General patterns of pathogenesis of hereditary diseases. Etiology of hereditary diseases

The initial link in the pathogenesis of hereditary diseases is mutations -a sudden abrupt change in heredity due to a change in the structure of a gene, chromosomes or their number, that is, the nature or volume of hereditary information.

Taking into account various criteria, several classifications of mutations have been proposed. According to one of them, there are spontaneousand inducedmutations. The first ones arise in the conditions of the natural background of the surrounding and internal environment of the organism, without any special influences. They can be caused by external and internal natural radiation, the action of endogenous chemical mutagens, etc. Induced mutations are caused by special targeted effects, for example, under experimental conditions.

According to another classification, there are specificand non-specificmutations. Let's make a reservation that most geneticists do not recognize the presence specificmutations, assuming that the nature of the mutations does not depend on the quality of the mutagen, that the same mutations can be caused by different mutagens, and the same mutagen can induce different mutations.

By the type of cells damaged by the mutation, they are distinguished somatic,arising in the cells of the body, and gametemutations - in the germ cells of the body. The consequences of both are ambiguous. With somatic mutations, the disease develops in the carrier of mutations, the offspring does not suffer from this kind of mutation. For example, a point mutation or amplification (multiplication) of a protooncogene in a somatic cell can serve as the beginning of tumor growth in this organism, but not in its children. In case of gamete mutations, on the contrary, the organism carrying the mutation does not get sick. The offspring suffers from this mutation.

According to the amount of genetic material affected by the mutation, mutations are divided into geneor point(changes within one gene, the sequence or composition of nucleotides is disrupted), chromosomal aberrationsor rearrangements that alter the structure of individual chromosomes, and genomicmutations characterized by a change in the number of chromosomes.

Chromosomal aberrations, in turn, are subdivided into the following types:

deletion(lack) - a type of chromosomal rearrangement, in which individual sections and the corresponding genes of the chromosome fall out. An example of a congenital pathology associated with a deletion is the “crying cat” syndrome, which is based on the deletion of the short arm of the 5th chromosome. The disease is manifested by a number of developmental defects: a moon-shaped face, an antimongoloid eye shape, microcephaly, a flaccid epiglottis, a peculiar arrangement of the vocal cords, as a result of which the crying of a child resembles a cry of a cat. Deletion of one to four copies of Hb - genes is associated with the development of one of the forms of hereditary hemoglobinopathy - α-thalassemia;

duplication -a type of chromosomal rearrangement, in which a section of the chromosome and the corresponding block of genes are doubled. Today, various variants of duplications (partial trisomies) are known for almost all autosomes. They are relatively rare;

inversion -a type of chromosomal rearrangement in which a portion of the chromosome (for example, at the level of genes 3-6) is rotated 180 °.

translocation -a type of chromosomal rearrangement, characterized by the movement of a portion of a chromosome to another location on the same or a different chromosome. In the latter case, the genes of the translocated site fall into a different linkage group, a different environment, which can promote the activation of "silent" genes or, conversely, suppress the activity of normally "working" genes. Burkitt's lymphoma (reciprocal translocation between the 8th and 14th chromosomes) can be examples of serious pathology based on translocation phenomena in somatic cells.

The final link in the pathogenesis of hereditary diseases is the implementation of the action of the abnormal gene (s). There are 3 main options:

1. If the abnormal gene has lost the program code for the synthesis of a structural or functionally important protein; the synthesis of the corresponding messenger RNA and protein is disrupted.In the absence or in the absence of an insufficient amount of such a protein, processes are disrupted, in the implementation of which at a certain stage this protein plays a key role. Thus, a violation of the synthesis of antihemophilic globulin A (factor VIII), B (factor IX), the plasma precursor of thromboplastin (factor XI), which is extremely important in the implementation of various stages of the internal mechanism of phase I of blood coagulation, leads to the development of hemophilia (respectively: A , B and C). Clinically, the disease manifests itself as a hematoma type of bleeding with damage to the musculoskeletal system. Hemorrhages in large joints of the extremities predominate, profuse bleeding even with minor injuries, hematuria. Hemophilia A and B are inherited linked to the X chromosome, recessively. Hemophilia C is inherited in a dominant or semi-dominant manner, autosomally.

At the heart of the development of hepatocerebral dystrophy is a protein deficiency - cerruloplasmin, which is associated with an increase in absorption, impaired metabolism and excretion of copper, its excessive accumulation in tissues. The toxic effect of copper has a particularly strong effect on the state and function of the nervous system and liver (a process that ends with cirrhosis). The first symptoms of the disease appear at the age of 10-20 years, rapidly progress and end in death. Inheritance is autosomal recessive.

2. The loss by the mutant gene of the program code for the synthesis of one or another enzyme ends with a decrease or cessation of its synthesis, its deficiency in the blood and tissues, and disruption of the processes it catalyzes.As examples of the development of hereditary forms of pathology along this path, we can name a number of diseases of amino acid, carbohydrate metabolism, etc. Phenylpyruvic oligophrenia, for example, is associated with a violation of the synthesis of phenyl lanine hydroxylase, which normally catalyzes the conversion of phenylalanine consumed with food into tyrosine. Enzyme deficiency leads to excessive levels of phenylalanine in the blood, diverse changes in tyrosine metabolism, production of significant amounts of phenylpyruvic acid, brain damage with the development of microcephaly and mental retardation. The disease is inherited in an autosomal recessive manner. Its diagnosis can be made in the first days after the birth of a child, even before the manifestation of pronounced symptoms of the disease by the detection of phenylpyruvic acid and phenylalaninemia in the urine. Early diagnosis and timely treatment started (diet low in phenylalanine) help to avoid the development of the disease, the most severe manifestation of it - mental disability.

