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

The initial link in the pathogenesis of hereditary diseases are 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 hereditary information.

With considering various criteria Several classifications of mutations have been proposed. According to one of them, spontaneous and induced mutations. The first ones arise in the conditions of the natural background of the surrounding and internal environment of the body, without any special effects. They can be caused by external and internal natural radiation, the action of endogenous chemical mutagens, etc. Induced mutations are caused by a special targeted action, for example, under experimental conditions.

According to another classification, specific and non-specific mutations. Let's make a reservation that most geneticists do not recognize the existence specific mutations, believing that the nature of 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.

According to the type of cells damaged by the mutation, there are somatic, occurring in the cells of the body, and gametic mutations - in the germ cells of the body. The consequences of both are ambiguous. With somatic mutations, the disease develops in the carrier of the mutations; the offspring do not suffer from this kind of mutation. For example, a point mutation or amplification (multiplication) of a proto-oncogene in a somatic cell can initiate tumor growth in a given organism, but not in its children. In case of gametic mutations, on the contrary, the host organism of the mutation does not get sick. The offspring suffers from such a mutation.

According to the volume affected by the mutation, the genetic material of the mutation is divided into genetic or point(changes within a single gene, the sequence or composition of nucleotides is disturbed), chromosome aberrations or rearrangements that change the structure of individual chromosomes, and genomic mutations characterized by a change in the number of chromosomes.

Chromosomal aberrations, in turn, are divided 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 "cat's cry" 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 anti-Mongoloid incision of the eyes, microcephaly, a flaccid epiglottis, a peculiar arrangement of the vocal cords, as a result of which the crying of the child resembles the cry of a cat. With the deletion of one to four copies of Hb - genes, the development of one of the forms of hereditary hemoglobinopathies - α-thalassemia is associated;

duplication - a type of chromosomal rearrangement in which a portion of a 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) rotates 180 °.

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

The final link in the pathogenesis of hereditary diseases is the realization of the action of an abnormal gene (genes). 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 with not enough of such a protein, processes are disrupted, in the implementation of which at a certain stage this protein plays a key role. So, a violation of the synthesis of antihemophilic globulin A (factor VIII), B (factor IX), the plasma precursor of thromboplastin (factor XI), which are extremely important in the implementation various stages 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 the 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, autosomal.

The development of hepato-cerebral dystrophy is based on a protein deficiency - cerruloplasmin, which is associated with an increase in absorption, impaired metabolism and excretion of copper, and its excessive accumulation in tissues. Toxic action copper has a particularly strong effect on the condition and function nervous system and liver (a process that ends with cirrhosis). The first symptoms of the disease appear at the age of 10-20 years, progress rapidly 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 results in a decrease or cessation of its synthesis, its deficiency in the blood and tissues, and a violation of the processes catalyzed by it. As examples of the development of hereditary forms of pathology along this path, one 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 phenylalanine hydroxylase, which normally catalyzes the conversion of phenylalanine consumed with food into tyrosine. Enzyme deficiency leads to excessive levels of phenylalanine in the blood, various changes in the metabolism of tyrosine, the 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 (a diet low in phenylalanine) can avoid the development of the disease, its most severe manifestation - mental disability.

The absence of homogentisic acid oxidase 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 the joints, cartilage, connective tissue, causing with age (usually after 40 years) the development of severe arthritis. In this case, too, the diagnosis can 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 a mutation, a gene with a pathological code is formed, as a result of which abnormal RNA and an 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 (hemoglobin b-chain, the glutamine amino acid is replaced by valine, unstable HbS is formed. In the reduced state, its solubility sharply decreases, and its ability to polymerize increases. Crystals form. , disrupting the shape of erythrocytes, which are easily hemolyzed, especially under conditions of hypoxia and acidosis, leading to the development of anemia.Inheritance is autosomal recessive or semi-dominant.

An important condition for the occurrence and implementation of the action of mutations is the failure of the DNA repair system, which can be genetically determined or develop during life, under the influence of adverse factors of the external or internal environment of the body.

