Knowledge of the genetic nature of many congenital biochemical defects allows us to come close to the problem of their treatment and prevention (Fig. 10). As mentioned earlier, the consequences of a gene mutation for the body in many cases come down to the accumulation of large amounts of a substance as a result of enzyme deficiency. So, for example, in phenylketonuria, high concentrations of phenylalanine and phenylpyruvate in tissues lead to suppression of glucose uptake processes and, therefore, to energy hunger. In order to reduce the concentration of these substances in the body, immediately after the detection of phenylketonuria, the child is prescribed a diet containing very small amounts of phenylalanine. When using such a "synthetic" diet for a number of years, the clinical manifestations of phenylketonuria in such children are mild or completely absent.

Another treatment is to stimulate the residual activity of the mutant enzyme. So, in case of a genetic defect of glucose-6-phosphatase of the liver, one of the forms of glycogenosis in children, the induction of 1 abnormal enzyme with the help of cortisone, the hormone of the adrenal glands, is used. In homocystinuria, studies were carried out on cystathionine synthetase, an enzyme defective in this disease. As a result, a treatment regimen with vitamin Wb based on the induction of mutant enzyme activity was developed, and significant clinical improvement was achieved.

Unfortunately, in most cases of known genetic biochemical defects, it is not possible to select an appropriate diet or induce an inactive enzyme. In this regard, attempts are constantly being made to find a way to deliver a normal enzyme to the site of its normal activity in the body. With a number of gene mutations, temporary success has been obtained when patients are infused with a mass of normal white blood cells.

Induction - stimulation of the synthesis of this enzyme in response to a specific effect.

At present, it is possible to purify and isolate many enzymes in sufficiently pure form. To protect these proteins on their way to the tissues of patients from destruction by serum enzymes, various biological "capsules" are used.

"Gene engineering", its principles and difficulties. Microbial geneticists have long used the phenomenon of genetic transformation and transduction. The genetic transformation of individual traits of bacteria occurs when DNA of another variety is added to them. For example, in pneumococci that do not have a mucous membrane, it appears some time after their treatment with a DNA preparation obtained from bacteria of the "mucous" line. Genetic transformation is also possible for human cells. DNA that transforms genetic traits is apparently included in the cell genome and actively functions as a genetic unit. However, the "engraftment" of genes in this way in the whole body of a sick mutant is very difficult. The fact is that in biological fluids and cells, DNases are highly active - enzymes that destroy the introduced DNA.

Until recently, gene transduction seemed possible only in the world of bacteria. The concept of "transduction" can be defined as the transfer of one or a group of genes from one cell to another with the help of a virus. Gene transduction involving one of the human Escherichia coli viruses, known as the lambda phage, has been studied in the most detail.

When a bacterial cell is infected with the lambda phage, the viral DNA is inserted into the circular chromosome of the host cell. The infected cell does not die and, multiplying, reproduces the genome of the phage in myriad numbers. When the virus is activated again and destroys the host cell, the newly formed phage particles, in addition to their genes, may contain the genes of the bacterium. Thus, it was possible to obtain the lines of the "lambda" phage, which have in their

as part of the gene for galactose-1-phosphate uridyl transferase, an important enzyme in sugar metabolism.

The transplantation of this gene into human cells was successful in 1971 by the American scientists Merill, Geyer and Petrichchiani. The object in these experiments were the skin cells of patients with a lack of activity of galactose-1-phosphate uridyltransferase (galactosemia). The aforementioned lambda phage containing this gene of microbial origin served as a donor. In the infected cells of patients with galactosemia, the activity of galactose-1-phosphate uridyltransferase appeared. Thus, the transplantation of a gene from a bacterium to a human became a fact. The enzyme activity acquired by the cells was inherited by daughter cells, i.e., the transplanted gene was not "rejected".

The sensational message of American scientists aroused wide interest. The prospect of treating severe congenital metabolic errors has opened up. However, work in this direction does not promise quick success. The problem is to obtain a sufficient range of viruses carrying certain genes that can integrate into the genome of human cells in the body.

Recently, techniques have been developed for the synthesis of individual genes. So, polyribosomes were isolated from rabbit red blood cells, and from them - globin mRNA (the protein part of hemoglobin). From these differentiated cells, it is relatively easy to isolate. Further, using the viral enzyme RNA-dependent DNA polymerase, American scientists for the first time synthesized a DNA copy of this mRNA. However, this method can only obtain a structural region of the gene without important regulatory "appendages". Nevertheless, methods for obtaining genes "in vitro" are of great interest.