The absence of the oxidase of homogentisic acid, which is involved in the metabolism of tyrosine, leads to the accumulation of an intermediate product of tyrosine metabolism - homogentisic acid, which is not oxidized into maleylacetoacetic acid, but is deposited in joints, cartilage, connective tissue, causing with age (usually after 40 years) the development of severe arthritis. In this case, the diagnosis can also be made very early: in the air, the urine of such children turns black due to the presence of homogentisic acid in it. It is inherited in an autosomal recessive manner.

3. Often as a result of the mutation, a gene with a pathological code is formed, as a result of which abnormal RNA and abnormal protein with altered properties are synthesized.The most striking example of this type of pathology is sickle cell anemia, in which in the 6th position (the b-chain of hemoglobin the glutamic amino acid is replaced by valine, unstable HbS is formed. In the restored state, its solubility sharply decreases, its ability to polymerize increases. Crystals are formed. , disrupting the shape of erythrocytes, which are easily hemolyzed, especially in conditions of hypoxia and acidosis, leading to the development of anemia. Inheritance is autosomal recessive or semi-dominant.

An important condition for the emergence and implementation of the action of mutations is the failure of the DNA repair system, which can be genetically determined or develop in the process of life, under the influence of unfavorable factors of the external or internal environment of the organism.

So, in the genotype of healthy people there is a gene with the code of the program for the synthesis of the enzyme exonuclease, which ensures the "excision" of pyrimidine dimers, which are formed under the influence of ultraviolet radiation. The abnormality of this gene, expressed in the loss of the exonuclease synthesis program code, increases the sensitivity of the skin to sunlight. Under the influence of even a short insolation, dry skin occurs, its chronic inflammation, pathological pigmentation, and later neoplasms appear that undergo malignant transformation. Two thirds of patients die before the age of 15. The disease - xeroderma pigmentosa - is inherited in an autosomal recessive manner.

The functional potential of the DNA repair system weakens with age.

A certain role in the pathogenesis of hereditary forms of pathology may belong, apparently, to persistent violations of the regulation of gene activity, which, as already noted, may be one of the possible causes of the manifestation of a hereditary disease only many years after birth.

So, the main mechanisms of the development of hereditary pathology are associated with:

1) mutations resulting in:

a) loss of normal hereditary information;

b) an increase in the volume of normal hereditary information;

c) replacement of normal hereditary information with pathological;

2.disorder of damaged DNA repair

3. persistent changes in the regulation of gene activity.

Chromosomal diseases

A special group of diseases associated with structural changes in the genetic material are chromosomal diseases,conditionally related to the category of hereditary. The fact is that in the vast majority of cases chromosomal diseases are not transmitted to offspring, since their carriers are most often infertile.

Chromosomal diseases are caused by genomic or chromosomal mutations that have occurred in the gamete of one of the parents, or in the zygote formed by gametes with a normal set of chromosomes. In the first case, all cells of the unborn child will contain an abnormal chromosome set. (full form of chromosomal disease),in the second, a mosaic organism develops, only part of the cells of which with an abnormal set of chromosomes (mosaic form of the disease).The severity of pathological signs with a mosaic form of the disease is weaker than with a complete one.

The phenotypic basis of chromosomal diseases is formed by disorders of early embryogenesis, as a result of which the disease is always characterized by multiple developmental defects.

The frequency of chromosomal abnormalities is quite high: out of every 1000 live-born babies, 3-4 have chromosomal diseases, in stillborn babies they account for 6%; chromosome imbalance is due to about 40% of spontaneous abortions (N.P. Bochkov, 1984). An imbalance affecting all pairs of chromosomes causes such significant disturbances in the body that, as a rule, they turn out to be incompatible with life already in the early or later stages of embryogenesis. Changes in the number or structure of individual chromosomes are more common. Lack of genetic material causes more significant defects than excess. Complete monosomies, for example, on autosomes, are practically not found. Apparently, this imbalance causes death already in gametogenesis or at the stage of zygote and early blastula.

The basis for the development of chromosomal diseases associated with a change in the number of chromosomes is formed in gametogenesis, during the first or second meiotic divisions or during the cleavage of a fertilized egg, most often as a result of chromosome nondisjunction. When an abnormal egg is fertilized with a sperm with a normal set of chromosomes or a normal egg with an abnormal sperm, less often with a combination of two gametes containing an altered number of chromosomes, prerequisites are created for the development of a chromosomal disease.

The likelihood of such violations, and, consequently, the birth of children with chromosomal diseases, increases with the age of the parents, especially the mother.

Down's disease is the most common chromosomal disorder. The karyotype of patients in 94% consists of 47 chromosomes due to trisomy on 21 chromosomes. In about 4% of cases, there is a translocation of the extra 21st chromosome into the 14th or 22nd, the total number of chromosomes is 46. The disease is characterized by a sharp delay and impairment of the child's physical and mental development. Such children are undersized, they start to walk and talk late. The appearance of the child is striking (the characteristic shape of the head with a sloping nape, wide, deeply sunken nose bridge, Mongoloid eye incision, open mouth, abnormal growth of teeth, macroglossia, muscle hypotension with loose joints, especially the little finger, brachydactyly, transverse fold in the palm, etc. .) and severe mental retardation, sometimes to complete idiocy. Violations are noted in all systems and organs. Malformations of the nervous (67%) and cardiovascular (64.7%) systems are especially common. As a rule, the reactions of humoral and cellular immunity are changed, the repair system of damaged DNA suffers. Associated with this is an increased susceptibility to infection, a higher percentage of the development of malignant neoplasms, especially leukemia. In most cases, patients are infertile. However, there are cases of a sick woman giving birth to children, some of them suffer from the same disease.