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

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

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

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

1) mutations that result 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 information;

2. impaired repair of damaged DNA

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 disease, conventionally classified as 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 a 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. (complete form of chromosomal disease), in the second, a mosaic organism develops, only some of whose cells have an abnormal set of chromosomes (mosaic form of the disease). The severity of pathological signs in the mosaic form of the disease is weaker than in the complete form.

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

The frequency of chromosomal disorders is quite high: out of every 1000 live-born babies, 3-4 have chromosomal diseases, in stillborn children they make up 6%; about 40% of spontaneous abortions are caused by an imbalance of chromosomes (N.P. Bochkov, 1984). An imbalance affecting all pairs of chromosomes causes such significant disturbances in the body that they, as a rule, 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. A lack of genetic material causes more significant defects than an excess. Complete monosomy, for example, on autosomes is practically not found. Apparently, such an imbalance causes a lethal outcome already in gametogenesis or at the stage of the 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 crushing of a fertilized egg, most often as a result of chromosome nondisjunction. When an abnormal egg is fertilized by a sperm with a normal set of chromosomes or a normal egg by an abnormal sperm, less often when two gametes containing an altered number of chromosomes are combined, prerequisites are created for the development of a chromosomal disease.

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

Down syndrome is the most common chromosomal disorder. The karyotype of patients in 94% consists of 47 chromosomes due to trisomy on chromosome 21. In about 4% of cases, there is a translocation of the extra 21st chromosome to the 14th or 22nd, the total number of chromosomes is 46. The disease is characterized by a sharp delay and impaired physical and mental development of the child. Such children are undersized, they start walking and talking late. Are striking appearance a child (a characteristic shape of the head with a sloping occiput, a wide, deeply sunken bridge of the nose, a Mongoloid incision of the eyes, an open mouth, abnormal tooth growth, macroglossia, muscular hypotension with loose joints, especially the little finger, brachydactyly, a transverse crease in the palm, etc.) and pronounced mental backwardness, sometimes to complete idiocy. Violations are noted in all systems and organs. Malformations of the nervous (in 67%), cardiovascular (64.7%) systems are especially frequent. As a rule, the reactions of humoral and cellular immunity are changed, the system of repair 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 the birth of children by a sick woman, some of them suffer from the same disease.

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

The third place (1:7000 births) among polysomy of autosomes is occupied 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, defects of the valves of the pulmonary artery, aorta), nail hypoplasia, horseshoe kidney, cryptorchidism in boys . 90% of patients die in the first year of life.

Chromosomal diseases associated with non-disjunction of sex chromosomes are much more common. Known variants of gonosomal polysomy are shown in Table 6.

Table 6

Types of gonosomal polysomies found in newborns

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

As follows from the table, the overwhelming number of polysomy on sex chromosomes falls on trisomy 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 bodies instead of one and by the 47,XXX karyotype. 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.

Variants of polysomy involving Y-chromosomes are more numerous and diverse. The most common of them - Klinefelter's syndrome - is due to an increase in the total number of chromosomes up 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, a female type of skeletal structure, inertia and mental retardation. Genetic imbalance usually begins to manifest itself during puberty with underdevelopment of male sexual characteristics. The testicles are reduced in size, there is aspermia or oligospermia, often gynecomastia. A reliable diagnostic sign of the syndrome is the detection of sex chromatin in the cells of the male organism. Superklinefelter's syndrome (XXXY, two Barr bodies) is characterized by a greater severity of these signs, mental failure reaches the degree of idiocy.

The owner of the karyotype 47, XYY - "superman" characterized by impulsive behavior with pronounced elements of aggressiveness. Big number such individuals are found among prisoners.

Gonosomal monosomy is much less common than polysomy, and is limited only to monosomy X (Shereshevsky-Turner syndrome). The karyotype consists of 45 chromosomes, there is no sex chromatin. Patients (women) are characterized by short stature, short neck, cervical lateral skin folds. Characterized by lymphatic edema of the feet, poor development of sexual characteristics, absence of gonads, hypoplasia of the uterus and fallopian tubes, primary amenorrhea. Such women are infertile. Mental ability, as a rule, does not suffer.