Medical genetic consultation. Despite significant advances in the treatment of hereditary diseases, the leading role in the fight against them belongs to prevention. Significant progress has been made in this direction.

Preventive measures can be carried out in various directions. This includes the study of specific mechanisms of the mutation process, control over the level of radiation and exposure to various mutagens. The pathological development of the organism, the death of the embryo, fetus or child can be caused by any of the known types of mutations. Mutations that lead to the death of the fetus during the prenatal period or shortly after birth are called lethal. The study of the mechanisms of the lethal effects of chromosomal and gene mutations has only just begun, but is of great importance for the prevention of hereditary pathology.

No less important is the prevention of infections and injuries, which in many cases contribute to the manifestation or worsening of the course of a hereditary disease. The harmful effects of environmental factors interacting with genetic factors are especially pronounced in the embryonic period of an organism's development. The advanced age of the mother also significantly affects the risk of having sick offspring in her.

Currently, medical genetic counseling is of the greatest importance for the prevention of hereditary diseases. For this purpose, special medical genetic consultations or medical genetic rooms have been deployed at large medical and preventive associations, where it is possible to conduct special research methods - cytological, biochemical and immunological.

Genetic counseling for preventive purposes is most effective not when people apply after the birth of a sick child, but when the degree of risk of the birth of children with any genetic defects in the parent couple is assessed, especially in cases where the family has or is suspected of a hereditary pathology.

Questions about the medical genetic prognosis for offspring may also arise in persons who are in a consanguineous marriage, in spouses who have a discrepancy in the Rh factor of blood, as well as in cases where women have recurrent miscarriages and stillbirths. At present, a significant role of chromosomal abnormalities in stillbirths and spontaneous abortions has been proven.

Medical genetic counseling is based on establishing the nature of inheritance in each case. Calculation of the risk of disease is determined

the degree of its hereditary conditionality and the type of hereditary transmission. With dominant inheritance of a pathological gene, 50% of children will be sick and will pass on their disease to the next generation. The remaining 50% will remain healthy and will have quite healthy offspring.

In autosomal recessive inheritance, in cases where both parents are heterozygous carriers of the mutant gene, 25% of their children will be diseased (homozygotes), 50% are phenotypically healthy, but are heterozygous carriers for the same mutant gene that they can pass on to their offspring, 25 % remain disease-free. With recessively transmitted diseases, consanguineous marriages are contraindicated. From this point of view, it is an important task to identify heterozygosity in members of a burdened family and in the population in general, since it is heterozygous carriers of the mutant gene that maintain its constant concentration in the population.

When inheriting diseases linked to sex (X chromosome), a phenotypically healthy woman passes the disease on to half of her sons, who are sick. Half of her daughters are also carriers of the mutated gene, being outwardly healthy.

Sometimes giving a conclusion is very difficult. This is due to the fact that there are a number of diseases similar in their manifestation to hereditary ones, but caused by the influence of environmental factors (the so-called phenocopies); many hereditary diseases have significant variations in their manifestation (the so-called polymorphism).

Not every congenital and not every familial disease is hereditary, just as not every disease with a hereditary etiology is congenital or familial. This is especially true of congenital malformations, which in some cases can be caused not by genetic mechanisms, but by pathogenic effects on the fetus during pregnancy. So, in some foreign countries, women who took sleeping pills during pregnancy gave birth to children with deformities.

The probability of inheriting a pathological gene in a burdened family remains for each subsequent child, regardless of whether the previously born child was healthy or sick.

In cases where the type of hereditary transmission of a mutant gene cannot be established or is polygenic in nature, medical genetic counseling is based on the empirically established probability of the risk of having a sick child. Medico-genetic counseling, based on the calculation of the degree of risk of the disease in relatives of patients, has recently been increasingly specified due to the expansion of the possibilities for diagnosing heterozygous carriage. Methods for detecting heterozygous carriage have been developed for a long time, but its reliable determination became possible only in connection with the progress of biochemical diagnostic methods. Currently, in more than 200 diseases, heterozygous carriage has been established, which is necessary for a scientifically based medical genetic consultation.

Prenatal diagnostics can be considered a very promising method for the prevention of hereditary diseases. If you suspect the birth of a child with a hereditary defect, an amniocentesis is performed at the 14-16th week of pregnancy and a certain amount of amniotic fluid is obtained. It contains desquamated epithelial cells of the embryo. The study of this material allows you to determine the hereditary defect even before the birth of the child. Currently, this method can diagnose more than 50 hereditary metabolic diseases and all chromosomal diseases.