The second most frequent (1: 5000-7000 births) pathology caused by a change in the number of autosomes is Patau syndrome (trisomy 13). The syndrome is characterized by severe defects of the brain and face (defects in the structure of the bones of the brain and facial skull, brain, eyes; microcephaly, cleft of the upper lip and palate), polydactyly (more often - hexodactyly), defects of the heart septum, incomplete bowel rotation, polycystic kidney disease, malformations development of other organs. 90% of children born with this pathology die within 1 year of life.

The third place (1: 7000 births) among autosomal polysomy is taken by trisomy 18 (Edwards syndrome). The main clinical manifestations of the disease: numerous defects of the skeletal system (pathology of the structure of the facial part of the skull: micrognathia, epicanthus, ptosis, hypertelorism), cardiovascular (defects of the interventricular septum, valvular defects of the pulmonary artery, aorta), nail hypoplasia, horseshoe kidney, cryptorchidism in boys ... 90% of patients die in the first year of life.

Much more common are chromosomal diseases associated with nondisjunction of sex chromosomes. Known variants of gonosomal polysomies are shown in Table 6.

Table 6

Types of gonosomal polysomies found in newborns

(after N.P. Bochkov, A.F. Zakharov, V.I. Ivanov; 1984)

As follows from the table, the overwhelming number of polysomies for sex chromosomes falls on trisomies XXX, XXY, XYY.

With trisomy on the X chromosome ("Superwoman")clinical signs of the disease are often absent or minimal. The disease is diagnosed by the detection of two Barr's bodies instead of one and by the karyotype 47, XXX. In other cases, patients have hypoplasia of the ovaries, uterus, infertility, various degrees of mental disability. An increase in the number of X chromosomes in the karyotype increases the manifestation of mental retardation. Such women are more likely than in the general population to suffer from schizophrenia.

Polysomy variants with the participation of Y chromosomes are more numerous and varied. The most common of these, Klinefelter's syndrome, is caused by an increase in the total number of chromosomes to 47 due to the X chromosome. A sick man (the presence of a Y chromosome dominates with any number of X chromosomes) is distinguished by high growth, female type of skeletal structure, inertia and mental retardation. Genetic imbalance usually begins to manifest itself during puberty with underdeveloped male sexual characteristics. The testicles are reduced in size, aspermia or oligospermia is observed, often gynecomastia. A reliable diagnostic sign of the syndrome is the detection of sex chromatin in the cells of the male body. Superklinefelter's syndrome (XXXY, two Barr's bodies) is characterized by a greater severity of these signs, mental incapacity reaches the degree of idiocy.

Karyotype 47, XYY - "Superman"differs in impulsive behavior with pronounced elements of aggressiveness. A large number of such individuals are found among prisoners.

Gonosomal monosomy is much less common than polysomy, and is limited to X monosomy (Shereshevsky-Turner syndrome). The karyotype consists of 45 chromosomes; sex chromatin is absent. Patients (women) are characterized by short stature, short neck, cervical lateral skin folds. Lymphatic edema of the feet, poor development of sexual characteristics, absence of gonads, hypoplasia of the uterus and falopian tubes, primary amenorrhea are characteristic. Such women are sterile. Mental ability is usually not affected.

No cases of V monosomy have been identified. Apparently, the absence of the X chromosome is incompatible with life and individuals of the "OV" type die at the early stages of embryogenesis.

Chromosomal diseases caused by structural changes in chromosomes are less common and, as a rule, lead to more severe consequences: spontaneous abortion, prematurity, stillbirth, and early infant mortality.

Hereditary diseases arise as a result of changes in the hereditary apparatus of the cell (mutations), which are caused by radiation, thermal energy, chemicals and biological factors. A number of mutations are caused by genetic recombinations, imperfect repair processes, and arises as a result of errors in the biosynthesis of proteins and nucleic acids.

Mutations affect both somatic and germ cells. Distinguish between genomic, gene mutations and chromosomal aberrations. Since the pathogenesis of hereditary diseases is largely determined by the nature of the mutational change, it is worth considering mutations in more detail.

Genomic mutations are a change in ploidy, usually an increase: triploidy, tetraploidy. In humans, polyploidy is usually incompatible with life.

Chromosomal aberrations are changes in the structure of chromosomes: deletion (separation of a part of a chromosome), inversion (rotation of part of a chromosome by 180 0), translocations (movement of a part of one chromosome to another), etc. The study of chromosome aberrations became more accessible after the development of a method for differential chromosome coloring. Chromosomal aberrations tend to result in less severe defects in the body compared to monosomy or trisomy on an entire chromosome.

Gene mutations are caused by changes in the structure of DNA. This leads to disruption of the synthesis of polypeptide chains of protein molecules, structural, transport proteins or protein-enzymes. Almost half of hereditary diseases are the result of gene mutations.

Mutations are spontaneous and induced. Spontaneous mutations occur at approximately 10-15 and 10-10 per gene over a 30-year period. Spontaneous mutations are of great importance for evolution, many of them are picked up by selection. Induced mutations are caused by radiation, thermal and mechanical energy, as well as chemicals, including medications, and some biological factors.

With mutations, various changes in the DNA molecule occur:

• 1. Replacement of one similar nitrogenous base with another (transition);
• 2. Change in the number of nucleotides;
• 3. Inversion - by turning the DNA section by 180 0;
• 4. Translocation - transfer of one piece of DNA to another;
• 5. Transposition - the introduction into the genome of a variety of "jumping" genes or viruses and virus-like elements.
• 6. Chemical modification of the nitrogenous base, single- or double-stranded DNA break, the formation of their cross-links.

