Hereditary diseases

The development of each individual is the result of the interaction of genetic and external factors. A set of human genes is established during fertilization and then, together with environmental factors, determines the characteristics of development. The totality of the genes of the organism was called the genome. The genome as a whole is very stable, but under the influence of changing environmental conditions, mutations can occur in it.

The main units of heredity are genes( sections of the DNA molecule).The mechanism of transmission of hereditary information is based on the ability of DNA to self-duplication( replication).DNA contains a genetic code( a system for recording information about the location of amino acids in proteins using a sequence of nucleotides in DNA and information RNA), which determines the development and metabolism of cells. Genes are located in chromosomes, structural elements of the cell nucleus, containing DNA.The place occupied by a gene is called a locus. Monogenic

diseases - monolocus, polygenic diseases( multifactorial) - multilocus.

Chromosomes( visible in the light microscope bacillary structures in the nuclei of cells) consist of many thousands of genes. In humans, each somatic, that is, non-sexual, cell contains 46 chromosomes, represented by 23 pairs. One of the pairs - the sex chromosomes( X and Y) - determines the sex of the individual. In the somatic cell nucleus, two X chromosomes are present in women, one for chromosome X and one for chromosome Y in men. The sex chromosomes of men are heterologous: chromosome X is larger, it contains many genes responsible for both sex determination and other body signs;Y chromosome is small, has a form different from the X chromosome and carries mainly the genes that determine the male sex. Cells contain 22 pairs of autosomes. Human autosomal chromosomes are divided into 7 groups: A( 1-, 2-, 3-y pairs of chromosomes), B( 4-, 5-th pairs), C( 6-, 7-, 8-, 9-, 10-, 11th, 12th pairs, as well as chromosome X, similar in size to chromosomes 6 and 7), D( 13-, 14-, 15-th pairs), E( 16-, 17-, 18-), F( 19-, 20-th pairs), G( 21, 22 pairs and chromosome Y).

Genes are arranged linearly along the chromosomes, each gene occupying a strictly defined place( locus).Genes occupying homologous loci are called allelic. Each person has two alleles of the same gene: one on each chromosome of each pair, with the exception of most genes on the X and Y chromosomes in men. In those cases when identical alleles are present in the homologous sections of the chromosome, they speak of homozygosity, but when they contain different alleles of the same gene, it is customary to speak of heterozygosity for a given gene. If the gene( allele) shows its effect, being present only in one chromosome, it is called dominant. A recessive gene appears only if it is present in both members of the chromosome pair( or on a single X chromosome in men or in women with X0 genotype).The gene( and its corresponding sign) is called X-linked if it is localized in chromosome X. All other genes are called autosomal.

Distinguish between the dominant and the recessive type of inheritance. With dominant inheritance, the symptom manifests itself in both homozygous and heterozygous states. In recessive inheritance phenotypic( a collection of external and internal signs of an organism) manifestations are observed only in the homozygous state, while they are absent when heterozygous. A sex-linked dominant or recessive type of inheritance is also possible;thus, traits associated with genes localized in sex chromosomes are inherited.

With dominantly inherited diseases, several generations of one family are usually affected. With recessive inheritance, the latent heterozygous carrier of the mutant gene can exist for a long time in the family, so that sick children can be born in healthy parents or even in families in which this disease was absent in several generations.

Genetic mutations are the basis of hereditary diseases. Understanding mutations is impossible without a modern understanding of the term "genome".Currently, the genome is considered as a multi-genomic symbiotic

design, consisting of obligate and optional elements. The basis of obligate elements are structural loci( genes), the number and location of which in the genome are quite constant. Structural genes account for about 10-15% of the genome. The term "gene" includes the transcribed region: exons( the actual coding region) and introns( non-coding, exon-sharing site);and the flanking sequences are the leader sequence preceding the start of the gene, and the tail untranslated region. Optional elements( 85-90% of the entire genome) are DNA that does not carry information about the amino acid sequence of proteins and is not strictly mandatory. This DNA can participate in the regulation of gene expression, perform structural functions, increase the accuracy of homologous pairing and recombination, and facilitate the successful replication of DNA.The participation of facultative elements in the hereditary transmission of features and the formation of mutational variability has now been proved. Such a complex structure of the genome determines the variety of gene mutations.

In the broadest sense, a mutation is a stable, inherited change in DNA.Mutations can be accompanied by visible changes in the structure of chromosomes during microscopy: deletion - prolapse of the chromosome region;duplication - doubling of the chromosome region, insertion( inversion) - disruption of the chromosome region, its rotation by 180 ° and attachment to the rupture site;translocation - separation of a site of one chromosome and its attachment to another. Such mutations have the greatest damaging effect. In other cases, mutations may consist of replacing one of the purine or pyrimidine nucleotides of a single gene( point mutations).Such mutations include: missense mutations( mutations with a change in meaning) - replacement of nucleotides in codons with phenotypic manifestations;nonsense mutations( meaningless) - substitutions of nucleotides at which terminating codons are formed, as a result, the synthesis of the protein encoded by the gene prematurely terminates;splice-syng mutation - replacement of nucleotides at the junction of exons and introns, which leads to the synthesis of elongated protein molecules.

