Phenylketonuria: mechanisms of CNS damage
Phenylketonuria is a severe pathological condition with predominant involvement of the nervous system. It is based on a mutation in the gene encoding the enzyme phenylalanine 4-hydroxylase.
- A metabolic block occurs in the conversion of phenylalanine to tyrosine.
- An alternative metabolic pathway is activated with the deamination of phenylalanine and the synthesis of toxic compounds such as phenylpyruvic, phenyllactic, and phenylacetic acids.
- There is a deficiency of tyrosine, which is a precursor of catecholamines and melanin.
Key links in the pathogenesis include the direct toxic effect of metabolites on neurons, generalized hyperaminoacidemia, and impaired synthesis of crucial neurotransmitters and hormones.
Maple syrup urine disease and ketoacidosis
The disease develops due to a deficiency of the enzyme branched-chain $\alpha$-keto acid dehydrogenase. This defect is localized in the cells of the liver, myocardium, muscles, kidneys, and adipose tissue.
As a result of the pathological process:
- Leucine and isoleucine $\alpha$-keto acids accumulate.
- Metabolic ketoacidosis develops.
- Hyperammonemia occurs.
The combination of these factors exerts a pronounced toxic effect on the central nervous system.
Alkaptonuria and ochronosis
The pathology is associated with a disruption of tyrosine and phenylalanine hydrolysis, in which tyrosine metabolism halts at the stage of homogentisic acid. The cause is a congenital defect of the enzyme homogentisate 1,2-dioxygenase.
Uncleaved homogentisic acid accumulates in the body and transforms into a melanin-like pigment. This pigment is deposited in the skin, sclerae, bones, cartilage, and internal organs, causing them to turn a dark brown color.
Clinically, the condition manifests as ochronosis: in later stages, joint and spinal involvement is recorded, and after 20–30 years, multiple arthroarthrites and cartilage deformations develop.
Albinism: pigmentation deficiency
Albinism is a congenital or inherited disorder of tyrosine metabolism with an autosomal recessive transmission pattern.
- Pathogenesis: Deficiency of the enzyme tyrosinase in melanocytes leads to a sharp decrease in the synthesis of the pigment melanin.
- Clinical presentation: Absence or reduction of pigmentation of the skin, hair, as well as the iris and retina of the eyes.
- Complications: Photophobia, nystagmus, and a noticeable decrease in visual acuity.
Briefly: answers to topical questions
What biochemical tests are used for the diagnosis of phenylketonuria?
For screening diagnosis of phenylketonuria, the source indicates a double urine test at the age of 2–3 months:
- Felling's test — reaction with ferric chloride;
- reaction with dinitrophenylhydrazine.
Metabolism of which specific amino acids is impaired in maple syrup urine disease?
In maple syrup urine disease, the source indicates the accumulation of branched-chain $\alpha$-keto acids of leucine and isoleucine. The cause is a deficiency of branched-chain $\alpha$-keto acid dehydrogenase; the localization of the defect is in the cells of the liver, muscles, myocardium, kidneys, and adipose tissue. The disorder is accompanied by metabolic ketoacidosis, hyperammonemia, and toxic effects on the central nervous system.
What is the mechanism of joint damage in alkaptonuria?
The mechanism of joint damage in alkaptonuria is associated with the accumulation and deposition of a pathological pigment in cartilage and joints. A hereditary defect in homogentisic acid dioxygenase disrupts tyrosine catabolism in the liver at the stage of homogentisic acid cleavage; tyrosine metabolism stops at the stage of homogentisic acid, and it accumulates.
- Homogentisic acid is excreted in the urine and oxidized by atmospheric oxygen to form black pigments — alkaptons.
- Ochronosis: deposition of alkaptons in cartilage and joints; progressive joint damage, predominantly of the spine.
- Complications: after 20–30 years, multiple osteoarthritis and joint deformities develop due to cartilage damage.
Class and exam questions
Which enzyme is impaired in phenylketonuria?
Phenylketonuria features a mutation in the gene encoding phenylalanine-4-hydroxylase, which blocks the conversion of phenylalanine to tyrosine.
What causes the clinical manifestations of alkaptonuria?
Accumulation of homogentisic acid due to homogentisic acid oxidase deficiency, leading to the formation of a melanin-like pigment and joint damage.
What are the main manifestations of maple syrup urine disease?
The disease is caused by branched-chain $\alpha$-keto acid dehydrogenase deficiency, leading to the accumulation of leucine and isoleucine, metabolic ketoacidosis, hyperammonemia, and toxic effects on the CNS.
What else to study on this topic
- The role of tyrosine in the synthesis of catecholamines and melanin
- Biochemical pathways of branched-chain amino acid metabolism
- Mechanisms of joint complications in ochronosis
- Functions of melanocytes and the significance of tyrosinase
- Differential diagnosis of metabolic acidoses in aminoacidopathies
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