The cell has several defense systems that prevent the development of primary DNA damage and its implementation into a mutation. First of all, it is an antioxidant defense system that reduces the concentration of free radicals in the cell. This includes various enzymes, endogenous and exogenous antioxidants and anteradical compounds, etc. This antioxidant defense system protects genetically important molecules from damage by free radicals and other reactive compounds. After the primary DNA damage has taken place, complex repair processes are triggered - photoreaction, excisional, post-replication, SOS-repair and other, still poorly understood or completely unknown mechanisms of cell and genetic nucleic acid restoration. If the damage is not repaired, the anti-information protection system comes into action, the task of which is to neutralize the effect of the changed information. In the event of a breakthrough of one barrier, other mechanisms of anti-mutation barriers are activated into mutation. Let's name some of them. First, these are all the mechanisms that ensure the reliability of biological systems: duplication of cellular structures, the presence of bypass metabolic pathways, a special organization of the genetic code and the apparatus for protein synthesis. Secondly, if an amino acid has been replaced in the bulk polypeptide chain, then it is important to preserve the hydrophilic or hydrophobic nature of the new amino acid, which affects the preservation of the tertiary - globular - structure of the protein molecule. Approximately 1/3 of all amino acid substitutions retain the spatial structure of globular proteins and their biological function - potentially mutational primary damage to DNE is extinguished and neutralized.

The anti-mutational barriers of the cell and organism are numerous and varied; they are not yet fully understood. They allow a person to live in a hostile world of mutagenic factors.

Gene mutations are usually not accompanied by a change in the shape of chromosomes, so they cannot be seen in a light microscope.

They are manifested in changes in the characteristics of the organism due to the synthesis of altered proteins, enzymes or structural or regulatory proteins. As a result of mutation, the activity of the enzyme can change - increase or decrease. The degree of change in enzyme activity depends on the site of the mutation in the corresponding gene and the size of the defect. Therefore, in the street picture, the severity of hereditary diseases is always different, although the defective gene is the same. In addition, there is a different expression of the normal and altered alleles of the defined gene. In humans, a set of zromosomes and, accordingly, genes are diploid. Mutations usually affect one of two alleles of the same gene. The result is heterozygosity. The phenotype of such heterozygotes is determined by the interaction of the corresponding alleles and the genetic or epigenetic field created by all other genes in interaction with the environment. The molecular mechanisms of some hereditary diseases caused by gene mutation have more or less been studied. Such hereditary diseases are called molecular.

The manifestation of genes is mediated through the regulation of protein-synthetic processes. In the gene-trait chain, complex processes proceed, depending on many factors. Structural genes that are directly responsible for protein synthesis alone are not able to provide developmental determination. In the process of metabolism, synthesis is simultaneously activated by not one, a whole group of enzymes that ensure the sequence of a certain chain of reactions, since each enzyme is associated with its own gene for structural and functional organization.

According to the process of genetic regulation of protein synthesis, the activity of the structural gene is under the control of the operator gene, the activity of which, in turn, is determined by the regulator gene, the product of the duration of which is a repressor protein capable of binding to one or another substance formed in the cell during metabolism ... At the same time, depending on the nature of the substance with which the repressor binds, its two-fold effect on the operon is possible: on the one hand, it is inhibitory, on the other hand, if the overwhelming effect of the repressor is eliminated (connection with the substance), the activity of the corresponding operon begins - activation of synthesis.

It can be assumed that certain changes in control genes, along with structural mutations, are responsible for the occurrence of genetically determined diseases. In addition, in some cases, environmental factors disrupt the implementation of the action of a normal gene, i.e. hereditary information. Hence, there is a basis for the assertion that in a number of cases the diseases are associated not so much with the pathology of the regulation of hereditary information as with the pathology of its implementation.

Under experimental conditions, it is possible to block the receptor field of the cell - the target for the action of steroid hormones using, for example, aniline dyes. In this regard, there is a removal of the regulatory influence of hormones and a violation of protein synthesis - the implementation of the action of a normal gene is disrupted.

This mechanism is demonstrative in testicular feminization - a disease in which pseudohermaphroditis is formed with female external genitals (internal genital organs are absent). Genetic examination reveals a male set of sex chromosomes, sex chromatin is absent in mucosal cells. The pathogenesis of suffering is associated with the primary androgen resistance of target organs.

One and the same mutant gene in different organisms can manifest its effect in different ways. The phenotypic expression of a gene can vary according to the severity of the trait. This phenomenon is associated with the expressiveness of the gene - the degree of manifestation of the action in the phenotypic relation. One and the same trait can manifest itself in some and is not manifested in other individuals of the related group - this phenomenon is called the penetrance of the gene -% of individuals in the population with a mutant phenotype (the ratio of the number of carriers of a pathological trait to the number of carriers of a mutant gene). Expressiveness and penetrance characterize the phenotypic manifestations of a gene, which is due to the interaction of genes in the genotype and different responses of the genotype to environmental factors. Penetrance reflects the heterogeneity of a population not by the main gene, which determines a specific trait, but by modifiers that create a genotypic environment for the manifestation of a gene. Modifiers include prostaglandins, active metabolites, bioactive substances of various origins.