A new class of mutations has recently been discovered - dynamic mutations or expansion mutations associated with instability of the number of trinucleotide repeats in functionally important parts of genes. Many trinucleotide repeats localized in the transcribed or regulatory regions of genes are characterized by a high level of population variability, within which phenotypic disorders are not observed( i.e., the disease does not develop).The disease develops only when the number of repetitions in these sites exceeds a certain critical level. Such mutations are not inherited in accordance with Mendel's law.

Thus, hereditary diseases of are diseases caused by damage to the genome of a cell that can affect the entire genome, separate chromosomes and cause chromosomal diseases, or affect individual genes and cause gene diseases.

All hereditary diseases are divided into three large groups [Berkow R., 1997]:

■ monogenic;

■ polygenic, or multifactorial, in which mutations of several genes and non-genetic factors interact;

■ chromosomal abnormalities, or abnormalities in the structure or number of chromosomes.

Diseases related to the first two groups are often called genetic, and to the third - chromosomal diseases( Table).

Table Classification of hereditary diseases

Chromosomal

Anomalies in the number of sex chromosomes:

- Shereshevsky-Turner syndrome;

- Klinefelter's syndrome;

- a syndrome of trisomy X;

- syndrome 47, XYY Autosom:

- Down's disease;

- Edwards syndrome;

- the Patau syndrome;

- partial trisomy 22

Structural chromosome abnormalities:

catnip scream syndrome;

4p-deletion syndrome;syndromes of microdeletions of neighboring

genes Monogenic

Autosomal dominant: Marfan syndrome;von-lelbrand's disease;

anemia of Minkowsko-go-Choffar and others Autosomal recessive:

- phenylketonuria;

- galactosemia;

- cystic fibrosis, etc. X-linked recessive:

hemophilia A and B;Duchesne's myopathy;

X-linked dominant:

- Vitamin D-Resistant rickets;

- brown color of tooth enamel, etc.

Multifactorial( polygenic)

CNS: some forms of epilepsy, schizophrenia, etc. Cardiovascular system: rheumatism, hypertonic disease, atherosclerosis, etc.

Skin: atopic dermatitis, psoriasis, etc. Respiratorysystem: bronchial asthma, allergic alveolitis, etc. Urinary system: urolithiasis, enuresis, etc. Digestive system: peptic ulcer, ulcerative colitis, etc.

Chromosomal diseases can be caused by quantitative anomaliesiyami chromosomes( genome mutations), as well as structural abnormalities of chromosomes( chromosome aberrations).Clinically, almost all chromosomal diseases manifest themselves as a violation of intellectual development and multiple congenital malformations, often incompatible with life.

Monogenic diseases develop due to damage to individual genes. Monogenic diseases include the majority of hereditary metabolic diseases( phenylketonuria, galactosemia, mucopolysaccharidosis, cystic fibrosis, ACS, glycogenoses, etc.).Monogenic diseases are inherited in accordance with Mendel's laws and can be divided into autosomal dominant, autosomal recessive and linked to chromosome X. According to the type of inheritance X.

Multifactorial diseases are polygenic, their development requires the influence of certain environmental factors. Common signs of multifactorial diseases are as follows.

■ High frequency among the population.

■ Strong clinical polymorphism.

■ Similarity of clinical manifestations in a proband and close relatives.

■ Age and sex differences.

■ Earlier onset and some increase in clinical manifestations in descending generations.

■ Variable therapeutic efficacy of drugs.

■ The similarity of clinical and other manifestations of the disease in immediate relatives and probands( the coefficient of heritability for multi-factorial diseases exceeds 50-60%).

■ Mismatched laws of inheritance laws Mendel.

For clinical practice it is important to understand the essence of the term "congenital malformations", which can be single or multiple, hereditary or sporadic. It is not possible to refer to hereditary diseases those congenital diseases that arise during critical periods of embryogenesis under the influence of unfavorable environmental factors( physical, chemical, biological, etc.) and are not inherited. An example of such a pathology may be congenital heart defects, which are often caused by pathological influences during the period of cardiac laying( I trimester of pregnancy), for example, a viral infection tropic to the tissues of the forming heart;alcoholic fetus syndrome, anomalies in limb development, auricles, kidneys, digestive tract, etc. In such cases, genetic factors only form a hereditary predisposition or an increased susceptibility to the action of certain environmental factors. According to WHO, developmental abnormalities are present in 2.5% of all newborns;1.5% of them are caused by unfavorable exogenous factors during pregnancy, the rest are mainly of a genetic nature. The delineation of hereditary and congenital diseases, which are not inherited, is of great practical importance for predicting offspring in a given family.