Diseases associated with a violation of amino acid metabolism
Phenylketonuria( phenyl pyruvic oligophrenia, Fellin-ha disease) is one of the most common hereditary diseases, more often due to the deficiency of phenylalanine hydroxylase( 261600, 12q24.1);in the absence of timely treatment leads to severe mental retardation. Type of inheritance is autosomal recessive. Patients are homozygous for the phenylketonuria gene, and their parents are heterozygous.
Due to a defect in the phenylalanine hydroxylase gene( FAG gene), the enzyme deficiency develops, and as a result, the block enters the normal conversion of phenylalanine to the amino acid tyrosine [Ginter EK, 2001].Phenylalanine accumulates in the body and its concentration in the blood rises 10-100 times. Further, it turns into phenylpyruvic acid, which has a toxic effect on the nervous system. The accumulation of phenylalanine in the body occurs gradually, so the clinical picture develops slowly. In this regard, the early diagnosis of phenylketonuria is very important.
The gene for phenylketonuria is localized on chromosome 12( 12q24.1).The most common type of mutation is single nucleotide replacement.
To diagnose phenylketonuria in newborns, biochemical screening tests have been developed. From molecular-genetic methods, both direct and indirect diagnosis of mutations in the phenyl-ketonuria gene is used. A very fast and effective method of PCR / StyI-diagnostics of the most frequent( major) mutation in Russia( more than 70%) R408W was developed.
In addition to phenylketonuria, hereditary diseases associated with a violation of the amino acid metabolism include type I and type II tyrosinoses( p-hydroxyphenylpyruvate dioxygenase deficiency and tyrosine-nontensferase, respectively), alkaponuria( homogeneity-1,2-dioxygenase defect), albinism( phenoxidase defect),maple syrup disease( decarboxylase defect), homocystinuria( cystathionine-tetaza defect), and many others.
Periodic disease is an autosomal recessive monogenic disease characterized by recurring attacks of fever, pain and polyserositis. The gene of the periodic disease( MEFV; 249100, 16p13, p) is mapped on the short arm of chromosome 16. Periodic disease is more often detected in persons of Sephardic, Jewish, Armenian, Arab and Turkish origin. In these populations, the heterozygote carrier frequency of the periodic disease gene reaches 1: 5.The protein of the pyridine encoded by the genome of the periodic disease has 781 amino acids. Among the identified mutations of the gene, three missense mutations are most common: Met-694-Val, Val-726-Ala and Met-680-Ile.
Cardiomyopathies - myocardial diseases of unclear etiology, associated with cardiac dysfunction. Dilate, hypertrophic, re-trictional and arrhythmogenic forms of the disease are distinguished( WHO, 1995).Some forms of cardiomyopathy are caused by genetic defects.
■ Hypertrophic cardiomyopathy is detected in 0.02-0.05% of the population, about half of all cases are
families [Godd M. et al., 1989].The main morphological sign of the disease is myocardial hypertrophy of the left ventricle, usually of an asymmetric nature, with a predominant thickening of the interventricular septum. The specific histological marker of hypertrophic cardiomyopathy is a disoriented, irregular, chaotic arrangement of cardiomyocytes and myofibrils in them. The gene for hypertrophic cardiomyopathy - FHC-1( gene for familial hypertrophic cardiomyopathy) - was identified by J. Jarcho et al.in 1989. More than 50 mutations are now described in the loci of genes that control the structure and function of myocardial contractile proteins. Abnormal genes are localized on chromosomes 1, 2, 7, 11, 14 and 15. Usually, the gene defect consists in breaking the sequence of amino acids( replacing one amino acid with another) and inheriting in an autosomal dominant type. Most known mutations( approximately 30%) lead to the synthesis of an abnormal P-myosin heavy chain and only some mutations to the synthesis of altered cardinal troponin T( for patients characterized by a high risk of sudden death) and a-tropomyosin.
■ Right ventricular arrhythmogenic dysplasia is characterized by replacement of the myocardium of the right ventricle with fatty or fibrous fat tissue with atrophy, thinning of the wall, the formation of aneurysmatic protrusions, dilatation of the cavity and ventricular arrhythmias( extrasystole, paroxysms of ventricular tachycardia).The disease is most often observed in Italy, and in 30% it is of a family nature with inheritance in an autosomal-dominant type. An abnormal gene responsible for the occurrence of familial arrhythmogenic right ventricular dysplasia is located on chromosome 14.