By the nature of the genome changes, the following mutations are distinguished:

1. Gene - associated with one pair of nucleotides in the polypeptide chain of DNA (cytologically invisible changes).

2. Chromosomal - at the level of an individual chromosome (deletion - fragmentation of chromosomes, leading to the loss of its part; duplication - duplication of a site, rearrangements of chromosomes caused by changes in groups of linked genes within chromosomes - inversion; movement of sites - insertion, etc.).

3. Genomic - a) polyploidy - change in the number of chromosomes, a multiple of the haploid set; b) aneuploidy (heteroploidy) - not multiple to the haploid set.

By manifestation in heterozygote:

1. Dominant mutations.

2. Recessive mutations.

Deviation from the norm:

1. Direct mutations.

2. Reversions (some of them are reverse, suppressor).

Depending on the reasons that caused the mutations:

1. Spontaneous

2. Induced

By localization in the cell:

1. Nuclear

2. Cytoplasmic

In relation to the features of inheritance:

1. Generative, occurring in the germ cells

2. Somatic

By phenotype (lethal, morphological, biochemical, behavioral, sensitivity to damaging agents, etc.).

Mutations can change behavior, affect any physiological characteristics of the organism, cause a change in an enzyme and, of course, affect the structure of an individual. By their influence on the viability, mutations can be lethal and semi-lethal, reducing to a greater or lesser degree the viability of the organism. They can be practically neutral under the given conditions, do not directly affect the viability and, finally, although rarely, mutations that turn out to be useful when they arise.

So, in this regard, according to the phenotypic classification, there are:

1. Morphological mutations, in which there is mainly a change in the growth and formation of organs.

2. Physiological mutations - increasing or decreasing the vital activity of the organism, inhibiting development in whole or in part (semi- and lethal mutations). There is a concept of lethal genes. Such genes (usually in a homozygous state) either lead to death or increase its likelihood in early embryogenesis or in the early postnatal period. In most cases, a specific pathology has not yet been identified.

3. Biochemical mutations - mutations that inhibit or alter the synthesis of certain chemicals in the body.

The above classification principles make it possible to systematize hereditary diseases according to the characteristics of a genetic defect.

Classification of forms of hereditary pathology.

Heredity and environment play the role of etiological factors in any disease, albeit with varying degrees of participation. In this regard, the following groups of hereditary diseases are distinguished:

1) actually hereditary diseases, in which a change in hereditary structures plays an etiological role, the role of the environment is only in modifying the manifestations of the disease. This group includes monogenic diseases (phenylketonuria, hemophilia, achondroplasia), as well as chromomic diseases.

2) ecogenetic diseases, which are also hereditary, caused by pathological mutations, however, their manifestation requires a specific effect of the environment. For example, sickle cell anemia in heterozygous carriers with reduced oxygen partial pressure; acute hemolytic anemia in individuals with a mutation in the glucose-6-phosphate dehydrogenase locus under the influence of sulfonamides.

3) in this group there are many common diseases, especially in the elderly - hypertension, ischemic heart disease, stomach ulcer. The etiological factor in their occurrence is the environmental impact, however, its implementation depends on the individual genetically determined predisposition of the organism, in connection with which these diseases are called multifactorial or diseases with a hereditary predisposition.

From a genetic point of view, hereditary diseases are divided into gene and chromosomal. Gene diseases are associated with gene mutations, and further, according to the number of affected genes, monogenic and polygenic diseases are distinguished. The isolation of monogenic diseases is based on their segregation in generations according to Mendel's law. Polygenic - diseases with a hereditary predisposition, since the predisposition is multifactorial.

Chromosomal diseases are a large group of pathological conditions, the main manifestations of which are multiple malformations and which are determined by deviations in the content of chromosomal material.

The division of hereditary diseases into these groups is not formal. Gene diseases are passed from generation to generation without changes, while most chromosomal diseases are not transmitted at all, structural rearrangements are transmitted with additional recombinations.

Gene diseases.

A gene can mutate, resulting in a change or complete absence of the protein. In this regard, separate forms of gene diseases are distinguished. So, a violation of the synthesis of structural protein leads to the occurrence of malformations (syndactyly, polydactyly, brachydactyly, achondroplasia, microcephaly, etc.), a violation of the transport protein leads to functional diseases (diseases of vision, hearing, etc.), fermentopathy - with violation of proteins - enzymes.

About 900 diseases are inherited according to the autosomal dominant type: polydactyly, syndactyly and brachydactyly, astigmatism, hemeralopia, anonychia, arachnodactyly and achondroplasia.

With an autosomal recessive type of inheritance, the trait is manifested only in individuals homozygous for this gene, i.e. when a recessive gene is obtained from each parent. More than 800 diseases are inherited according to this type, the main group is fermentopathies (phenylketonuria, alkaptonuria, amaurotic idiocy, galactosemia, mucopolysaccharidosis), various types of deafness and dumbness.

Incomplete dominance is also highlighted. This type of inheritance is shown for essential hypercholesterolemia: the corresponding gene in a heterozygous state determines only a predisposition to hypercholesterolemia, in a homozygous state it leads to a hereditary form of cholesterol metabolism pathology - xanthomatosis.

Gender inheritance has a number of characteristics. X and Y -chromosomes have common (homologous) regions in which genes are localized, inherited equally in both men and women. For example, xeroderma pigmentosa, spastic paraplegia, epidermal bullosis. The non-homologous section of the Y chromosome (holandric inheritance) contains genes for the membranes between the fingers and hairy ears, which are passed on only to sons.

The non-homologous region of the X chromosome (recessive for women and dominant for men due to hemizygosity) contains genes for hemophilia, agammaglobulinemia, diabetes insipidus, color blindness, and ichthyosis. Among the dominant, completely sex-linked along the X chromosome (with its non-homologous region) are hypophosphatemic rickets, the absence of incisors in the jaws. The possibility of transmission of hereditary characters through the cytoplasm of the egg (plasmogens) only through the mother was also revealed - blindness as a result of atrophy of the optic nerves (Leber's syndrome).