The doctor giving medical genetic advice explains to the person being consulted the degree of risk of the disease in his children or relatives. The final decision belongs to the consulted person himself, the doctor cannot forbid him to have children, but only helps to realistically assess the degree of danger. With the right medical genetic explanation, the patient usually comes to the right decision on his own. In this case, a significant role is played not only by the magnitude of the degree of risk, but also by the severity of hereditary pathology:

significant deformities, profound dementia. In these cases, especially if there is such a child in the family, even with a rare disease, the spouses limit further childbearing. Sometimes it also happens that the degree of risk of having a child with a hereditary pathology is exaggerated by family members and the doctor's advice dispels unfounded fears.

Until recently, the possibility of treating hereditary diseases caused skeptical smiles - the idea of ​​the fatality of a hereditary pathology, the complete helplessness of a doctor in front of an inherited defect, has become so strong. However, if this opinion could be justified to a certain extent until the mid-1950s, then now, after the creation of a number of specific and in many cases highly effective methods of treating hereditary diseases, such a misconception is associated either with a lack of knowledge, or, as rightly noted by K. S. Ladodo and S. M. Barashneva (1978), with the difficulty of early diagnosis of these pathologies. They are detected at the stage of irreversible clinical disorders, when drug therapy is not effective enough. Meanwhile, modern methods for diagnosing all types of hereditary anomalies (chromosomal diseases, monogenic syndromes and multifactorial diseases) make it possible to determine the disease at the earliest stages. The success rate of early treatment is sometimes astonishing. Although today the fight against hereditary pathology is the business of specialized scientific institutions, it seems that the time is not far off when patients, after establishing a diagnosis and starting pathogenetic treatment, will come under the supervision of doctors in ordinary clinics and polyclinics. This requires the practical physician to have knowledge of the main methods of treating hereditary pathology, both existing ones and those being developed.

Among the various hereditary human diseases, a special place is occupied by hereditary metabolic diseases due to the fact that a genetic defect manifests itself either in the neonatal period (galactosemia, cystic fibrosis) or in early childhood (phenylketonuria, galactosemia). These diseases occupy one of the first places among the causes of infant mortality [Veltishchev Yu. E., 1972]. The exceptional attention currently being paid to the treatment of these diseases is highly justified. In recent years, approximately 300 out of more than 1500 hereditary metabolic anomalies have been identified with a specific genetic defect that causes functional deficiency of the enzyme. Although the emerging pathological process is based on a mutation of one or another gene involved in the formation of enzyme systems, the pathogenetic mechanisms of this process can have completely different expressions. Firstly, a change or lack of activity of a "mutant" enzyme can lead to blocking of a certain link in the metabolic process, as a result of which metabolites or the initial substrate with a toxic effect will accumulate in the body. An altered biochemical reaction can generally go along the “wrong” path, resulting in the appearance in the body of “foreign” compounds that are not at all characteristic of it. Secondly, for the same reasons, there may be insufficient formation of certain products in the body, which can have catastrophic consequences.

Consequently, the pathogenetic therapy of hereditary metabolic diseases is based on fundamentally different approaches, taking into account individual links of pathogenesis.

SUBSTITUTION THERAPY

The meaning of replacement therapy for hereditary errors of metabolism is simple: the introduction of missing or insufficient biochemical substrates into the body.

A classic example of replacement therapy is the treatment of diabetes mellitus. The use of insulin made it possible to drastically reduce not only the mortality from this disease, but also the disability of patients. Replacement therapy is also successfully used for other endocrine diseases - iodine and thyroidine preparations for hereditary defects in the synthesis of thyroid hormones [Zhukovsky M. A., 1971], glucocorticoids for abnormal steroid metabolism, well known to clinicians as adrenogenital syndrome [Tabolin V. A., 1973]. One of the manifestations of hereditary immunodeficiency states - dysgammaglobulinemia - is treated quite effectively by the introduction of gamma globulin and polyglobulin. The treatment of hemophilia A is based on the same principle by transfusion of donor blood and the introduction of antihemophilic globulin.

The treatment of Parkinson's disease with L-3-4-dihydroxyphenylalanine (L-DOPA) has proven to be highly effective; this amino acid serves as a precursor of the dopamine mediator in the body. The introduction of L-DOPA or its derivatives to patients leads to a sharp increase in the concentration of dopamine in the synapses of the central nervous system, which greatly alleviates the symptoms of the disease, especially reduces muscle rigidity.

