following symptoms of phenylpyruvic oligophrenia: low growth, craniofacial anomalies (microcephaly, prominent upper jaw, widely spaced teeth, impaired tooth enamel development), increased muscle tone and tendon reflexes, hyperactivity, poor coordination of movements and awkward gait, increased irritability and other behavioral and neurological problems up to mental disorders.

Diagnosis of phenylpyruvic oligophrenia

The early diagnosis of phenylpyruvic oligophrenia and immediate treatment are extremely important, which reduce the risk of developing mental retardation from 80-90% to 6-8% (according to CLIMB - National Information Center for Metabolic Diseases, UK).

To this end, neonatal screening for phenylketonuria should be performed on babies on the third or fourth day after birth (in exceptional circumstances between 5 and 8 in the afternoon) by a microbiological blood test for phenylalanine, the so-called Guthrie test.

Biochemical analyzes of urine for the presence of phenylpyruvate also reveal phenylketonuria in newborns, but this analysis should be done only after 10-12 days from the moment of birth. Therefore, the international diagnostic standard is the determination of the concentration of phenylalanine in the blood plasma.

Modern instrumental diagnostics on the basis of such new technologies as tandem mass spectrometry allows to detect many congenital metabolic disorders leading to defects of the intellect. Thus, differential diagnosis of genetic pathologies of metabolic nature is provided, including: galactosemia, ketonuria (metabolic disorders of leucine, isoleucine and valine), homocystinuria, glutaric aciduria, isovaleric acidemia, sickle cell anemia, tyrosinemia, congenital hypothyroidism, etc.

[12], [13], [14], [15], [16],

Treatment of phenylpyruvic oligophrenia

Diet therapy is practically the only effective treatment of phenylpyruvic oligophrenia, which allows the brain to develop normally. But at the beginning of treatment of children older than three to four years, the symptoms of pathology that have already arisen will not eliminate diet therapy.

Fetal children with a deficiency of phenylalanine hydroxylase can not use mother's milk, and for them there are special mixtures without phenylalanine - Lofenalac, Afenilak, Aminogran, Milupa pku1 (pku2 and pku3), Periflex Infanta, XP Maxamum.

The diet excludes the consumption of meat, fish, poultry, milk, eggs, cheese, cottage cheese, ice cream, beans, nuts and many other products containing protein. As a food substitute for prohibited products to maintain the balance of proteins in the body, casein hydrolyzate is used - a mixture of amino acids extracted from the milk protein without phenylalanine (Berlofan or Ipofenat preparations).

Previously, doctors believed that taking the mixture without phenylalanine and adherence to a special diet should last up to 10 years (that is, until the end of brain myelination), it is now known that discontinuing treatment can lead to a more intense course of phenylpyruvic oligophrenia and irreversible consequences. While patients who observe dietary restrictions do not show any symptoms.

To date, drugs for the treatment of phenylpyruvic oligophrenia (phenylketonuria) are represented by Kuvan on the basis of sapropterin dihydrochloride, a synthetic substitute for the enzyme phenylalanine hydroxylase tetrahydrobiopterin (BH4) cofactor. Tablets Kuvan, dissolved in water, are taken once a day - in the morning, while eating. The dose is calculated individually - according to the patient's body weight (10 mg per kilogram). Among the side effects of the drug are watery discharge from the nose, nasal congestion, headache, pain in the larynx, vomiting, diarrhea, occasionally - pain in the abdomen. Admission of this drug does not cancel the antiphenylalanine diet. In the instructions to the medicine it is noted that its use for children under the age of four was not investigated.

In this case, the treatment of phenylpyruvic oligophrenia is carried out with a constant monitoring of the level of phenylalanine in the blood.

Phenyl pyruvic oligophrenia or phenylketonuria is a hereditary disease and can not be prevented. However, when planning the birth of children, prophylaxis is possible - enzymatic analysis of the blood and genetic analysis for the establishment of the carrier of the mutant gene by future parents. Analyzes for phenylalanine in the blood can also be carried out during pregnancy.

According to the Journal of Inherited Metabolic Disease, "the prognosis of patients with this pathology in the absence of treatment is a maximum life expectancy of up to 30 years in the status of a disabled person with severe impairment of brain functions (since the level of phenylalanine in the blood will increase with time ), and in the treatment - to old age, with higher education and a successful career ".