Chromosomal diseases differ from other hereditary diseases in that, with rare exceptions, they are limited to spread within one generation due to the complete lack of fertility in carriers. Nevertheless, chromosomal diseases belong to the group of hereditary ones, since they are caused by a mutation of a hereditary substance in the germ cells of one or both parents at the chromosomal or genomic level. Clinically, these diseases are manifested by severe mental disorders in combination with a number of defects in somatic development. Chromosomal diseases occur on average with a frequency of 1: 250 newborns. In 90% of embryos with chromosomal abnormalities, chromosomal imbalance occurs and most of them stop developing at an early stage.

The factors leading to chromosomal abnormalities appear to be common:

1. The age of the mother. Compared to the average age (19-24) in women after 35 years, the probability of having children with chromosomal abnormalities increases 10 times, after 45 years - 60 times. There is almost no data on the age of fathers. The influence of age can be the opposite, for example, Shereshevsky-Turner syndrome appears more often in children of young mothers.

2. Ionizing radiation - since all types of ionizing radiation cause chromosomal aberrations in germ and somatic cells.

3. Viral infections - measles, rubella, chickenpox, shingles, yellow fever, viral hepatitis, toxoplasmosis.

Chromosomal diseases at their core can have either structural or numerical abnormalities both on the part of autosomes and chromosomes of germ cells.

1. Structural abnormalities of autosomes: 5p - loss of a short shoulder (deletion) - “cat cry” syndrome - the name is due to the similarity of a crying baby with a cat's meow. This is due to disorders of the central nervous system and a violation of the larynx. The syndrome is also characterized by micrognathia, syndactyly. There is a decrease in resistance to infections, so patients die early. Various malformations (anomalies of the heart, kidneys, hernia) are revealed. There are also other chromosomal aberrations of the deletion type: syndromes 4p, 13p, 18p and 18q, 21p, 22q. Translocations can be unbalanced, which leads to pathological states of their carriers and balanced - phenotypically not manifested. Structural abnormalities on the part of sex chromosomes are described in Shereshevsky-Turner syndrome on the part of a single X chromosome (p, q, r, isochromosomes p and q).

2. Numerical violations. Abnormalities of large chromosomes 1-12 pairs are usually fatal. Sufficient viability occurs with 21-pair trisomy, abnormal sex chromosomes, and partial abnormalities. Nullisomy - absence of a pair - non-viability. Monosomy - viability only with CO syndrome. Polyploidy is usually fatal. Trisomy 13 pairs - Patau syndrome - is characterized by multiple defects of the brain, heart, kidneys, (children usually die at 3-4 months of age). Trisomy for 18 pairs - Edwards syndrome - multiple defects of vital organs, up to 1 year usually no more than 7% of patients survive. The translocation form of Down's disease is expressed by the transfer of an extra chromosome from 22, 4, 15 to 21 pairs. Numerical abnormalities on sex chromosomes occur in the form of Kleinfelter's syndrome - XXY and its variants (XXXY, XXXXY), characterized by a decrease in intelligence and hypogonadism. Known XXX syndromes and variants, as well as XYY - in this case, the additional Y chromosome affects behavior more than intelligence. Patients are aggressive, differ in wrong, even criminal behavior.

The phenomenon of mosaicity is associated with different types of ratio of normal and abnormal cells. In this case, it is an intermediate position between healthy and sick (clinically erased forms).

Family planning is an important method of preventing chromosomal diseases. So, in particular, conception on the day of ovulation is considered the ideal condition. Also, 1 month before conception there should be no exposure to mutagens (chemical - their main source of production; physical - X-ray irradiation for diagnostic or therapeutic purposes). Viral infections are especially dangerous and, accordingly, conception is recommended only 6 months after infection. It is also important to increase the introduction of vitamins - A, C, E, folic acid, trace elements - Ca, Mg, Zn.

Prenatal diagnostics is also important: screening examinations are carried out from 16 weeks, the assessment of a-fetoprotein, if indicated, also amniocentesis, karyogram, chorion diagnostics.

Discipline: "Pathophysiology"
Author: Gerasimova Lyudmila Ivanovna,
Candidate of Medical Sciences, Associate Professor
:
Role of heredity
in pathology
Etiology and pathogenesis
hereditary diseases

Key concepts of the topic

Heredity
Genotype, phenotype
Mutations, mutagenic factors
Hereditary diseases
2007
autosomal dominant,
autosomal recessive,
floor-linked
Chromosomal diseases
Congenital diseases, phenocopies
Diagnostics, treatment and prevention
hereditary human diseases
Copyright L. Gerasimova
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The origin of diseases