No cases of monosomy V were 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 abortions, 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, imperfection of repair processes, resulting from errors in the biosynthesis of proteins and nucleic acids.

Mutations affect both somatic and germ cells. There are 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 a change in the structure of chromosomes: deletion (separation of part of the chromosome), inversion (rotation of part of the chromosome by 180 0), translocations (moving part of one chromosome to another), etc. The study of chromosome aberrations became more accessible after the development of the method of differential staining of chromosomes. Chromosomal aberrations tend to lead to less severe body defects compared to monosomy or trisomy for the entire chromosome.

Gene mutations are caused by changes in the structure of DNA. This leads to a disruption in 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 about 10 -15 and 10 -10 per gene over 30 years. 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 drugs, and some biological factors.

Mutations cause a variety of changes in the DNA molecule:

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

There are several defense systems in the cell that prevent the development of primary DNA damage and its conversion 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 antineradical compounds, and the like. 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 activated - photoreactivation, excisional, post-replication, SOS-repair, and other still little-studied or completely unknown mechanisms for the restoration of the cell and genetic nucleic acid. If the damage is not eliminated, the system of promy-information protection 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 involved in the transformation of the primary damage into a mutation. Let's name some of them. First, these are all mechanisms that ensure reliability biological systems: duplication of cellular structures, the presence of bypass metabolic pathways, special organization genetic code and apparatus for protein synthesis. Secondly, if an amino acid has been replaced in the polypeptide chain of the beam, then the preservation of the hydrophilic or hydrophobic nature of the new amino acid, which affects the preservation of the tertiary - globular - structure of the protein molecule, is important. At approximately 1/3 of all amino acid substitutions, the spatial structure of globular proteins and their biological function are preserved - the potentially mutational primary damage to DNE is extinguished and neutralized.

The anti-mutation 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 manifest themselves in a change in the characteristics of the organism due to the synthesis of altered enzyme proteins or structural or regulatory proteins. As a result of a mutation, the activity of the enzyme can change - increase or decrease. The degree of change in enzyme activity depends on the location of the mutation in the corresponding gene and the size of the defect. Therefore, in the clinical picture, the severity of hereditary diseases is always different, although the defective gene is the same. In addition, there are different expressions of the normal and altered alleles of the predetermined gene. In humans, the set of germosomes and, accordingly, the genes is 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 a gene mutation have already been more or less understood. Such hereditary diseases are called molecular.

The manifestation of genes is mediated through the processes of regulation of protein-synthetic processes. Complex processes occur in the gene-trait chain, depending on many factors. Structural genes alone, which are directly responsible for protein synthesis, are not able to ensure developmental determination. In the process of metabolism, synthesis is simultaneously activated by not one, but by a whole group of enzymes that provide the sequence of a certain chain of reactions, since each enzyme is associated with its gene of 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 twofold effect on the operon is possible: on the one hand, it is inhibitory, on the other hand, if the inhibitory effect of the repressor is eliminated (the 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 a number of 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 diseases are associated not so much with the pathology of the regulation of hereditary information, but 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, the regulatory influence of hormones is removed and protein synthesis is disturbed - the implementation of the action of a normal gene is disrupted.

This mechanism is demonstrative in testicular feminization, a disease in which a pseudohermaphrodite is formed with external genitalia of the female type (there are no internal genital organs). A genetic examination reveals a male set of sex chromosomes, there is no sex chromatin in the mucosal cells. The pathogenesis of suffering is associated with the primary androgen resistance of target organs.

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

According to the nature of the changes in the genome, the following mutations are distinguished:

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

2. Chromosomal - at the level of a single chromosome (deletion - fragmentation of chromosomes, leading to the loss of part of it; duplication - doubling the site, rearrangement of chromosomes due to changes in groups of linked genes within chromosomes - inversion; movement of sections - insertion, etc.).

3. Genomic - a) polyploidy - a change in the number of chromosomes, a multiple of the haploid set; b) aneuploidy (heteroploidy) - non-multiple of the haploid set.