Relatively simple replacement therapy is carried out for some hereditary metabolic diseases, the pathogenesis of which is associated with the accumulation of metabolic products. This is a transfusion of a leukocyte suspension or blood plasma of healthy donors, provided that "normal" leukocytes or plasma contain enzymes that biotransform the accumulated products. Such treatment gives a positive effect in mucopolysaccharidoses, Fabry disease, myopathies [Davidenkova E.F., Lieberman P.S., 1975]. However, replacement therapy for hereditary metabolic diseases is hindered by the fact that many enzyme anomalies are localized in the cells of the central nervous system, liver, etc. Delivery of certain enzymatic substrates to these target organs is difficult, since when they are introduced into the body, corresponding immunopathological reactions develop. As a result, inactivation or complete destruction of the enzyme occurs. Currently, methods are being developed to prevent this phenomenon.

VITAMIN THERAPY

Vitamin therapy, that is, the treatment of certain hereditary metabolic diseases by the administration of vitamins, is very reminiscent of replacement therapy. However, during substitution therapy, physiological, “normal” doses of biochemical substrates are introduced into the body, and with vitamin therapy (or, as it is also called, “megavitamin” therapy), doses that are tens and even hundreds of times greater [Barashnev Yu. I. et al. ., 1979]. The theoretical basis of this method of treatment of congenital disorders of metabolism and function of vitamins is the following. Most vitamins on the way to the formation of active forms, i.e. coenzymes, must go through the stages of absorption, transport and accumulation in target organs. Each of these steps requires the participation of numerous specific enzymes and mechanisms. Change or perversion of genetic information that determines the synthesis and activity of these enzymes or their mechanisms can disrupt the conversion of the vitamin into an active form and thereby prevent it from fulfilling its function in the body [Spirichev V. B., 1975]. The causes of dysfunction of vitamins that are not coenzymes are similar. Their defect, as a rule, is mediated by interaction with a certain enzyme, and if its synthesis or activity is disturbed, the function of the vitamin will be impossible. Other variants of hereditary violations of the functions of vitamins are possible, but they are united by the fact that the symptoms of the corresponding diseases develop with the full nutrition of the child (as opposed to beriberi). Therapeutic doses of vitamins are ineffective, but sometimes (in violation of vitamin transport, coenzyme formation), parenteral administration of exceptionally high doses of a vitamin or a ready-made coenzyme, increasing to some extent the trace activity of disturbed enzyme systems, leads to therapeutic success [Annenkov G. A., 1975 ; Spirichev B.V.. 1975].

For example, the disease "urine with the smell of maple syrup" is inherited in an autosomal recessive manner, occurs with a frequency of 1:60,000. In this disease, isovaleric acid and other metabolic products of keto acids are excreted from the body in large quantities, which gives the urine a specific smell. Symptoms consist of muscle rigidity, convulsive syndrome, opisthotonus. One form of the disease is successfully treated with excessive doses of vitamin B1 from the first days of a child's life. Other thiamine-dependent metabolic disorders include subacute necrotizing encephalomyelopathy and megaloblastic anemia.

In the USSR, vitamin B6-dependent conditions are most common [Tabolin V. A., 1973], which include xanthurenuria, homocystinuria, etc. In these diseases, associated with genetic defects in pyridoxal-dependent enzymes of kynureninase and cystathionine synthase, profound changes in intelligence develop, neurological disorders , convulsive syndrome, dermatoses, allergic manifestations, etc. The results of early treatment of these diseases with high doses of vitamin B6 are very encouraging [Barashnev Yu. I. et al., 1979]. Known vitamin-dependent metabolic disorders are as follows [according to Yu. I. Barashnev et al., 1979].

SURGERY

Surgical methods have found wide application in the treatment of hereditary anomalies, primarily in the correction of such malformations as cleft lip and palate, polydactyly, syndactyly, congenital pyloric stenosis, congenital dislocation of the hip joint. Thanks to the successes of surgery in recent decades, it has become possible to effectively correct congenital anomalies of the heart and great vessels, and transplant kidneys in case of their hereditary cystic lesion. Certain positive results are obtained by surgical treatment for hereditary spherocytosis (removal of the spleen), hereditary hyperparathyroidism (removal of parathyroid adenomas), testicular ferminization (removal of the gonads), hereditary otosclerosis, Parkinson's disease and other genetic defects.