Congenital
Diseases manifested mainly
at birth
Hereditary
Acquired
Diseases arising
in the postnatal period
Non-hereditary
Related to restructuring Are the result
hereditary
effects of pathogenic
material
factors on the body in
Genetic molecular
antenatal
illness
and perinatal
Chromosomal diseases
periods of development
(congenital syphilis,
toxoplasmosis, AIDS,
hemolytic disease
newborn, etc.)
2007
Copyright L. Gerasimova
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Heredity is the property of organisms to preserve and ensure the transmission of hereditary traits to descendants, as well as

program their features
individual development in specific environmental conditions.
Normal and pathological signs of the body are
the result of the interaction of hereditary (internal) and
environmental (external) factors.
2007
Copyright L. Gerasimova
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Genotype - the totality of all genes in the body

stability
variability
Basis of genotype stability:
duplication (diploidy) of its structural
elements;
dominance of the normal allele over
pathological recessive gene, due to which
a huge number of diseases transmitted by
recessive type, does not manifest itself in heterozygous
the body;
repression operon system
(blocking) a pathological gene (for example,
oncogene);
DNA repair mechanisms that allow
a set of enzymes (insertase, exo- and endonuclease,
DNA polymerase, ligase) quickly fix
damage arising in it.
2007
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Variability
Genotypic
(inherited)
Phenotypic
(non-inherited)
Phenocopies
Somatic
(in somatic cells)
Inherited trait - result
mutations - permanent change
genetic material
The result is random
recombination of alleles
independent divergence
chromosomes in meiosis
crossing over
chance encounter of gametes
2007
Copyright L. Gerasimova
Generative
(in germ cells)
Mutational
Combinative
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Mutation is the main cause of a hereditary disease.

Mutations - quantitative or
qualitative changes in the genotype,
transmitted during replication
genome from cell to cell,
from generation to generation.
2007
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Causes of mutations

Spontaneous mutations
Induced mutations
Mutagenic factors - mutagens
Exogenous
Endogenous
2007
Ionizing radiation, UVL, electromagnetic fields,
temperature factor
Chemicals (oxidants: nitrates, nitrites,
reactive oxygen species; phenol derivatives,
alkylating agents, pesticides, PAHs ...)
Viruses
and etc.
Antimutagenic factors
Parents age
Chronic stress
Hormonal disorders
Vit. C, A, E, folic acid
Antioxidants (ionol, selenium salts ...)
Enzymes (peroxidase, NADPoxidase, glutathione peroxidase,
catalase ...)
Amino acids (arginine, histidine,
methionine cystamine ...)
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Gene mutations
gene structure change -
falling out, replacing or inserting
new nucleotides in the DNA chain
"Point" mutations
DNA reading frame change
2007
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Deletion
Translocation
Chromosomal
mutations
Structural rearrangements of chromosomes:
deletions,
duplications,
translocations,
inversion.
Deletion of the short shoulder
chromosome 5 - c-m cat cry
Trisomy of the short arm of chromosome 9
- microcephaly, mental
backwardness, CDF
Inversion
Robertson translocation
The fragile X chromosome
sm Martina-Bella
2007
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Genomic mutations
change in the number of chromosomes
The result of combinative variability
Violation of meiosis
Incorrect chromosome separation
in meiosis
polyploidy -
multiple increase in the complete set of chromosomes
Triploidy
Tetraploidy
In humans - incompatible with life -
spontaneous abortion.
aneuploidy -
change in the number of chromosomes in one or
several pairs
Monosomy
S. Shereshevsky-Turner (XO)
Trisomy
2007
S. Down - 21 couple
S. Edwards - 18 pair
St. Patau - 13 pair
Trisomy X
S. Klinefelter - XXY
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General pathogenesis of genetic molecular diseases

Gene
Localization
gene
Protein
(structural b.
or enzyme)
Sign
Autosomes
Sex chromosomes
(X chromosome)
dominant
Autosomal dominant
Linked to the X chromosome
dominant
recessive
Autosomal recessive
Linked to the X chromosome
recessive
A type
inheritance
2007
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12

The gene is localized in the autosome
Genotype: homo- and heterozygote
Does not depend on gender
"Vertical" distribution of the disease
Healthy individuals do not transmit disease
subsequent generations
Do not restrict reproductive opportunities
Parents
Possible
2007
genotype of children
Copyright L. Gerasimova
Patients - heterozygotes
13

Autosomal dominant diseases

Achondroplasia
Gd Gettington
Congenital telangiectasia (with Osler-Weber-Randu)
Antithrombin deficiency
Hereditary spherocytosis
Neurofibromatosis
Lactose intolerance
Osteogenesis imperfecta
Polycystic kidney disease
Progressive ossifying fibrodysplasia
Familial hypercholesterolemia
Familial intestinal polyposis
S. Marfana
S. Charcot-Marie-Tutta
Maxillofacial dysostosis
2007
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Arachnodactyly Brachydactyly Polydactyly Syndactyly
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The gene is localized in the autosome
Genotype: homozygote
Does not depend on gender
"Horizontal" distribution pattern
illness
Healthy individuals (heterozygotes) transmit
diseases for subsequent generations
Shorten life expectancy
limit reproductive
opportunities
"carrier"
- father
Homozygotes - sick
Heterozygotes - carriers
2007
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Autosomal recessive diseases
Adreno-genital syndrome
Albinism
Fanconi anemia
Frederiksen's ataxia
Wilson-Konovalov disease
Galactosemia
Hemochromatosis
Glykygenoses
Homocystinuria
Alpha-1-antitrypsin deficiency

(hemolytic anemia)
Cystic fibrosis (cystic fibrosis)
Mucopolysaccharidoses
Pigmented xeroderma
Familial Mediterranean fever
Rotor syndrome (jaundice)
S. Dabin-Johnson
Spinal muscular atrophy
Thalassemia
Phenylketonuria
2007
Cystic fibrosis
CFTR defect → increased viscosity
secretions → obturation of glandular ducts
→ cystic fibrous degeneration
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16

Autosomal recessive diseases

Phenylketonuria
(phenylpyrovirograde oligophrenia)
Phenylalanine
Accumulation
phenylpyruvic
acids → intoxication
Violation of education
catecholamines →
decreased central nervous system function →
oligophrenia
Newborn hair
with phenylketonuria
2007
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Violation of synthesis
melanin →
depigmentation
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X-linked diseases

