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Phenylpyruvine oligophrenia or phenylketonuria
Last reviewed: 05.07.2025
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According to statistics, one in 10-15 thousand newborns is diagnosed with a genetically determined neurocognitive pathology - phenylpyruvic oligophrenia, which develops due to a congenital disorder of metabolism of the essential amino acid phenylalanine.
The disease was first identified in the 1930s in Norway by physician Ivar Foelling, who called it hyperphenylalaninemia. Now the pathology is commonly called phenylketonuria, its ICD 10 code is E70.0.
[ Causes of phenylpyruvic oligophrenia
Genetic causes of phenylpyruvic oligophrenia are recessive inheritance by a child from parents who are carriers of two mutated alleles of the enzyme phenylalanine hydroxylase (phenylalanine-4-monooxygenase). As a result, the child completely or partially lacks this enzyme, which is necessary for the breakdown of phenylalanine (proteinogenic α-amino-β-phenylpropionic acid) to tyrosine [2-amino-3-(4-hydroxyphenyl)propanoic acid].
Geneticists have established that the pathogenesis of this disease is associated with more than 500 different homozygous or heterozygous structural mutations in chromosome 12 - in the genes of the liver enzyme phenylalanine hydroxylase 12q23.2 or 12q22-q24.1. The gene mutation leads to the fact that the level of this enzyme, necessary for the oxidation of phenylalanine contained in protein food, decreases by 4 or more times.
As a result, on the one hand, there is an accumulation of excess phenylalanine in the blood, which is toxic to the development of the brain. In this case, phenylalanine, which cannot be converted into tyrosine, breaks down by deamination to produce phenylpyruvic acid (2-oxo-3-phenylpropionic acid or phenylpyruvate). This acid, in turn, is converted into phenylacetic acid (phenylacetate) and phenyllactic acid (phenyllactate), which have a negative effect on the cells of the brain and central nervous system.
On the other hand, the primary causes of phenylpyruvic oligophrenia (congenital deficiency of phenylalanine hydroxylase and its consequence - excess phenylalanine) lead to a decrease in the levels of other amino acids in the brain (tryptophan, threonine, methionine, valine, isoleucine, leucine), which completely disrupts the process of biosynthesis of neurotransmitters that transmit nerve impulses - dopamine and norepinephrine - and causes progressive impairment of mental and physical development in children.
Symptoms of phenylpyruvic oligophrenia
Excess phenylalanine in the body manifests itself in infants, and its first signs are: lethargy and drowsiness; problems with sucking; convulsions; vomiting; eczematous lesions of the epidermis; musty (mousy) odor of the body, urine and breath (due to the increased content of phenylacetate, which is oxidized into phenylketones).
The following typical symptoms of phenylpyruvic oligophrenia are observed: growth retardation; muscle hyperkinesis, tremor or decreased muscle tone; psychotic attacks accompanied by unmotivated irritability and anger; decreased intellectual abilities or mental retardation.
Children with phenylketonuria also have hypopigmentation - significantly lighter and thinner skin, hair and eye color compared to their parents. The immediate cause of this symptom is a deficiency of tyrosine, which, when oxidized in the melanocytes of the epidermis, forms the pigment melanin.
As noted by specialists in the field of child psychiatry, the clinical picture of phenylpyruvic oligophrenia depends on the degree of damage to brain cells, and a baby with the pathology may seem normal during the first few months of life. If the disease was not detected immediately after birth, and the child did not receive treatment for a long time, then the consequences follow: irreversible brain damage and its complications in the form of severe or profound mental retardation (imbecility or idiocy).
And then the following symptoms of phenylpyruvic oligophrenia may occur: short stature, craniofacial abnormalities (microcephaly, protruding upper jaw, widely spaced teeth, impaired development of tooth enamel), 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
Early diagnosis of phenylpyruvic oligophrenia and prompt treatment are extremely important, reducing the risk of developing mental retardation from 80-90% to 6-8% (according to CLIMB – National Information Centre for Metabolic Diseases, UK).
To this end, neonatal screening for phenylketonuria should be performed in infants on the third to fourth day after birth (in exceptional circumstances between the 5th and 8th day) using a microbiological blood test for phenylalanine content – the so-called Guthrie test.
Biochemical urine tests for phenylpyruvate also reveal phenylketonuria in newborns, but this test should only be done 10-12 days after birth. Therefore, the international diagnostic standard is the determination of the concentration of phenylalanine in the blood plasma.
Modern instrumental diagnostics based on new technologies such as tandem mass spectrometry allows us to detect many congenital metabolic disorders that lead to intellectual disabilities. This ensures differential diagnostics of genetic metabolic pathologies, including: galactosemia, ketonuria (disorders of leucine, isoleucine and valine metabolism), homocystinuria, glutaric aciduria, isovaleric acidemia, sickle cell anemia, tyrosinemia, congenital hypothyroidism, etc.
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Treatment of phenylpyruvic oligophrenia
Diet therapy is practically the only effective treatment for phenylpyruvic oligophrenia, which allows the brain to develop normally. But when starting treatment for children over three or four years old, diet therapy will not eliminate the symptoms of the pathology that have already arisen.
Infants with phenylalanine hydroxylase deficiency cannot consume breast milk, and there are special formulas without phenylalanine for them - 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, legumes, nuts and many other products containing protein. Casein hydrolysate is used as a food substitute for prohibited products to maintain the balance of proteins in the body - a mixture of amino acids without phenylalanine extracted from milk protein (drugs Berlofan or Ipofenate).
If earlier doctors believed that taking mixtures without phenylalanine and following a special diet should continue for up to 10 years (that is, until the end of the brain myelination processes), now it is known that stopping treatment can lead to a more intense course of phenylpyruvic oligophrenia and irreversible consequences. While patients who follow dietary restrictions do not show any symptoms.
Today, medications for the treatment of phenylpyruvic oligophrenia (phenylketonuria) are represented by the drug Kuvan based on sapropterin dihydrochloride - a synthetic substitute for the cofactor of the enzyme phenylalanine hydroxylase tetrahydrobiopterin (BH4). Kuvan tablets, dissolved in water, are taken once a day - in the morning, during meals. The dose is calculated individually - in accordance with the patient's body weight (10 mg per kilogram). Side effects of the drug include watery nasal discharge, nasal congestion, headache, pain in the larynx, vomiting, diarrhea, and occasionally - abdominal pain. Taking this drug does not cancel the anti-phenylalanine diet. The instructions for the drug note that its use in children under four years of age has not been studied.
In this case, treatment of phenylpyruvic oligophrenia is carried out with constant monitoring of the level of phenylalanine in the blood.
Phenylpyruvic oligophrenia or phenylketonuria is a hereditary disease and cannot be prevented. However, when planning to have children, prevention is possible - an enzyme blood test and a genetic test to determine whether future parents are carriers of the mutant gene. Blood phenylalanine tests can also be performed during pregnancy.
As the Journal of Inherited Metabolic Disease writes, “the prognosis for patients with this pathology, if untreated, is a maximum life expectancy of up to 30 years in the status of a disabled person with severe impairment of brain function (since the level of phenylalanine in the blood will increase over time), and with treatment – to old age, with higher education and a successful career.”