Phenylketonuria: Mechanisms of CNS Damage
Phenylketonuria (PKU) is a severe condition predominantly affecting the nervous system. It is caused by a mutation in the gene encoding the enzyme phenylalanine-4-hydroxylase.
- A metabolic block occurs in the conversion of phenylalanine to tyrosine.
- Alternative metabolic pathways are activated, involving phenylalanine deamination and the synthesis of toxic compounds such as phenylpyruvic, phenyllactic, and phenylacetic acids.
- A deficiency of tyrosine, which serves as a precursor for catecholamines and melanin, is observed.
The key pathogenetic links include the direct toxic effect of metabolites on neurons, generalized hyperaminoacidemia, and impaired synthesis of essential neurotransmitters and hormones.
Maple Syrup Urine Disease and Ketoacidosis
This disease develops due to a deficiency of branched-chain $\alpha$-keto acid dehydrogenase. This defect is localized in the cells of the liver, myocardium, skeletal muscles, kidneys, and adipose tissue.
As a result of the pathological process:
- Leucine and isoleucine $\alpha$-keto acids accumulate.
- Metabolic ketoacidosis develops.
- Hyperammonemia occurs.
Together, these factors exert a marked toxic effect on the central nervous system.
Alkaptonuria and Ochronosis
This pathology is linked to impaired hydrolysis of tyrosine and phenylalanine, where tyrosine catabolism stops at the stage of homogentisic acid. The cause is an inherited defect in homogentisate 1,2-dioxygenase (homogentisic acid oxidase).
Uncleaved homogentisic acid accumulates in the body and transforms into a melanin-like pigment. This pigment deposits in the skin, sclerae, bones, cartilage, and internal organs, causing them to turn dark brown.
Clinically, the condition manifests as ochronosis: late-stage involvement of joints and the spine occurs, and after 20–30 years, multiple arthropathies and cartilage deformities develop.
Albinism: Pigment Deficiency
Albinism is a congenital or inherited disorder of tyrosine metabolism with an autosomal recessive inheritance 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 in the skin, hair, iris, and retina of the eyes.
- Complications: Photophobia, nystagmus, and a marked decrease in visual acuity.