By manifestation in a heterozygote:

1. Dominant mutations.

2. Recessive mutations.

By deviation from the norm:

1. Direct mutations.

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

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 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. In terms of their impact on viability, mutations can be lethal or semi-lethal, reducing the viability of the organism to a greater or lesser extent. They can be practically neutral under given conditions, not directly affecting the viability and, finally, although rarely, mutations that are already useful when they occur.

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, completely or partially inhibiting development (semi- and lethal mutations). There is a concept of lethal genes. Such genes (usually in the homozygous state) either lead to lethal outcome, or increase its probability 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 change the synthesis of certain chemicals in the body.

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

Classification of forms of hereditary pathology.

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

1) actually hereditary diseases, in which the etiological role is played by a change in hereditary structures, the role of the environment is only in modifying the manifestations of the disease. This group includes monogenically caused diseases (phenylketonuria, hemophilia, achondroplasia), as well as chromosomal diseases.

2) ecogenetic diseases, which are also hereditary, caused by pathological mutations, but their manifestation requires a specific environmental impact. 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, many common diseases, especially in the elderly - hypertension, coronary heart disease, stomach ulcers. The etiological factor in their occurrence is the environmental impact, but its implementation depends on the individual genetically determined predisposition of the organism, and therefore 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, monogenic and polygenic diseases are distinguished by the number of affected genes. 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 unchanged, while most chromosomal diseases are not transmitted at all, structural rearrangements are transmitted with additional recombinations.

Genetic 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 a 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 appears only in individuals homozygous for this gene, i.e. when a recessive gene is obtained from each parent. More than 800 diseases are inherited by this type, the main group is fermentopathy (phenylketonuria, alkaptonuria, amaurotic idiocy, galactosemia, mucopolysaccharidoses), different kinds deafness and dumbness.

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

Inheritance in connection with sex has a number of features. X and Y chromosomes have common (homologous) regions in which genes are localized that are inherited equally in both men and women. For example, pigment xeroderma, spastic paraplegia, epidermal bullosis. The non-homologous region of the Y chromosome (Holandric inheritance) contains the genes for webbing between fingers and hairy ears, with transmission 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, fully sex-linked on the X chromosome (with its non-homologous site) are hypophosphatemic rickets, the absence of incisors in the jaws. The possibility of transmission of hereditary traits 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 distribution within one generation due to the complete lack of fertility in carriers. However, chromosomal diseases belong to the group of hereditary diseases, since they are caused by a mutation of the 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, a violation of the chromosomal balance occurs and most of them stop developing in the early stages.

Factors leading to chromosomal abnormalities appear to be common:

1. Age of the mother. Compared with 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 are almost no data on the age of fathers. The influence of age can also be reversed, 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, chicken pox, shingles, yellow fever, viral hepatitis, toxoplasmosis.

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

1. Structural disorders of autosomes: 5p - loss of a short arm (deletion) - "cat's cry" syndrome - the name is due to the similarity of a child's crying with a cat's meow. This is due to disorders of the central nervous system and with 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 other chromosomal aberrations such as deletions: syndromes 4p, 13p, 18p and 18q, 21p, 22q. Translocations can be unbalanced, which leads to pathological conditions of their carriers, and balanced - phenotypically not manifested. Structural disorders on the part of the sex chromosomes are described in Shereshevsky-Turner syndrome from the side of a single X chromosome (p, q, r, p and q isochromosomes).

2. Numerical violations. Anomalies of large chromosomes 1-12 pairs are usually lethal. Sufficient viability occurs with trisomy 21, abnormal sex chromosomes, and partial anomalies. Nullisomy - the absence of a pair - non-viability. Monosomy - viability only in CW syndrome. Polyploidies are usually lethal. Trisomy for the 13th pair - Patau's syndrome - is characterized by multiple malformations of the brain, heart, kidneys (children usually die at 3-4 months of age). Trisomy 18 pair - 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 violations of the sex chromosomes occur in the form of Kleinfelter's syndrome - XXY and its variants (XXXY, XXXXX), characterized by a decrease in intelligence and hypogonadism. XXX syndromes and variants are known, as well as XYU - in this case, the extra Y chromosome affects behavior more than intelligence. Patients are aggressive, differ in wrong, even criminal behavior.