Agammaglobulinemia
Adrenoleukodystrophy
Hemophilia
Color blindness
Deficiency of glucose-6-phosphate dehydrogenase
(hemolytic anemia)
Ichthyosis
The fragile X chromosome
Becker muscular dystrophy
Duchenne muscular dystrophy
Androgen insensitivity
St. Wiskott-Aldrich
2007
Copyright L. Gerasimova
healthy
sick
carrier
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Chromosomal diseases

Age
mothers
15 - 19
20 - 24
25 - 29
30 - 34
35 - 39
40 - 44
45 - 49
1:1600
1:1400
1:1100
1:700
1:240
1:70
1:20
Down's disease
2007
Trisomy
13
1:17000
1:33000
1:14000
1:25000
1:11000
1:20000
1:7100
1:14000
1:2400
1:4800
1:700
1:1600
1:650
1:1500
Wide face
Enlarged tongue
Epicantus
Slanted eyes
Flat nose
Short, wide palm,
with a single transverse fold
The little finger is shortened and curved inward
Lagging physical development
Mental retardation
Heart defects, gastrointestinal tract, kidney
Immunodeficiency
Down's Trisomy 18
Copyright L. Gerasimova
transverse
fold
19

Chromosomal diseases
Klinefelter's syndrome (47 XXY, 48 XXXY)
High growth
Body type for women
type
Testicular hypoplasia
Eunuchoidism
Violation of spermatogenesis
Gynecomastia
Obesity tendency
Mental disorders
Mental retardation
2007
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Chromosomal diseases
Shereshevsky-Turner syndrome (45 XO)
Short stature, violation
ossification of the skeleton
(kyphosis, scoliosis ...)
Dysgenesis of the gonads
(underdevelopment of secondary
sexual characteristics,
infertility)
Appearance older than passport age
Pterygoid fold on the neck
Low hair growth
Deformed auricles
Wide nipple position
Multiple birthmarks on the skin
Mental retardation (rare)
2007
Copyright L. Gerasimova
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Congenital diseases

Fetal
alcohol syndrome
Thalidomide
syndrome
2007
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Diagnostics of congenital and hereditary diseases

Clinical and syndromological
method
Genealogical method
Cyto-genetic method
Karyotype
sex chromatin
(number of X chromosomes)
Biochemical method
Molecular diagnostics
(DNA analysis)
2007
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Prevention of congenital and hereditary diseases

2007
Elimination of the action of mutagens
(including medicinal)
Medical genetic counseling
- risk identification
Prenatal diagnosis
Ultrasound
Chorionic biopsy
Amniocentesis
α-fetoprotein
…
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Treatment of congenital and hereditary
diseases
Etiotropic - genetic engineering
Pathogenetic
Substitution therapy
hormones in case of their lack
(insulin, ADH ...)
cryoglobulin for hemophilia
Ig for agammaglobulinemia
…
Elimination of substances in violation
their metabolism
(phenylalanine for PKU, lactose for
lactose intolerance)
Symptomatic
2007
Copyright L. Gerasimova

Congenital diseases manifested immediately after birth. They can be both hereditary and non-hereditary - due to the effect of unfavorable environmental factors on the developing fetus during pregnancy and not affecting its genetic apparatus.

Hereditary-the cat is based on structural changes in the genetic material.

Mechanisms of the development of hereditary pathology.

Gene changes characterized by the transformation of the gene structure, i.e. the molecular organization of a DNA region containing nitrogenous bases (for example, replacing one base with another or changing their sequence). Gene mutations can also arise as a result of an increase in the number of triplet repeats of nucleotides to a limit, above the level that occurs without a change in the phenotype.

This expansion of certain triplets leads to gene disruption ("dynamic" mutations).

Chromosomal changes characterized by the transformation of the structure of chromosomes, which is often found during their separate morphological analysis. Chromosomal aberrations are manifested by deletion (separation of a portion of the chromosome), inversion (rotation of a portion of the chromosome), translocation (moving a portion to another place of the same or a different chromosome), fragmentation of the chromosome, and other phenomena.

Genomic changescharacterized by a deviation from the norm in the number of chromosomes, which is manifested by a decrease or increase in their number. Chromosomal and genomic mutations underlie a large group of hereditary diseases called chromosomal diseases.

In accordance with the patterns of information transfer in the cell (DNA - RNA - protein), the appearance of a mutated gene can lead to a decrease (loss) of protein synthesis, the appearance of an abnormal protein that is unable to perform a particular function, or gene derepression and the appearance of an embryonic protein.

Honey. genetics - a section of genetics that studies heredity and human variability from the point of view of pathology.

Tasks:

1. Study of hereditary forms of pathology:

Etiology, pathogenesis

The nature of the flow

Improving diagnostics

Development of methods of treatment and prevention

2. Study of hereditary predisposition and resistance to hereditary diseases.

3. Study of mutations and antimutagenesis.

4. Study of the role of heredity in the processes of compensation and decompensation.

5. Study of general biological and theoretical issues of medicine: malignancy, tissue incompatibility, etc.

Phenocopies - changes in the characteristics of the body under the influence of environmental factors during the period of embryonic development, in terms of the main manifestations, similar to hereditary pathology.

Reasons for phenocopy:

1. Oxygen starvation of the fetus.

2 Disease of the mother during pregnancy.

3. Mental trauma in a pregnant woman.

4. Endocrine diseases in a pregnant woman.

5. Nutrition of a pregnant woman (deficiencies C, B, P, PP vit., Co, Ca, Fe).

6. Medicines during pregnancy (antibiotics, sulfonamides).