Medical genetics. Contents module 4. Monogenic diseases. Disorders of amino acid metabolism

Abstract

General laws of pathogenesis. Schematically, the principal chains of pathogenesis of monogenic diseases can be represented as follows: mutant alleles → pathological primary product (qualitatively or quantitatively changed), a chain of biochemical subsequent processes → cell → bodies→ body. This is the basic pattern of monogenic diseases in all their diversity. Phenylketonuria (PKU) is the most common metabolic defect of phenylalanine (amino-acid). In a normal condition, phenylalanine (PhA) is decomposed via tyrosine pathway. Phenylalanine hydroxylase or tetrahydrobiopterin (its cofactor) deficient leads to PhA accumulation in biological liquids of the body. There are several clinically and biochemically heterogenic forms of PKU. Classical phenylketonuria is a disease caused by a mutation in the phenylalanine hydroxylase gene (PAH) localized on 12q24. 100 mutations are localized in PAH, including substitutions, insertions, deletions. Inheritance type is autosomal reccesive (AR). Diseases are developed as a result of the interaction of great amount of PhA and the products of its metabolism (phenyl-pyruvic, phenylacetic, phenyl-lactic acids, phenylethylamine and other) on the body, and these products accumulate in the body as a result of a full of partial absence of phenylalanine hydroxylase enzyme. PhA and its metabolites inhibit biochemical processes necessary for normal brain development: protein metabolism, glycol - and lipoprotein metabolism, AA transport, hormone metabolism, causing disorders of nervous system myelination in children, liver parenchyma lesions and other metabolic disorders.