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

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

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

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

Key Concepts of the Theme

Heredity
Genotype, phenotype
Mutations, mutagenic factors
hereditary diseases
2007
autosomal dominant,
autosomal recessive,
floor-linked
Chromosomal diseases
Congenital diseases, phenocopies
Diagnosis, treatment and prevention
human hereditary diseases
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Origin of diseases

Congenital
Diseases that are mainly
at birth
hereditary
Acquired
Diseases that occur
in the postnatal period
non-hereditary
Associated with restructuring Are the result of
hereditary
pathogenic
material
factors on the body
Gene-molecular
antenatal
disease
and perinatal
Chromosomal diseases
periods of development
(congenital syphilis,
toxoplasmosis, AIDS,
hemolytic disease
newborn, etc.)
2007
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Heredity is the property of organisms to preserve and ensure the transmission of hereditary traits to descendants, as well as

programming 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.
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Genotype is the totality of all genes in an organism

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 appear in the heterozygous
body;
operon system providing repression
(blocking) of a pathological gene (for example,
oncogene);
DNA repair mechanisms that allow, with the help of
a set of enzymes (insertase, exo- and endonuclease,
DNA polymerase, ligase) quickly fix
damage occurring in it.
2007
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Variability
Genotypic
(inherited)
Phenotypic
(non-inherited)
Phenocopies
Somatic
(in somatic cells)
Inherited trait - result
mutations - stable change
genetic material
Random result
allele recombination
independent discrepancy
chromosomes during meiosis
crossing over
chance meeting of gametes
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generative
(in sex 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 the replication process
genome from cell to cell,
from generation to generation.
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Causes of Mutations

Spontaneous Mutations
induced mutations
Mutagenic factors - mutagens
exogenous
Endogenous
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Ionizing radiation, UFL, electromagnetic fields,
temperature factor
Chemicals (oxidizing agents: nitrates, nitrites,
reactive oxygen species; phenol derivatives,
alkylating agents, pesticides, PAHs…)
Viruses
and etc.
Antimutagenic factors
Age of parents
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
change in the structure of the gene -
dropout, replacement or insertion
new nucleotides in the DNA chain
"point" mutations
changing the DNA reading frame
2007
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deletion
Translocation
Chromosomal
mutations
Structural rearrangements of chromosomes:
deletions,
duplications
translocation,
inversions.
Short arm deletion
chromosome 5 - s-m feline cry
Trisomy of the short arm of chromosome 9
- microcephaly, mental
backwardness, retardation
Inversion
Robertson translocation
Fragile X chromosome
s-m Martina-Bella
2007
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Genomic mutations
change in the number of chromosomes
The result of combinative variability
meiosis disorder
Misalignment of chromosomes
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 couples
Monosomy
S-m Shereshevsky-Turner (XO)
Trisomy
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S-m Down - 21 pairs
St. Edwards - 18 pairs
S-m Patau - 13 pairs
Trisomy X
S-m Klinefelter - XXY
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General pathogenesis of genetic and 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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The gene is located on the autosome
Genotype: homo- and heterozygote
Does not depend on gender
"Vertical" nature of the distribution of the disease
Healthy individuals do not transmit disease
next generations
Do not limit reproductive opportunities
Parents
Possible
2007
children's genotype
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Patients are heterozygotes
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Autosomal dominant diseases

Achondroplasia
B-n Gettington
Congenital telangiectasia (Osler-Weber-Randu s-m)
Antithrombin deficiency
hereditary spherocytosis
Neurofibromatosis
lactose intolerance
Osteogenesis imperfecta
Polycystic kidney disease
Progressive fibrodysplasia ossificans
Familial hypercholesterolemia
Familial intestinal polyposis
St. Marfana
S-m Charcot-Marie-Tutta
Maxillofacial dysostosis
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Arachnodactyly Brachydactyly Polydactyly Syndactyly
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The gene is located on the autosome
Genotype: homozygous
Does not depend on gender
"Horizontal" nature of distribution
disease
Healthy individuals (heterozygotes) transmit
diseases to future generations
Reduce life expectancy
restrict reproductive
opportunities
"carrier"
- father
Homozygotes are sick
Heterozygotes are carriers
2007
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Autosomal recessive diseases
adrenogenital syndrome
Albinism
Anemia Fanconi
Frederiksen's ataxia
Wilson-Konovalov disease
Galactosemia
Hemochromatosis
Glycigenoses
Homocystinuria
Alpha-1 antitrypsin deficiency

