Phenylketonuria

Genetic basis and etiology

The disease is inherited in an autosomal recessive manner. This means that for the clinical picture to develop, a child must inherit two defective gene copies from both parents.

The etiology is based on a mutation in the gene encoding the enzyme phenylalanine hydroxylase. This locus is located on the long arm of chromosome 12. The prevalence of this genetic anomaly in the population is approximately 1 case per 10,000 newborns. The absence or drastic decrease in hepatic enzyme activity makes the normal course of crucial biochemical reactions impossible.

Biochemical mechanisms and metabolism

To understand the pathogenesis, it is necessary to examine two pathways of phenylalanine amino acid metabolism:

1. Normal pathway. In a healthy body, phenylalanine undergoes hydroxylation under the action of the enzyme phenylalanine hydroxylase and is converted into tyrosine.
2. Pathological pathway. When the main enzyme is blocked, an excess of substrate occurs. The normal concentration of phenylalanine in the blood ranges between 0.003–0.04 g/L. As the pathology develops, the level critically rises, reaching values of 0.5–0.6 g/L (a significant excess).

The excess of the amino acid triggers alternative metabolism. Phenylalanine is partially converted into keto acids, among which phenylpyruvate and phenylacetic acid are distinguished. These compounds begin to circulate massively in the bloodstream.

Pathogenesis and clinical significance

The metabolites accumulating in the body exhibit a pronounced neurotoxic effect. The central nervous system takes the primary blow.

• Toxic damage: Along with phenylalanine, lactic acid accumulates in the blood. In combination with phenylpyruvate, these substances exert a destructive effect on the CNS, leading to irreversible intellectual decline if measures are not taken in time.
• Phenotypic manifestations: Due to the block in the transition of phenylalanine to tyrosine, the entire subsequent cascade of reactions suffers. Tyrosine is a precursor of DOPA (3,4-dihydroxyphenylalanine), from which melanin is synthesized with the participation of the enzyme tyrosinase. A deficiency of this dark pigment causes the characteristic phenotype of patients: they exhibit abnormally weak pigmentation of the hair and iris of the eyes.

For an accurate diagnosis in clinical practice, clinicians rely on the detection of high concentrations of phenylalanine in the blood and the presence of specific phenylpyruvic acid in the patient's urine.

Related genetic tyrosine metabolism defects

Since tyrosine is a direct product of phenylalanine metabolism, it is important to understand other genetic blocks associated with its further transformations. Normal tyrosine catabolism ends with the formation of carbon dioxide ($CO_2$) and water ($H_2O$), however, genetic breakdowns are possible at intermediate stages:

• Albinism: Occurs with a defect in the tyrosinase enzyme, when the formation of melanin from tyrosine is blocked.
• Tyrosinosis: Develops when the tyrosine transaminase enzyme is blocked at the first stage of catabolism (transition of tyrosine to p-hydroxyphenylpyruvate).
• Tyrosinemia: Associated with a disorder at the second stage, when the conversion of p-hydroxyphenylpyruvate to homogentisic acid is blocked.
• Alcaptonuria: Occurs when homogentisic acid cannot be cleaved into acetoacetic and fumaric acids.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Biochemical pathways of melanin synthesis from tyrosine
• Mechanism of the toxic effect of lactic acid on neurons
• Diagnostic markers of alcaptonuria and tyrosinemia
• The role of tyrosinase in the development of various forms of albinism
• End products of amino acid catabolism (Krebs cycle)

Other topics in the "Medical Genetics" section

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