(hemolytic anemia)
Cystic fibrosis (cystic fibrosis)
Mucopolysaccharidoses
Pigmented xeroderma
Familial Mediterranean Fever
Rotor syndrome (jaundice)
S-m Dubin-Johnson
Spinal muscular atrophies
Thalassemia
Phenylketonuria
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cystic fibrosis
CFTR defect → increased viscosity
secretion → obturation of gland ducts
→ cystic-fibrous degeneration
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Autosomal recessive diseases

Phenylketonuria
(phenylpyrovirus oligophrenia)
Phenylalanine
Accumulation
phenylpyruvic
acids → intoxication
Violation of education
catecholamines →
decreased CNS function →
mental retardation
newborn hair
with phenylketonuria
2007
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Synthesis disruption
melanin →
depigmentation
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X-linked diseases

Agammaglobulinemia
Adrenoleukodystrophy
Hemophilia
color blindness
Glucose-6-phosphate dehydrogenase deficiency
(hemolytic anemia)
Ichthyosis
Fragile X chromosome
Becker muscular dystrophy
Duchenne muscular dystrophy
Androgen insensitivity
Wiskott-Aldrich St.
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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
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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
epikant
slanted eyes
flat nose bridge
Short, wide palm
with a single transverse fold
The little finger is shortened and bent inward
Lagging behind in physical development
Mental retardation
Heart, gastrointestinal, kidney defects
Immunodeficiency
S-m Downa Trisomy 18
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transverse
fold
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Chromosomal diseases
Klinefelter syndrome (47 XXY, 48 XXXY)
High growth
Physique for women
type
Testicular hypoplasia
Eunuchoidism
Violation of spermatogenesis
Gynecomastia
prone to obesity
Mental disorders
Mental retardation
2007
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Chromosomal diseases
Shereshevsky-Turner syndrome (45 XO)
Short stature, violation
skeletal ossification
(kyphosis, scoliosis…)
Gonadal dysgenesis
(underdevelopment of secondary
sexual characteristics,
infertility)
Appearance older than passport age
Pterygoid fold on the neck
Low hair growth
Deformed ears
Wide nipple spacing
Multiple birthmarks on the skin
Mental retardation (rare)
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congenital diseases

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

Clinical and syndromic
method
genealogical method
Cytogenetic method
Karyotype
sex chromatin
(number of X chromosomes)
Biochemical method
Molecular Diagnostics
(DNA analysis)
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Prevention of congenital and hereditary diseases

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Exclusion 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
Replacement therapy
hormones in their deficiency
(insulin, ADH…)
cryoglobulin for hemophilia
Ig in agammaglobulinemia
…
Exclusion of substances in violation
their metabolism
(phenylalanine in PKU, lactose in
lactose intolerance)
symptomatic
2007
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congenital diseases, manifesting immediately after birth. They can be both hereditary and non-hereditary - due to the action of adverse 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 development of hereditary pathology.

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

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

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

Genomic changes characterized by a deviation from the norm of 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 laws of information transmission in the cell (DNA-RNA-protein), the appearance of a mutated gene can lead to a decrease (loss) of protein synthesis, the appearance of a pathological 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 the heredity and variability of a person from the point of view of pathology.

Tasks:

1. The 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. The study of general biological and theoretical issues of medicine: malignancy, tissue incompatibility, etc.

Phenocopies- changes in the signs of the body under the influence of factors External Environment during the period of embryonic development, according to the main manifestations, similar to hereditary pathology.

Causes of phenocopies:

1. Oxygen starvation of the fetus.

2 Illness 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. Medications during pregnancy (antibiotics, sulfonamides).