Specific, even pathogenetic, can be considered a surgical method in the treatment of immunodeficiency states. Transplantation of the embryonic (to prevent rejection) thymus gland (thymus) with hereditary immunopathology restores immunoreactivity to a certain extent and significantly improves the condition of patients. In some hereditary diseases accompanied by defects in immunogenesis, a bone marrow transplant (Wiskott-Aldrich syndrome) or removal of the thymus gland (autoimmune disorders) is performed.

Thus, the surgical method for the treatment of hereditary anomalies and malformations retains its significance as a specific method.

DIET THERAPY

Diet therapy (medical nutrition) in many hereditary metabolic diseases is the only pathogenetic and very successful method of treatment, and in some cases, a method of prevention. The latter circumstance is all the more important because only a few hereditary metabolic disorders (for example, deficiency of intestinal lactase) develop in adults. Usually, the disease manifests itself either in the first hours (cystic fibrosis, galactosemia, Crigler-Najjar syndrome), or in the first weeks (phenylketonuria, agammaglobulinemia, etc.) of a child's life, leading more or less quickly to sad consequences up to death.

The simplicity of the main therapeutic measure - the elimination of a certain factor from the diet - remains extremely tempting. However, although diet therapy is not an independent and so effective method of treatment for any other diseases [Annenkov G. A., 1975], it requires strict adherence to a number of conditions and a clear understanding of the complexity of obtaining the desired result. These conditions, according to Yu. E. Veltishchev (1972), are as follows: "Accurate early diagnosis of metabolic anomalies, excluding errors associated with the existence of phenotypically similar syndromes; compliance with the homeostatic principle of treatment, which means maximum adaptation of the diet to the requirements of a growing organism; careful clinical and biochemical monitoring of diet therapy.

Consider this using the example of one of the most common congenital metabolic disorders - phenylketonuria (PKU). This autosomal recessive hereditary disease occurs with an average frequency of 1:7000. In PKU, a gene mutation leads to a deficiency of phenylalanine-4-hydroxylase, and therefore phenylalanine, when it enters the body, does not turn into tyrosine, but into abnormal metabolic products - phenylpyruvic acid, phenylethylamine, etc. These derivatives of phenylalanine, interacting with the membranes of the cells of the central nervous system, prevent the penetration of tryptophan into them, without which the synthesis of many proteins is impossible. As a result, irreversible mental and neurological disorders develop rather quickly. The disease develops with the onset of feeding, when phenylalanine begins to enter the body. Treatment consists in the complete removal of phenylalanine from the diet, i.e., in feeding the child with special protein hydrolysates. However, phenylalanine is classified as essential, i.e. not synthesized in the human body, amino acids and must be supplied to the body in quantities necessary for the relatively normal physical development of the child. So, to prevent, on the one hand, mental, and on the other hand, physical inferiority is one of the main difficulties in the treatment of phenylketonuria, as well as some other hereditary "mistakes" of metabolism. Compliance with the principle of homeostatic diet therapy in PKU is a rather difficult task. The content of phenylalanine in food should be no more than 21% of the age physiological norm, which prevents both pathological manifestations of the disease and impaired physical development [Barashneva S. M., Rybakova E. P., 1977]. Modern diets for patients with PKU make it possible to dose the intake of phenylalanine into the body in exact accordance with its concentration in the blood according to biochemical analysis. Early diagnosis and immediate prescription of diet therapy (in the first 2-3 months of life) ensure the normal development of the child. The success of treatment started later is much more modest: within a period of 3 months to a year - 26%, from a year to 3 years - 15% of satisfactory results [Ladodo K. S., Barashneva S. M., 1978]. Therefore, the timeliness of the start of diet therapy is the key to its effectiveness in preventing the manifestation and treatment of this pathology. The doctor is obliged to suspect a congenital metabolic disorder and conduct a biochemical study if the child has poor body weight gain, vomiting, pathological "signs" from the nervous system are observed, a family history is aggravated (early death, mental retardation) [Vulovich D. et al., 1975].

Correction of metabolic disorders through appropriate specific therapy has been developed for many hereditary diseases (Table 8). However, the discovery of the biochemical foundations of ever new metabolic blocks requires both adequate methods of diet therapy and optimization of existing food rations. A great deal of work in this direction is being carried out by the Institute of Pediatrics and Pediatric Surgery M3 of the RSFSR together with the Institute of Nutrition of the USSR Academy of Medical Sciences.

The considered methods of treatment of hereditary diseases due to the established etiology or pathogenetic links can be considered specific. However, for the absolute majority of types of hereditary pathology, we do not yet have methods of specific therapy. This applies, for example, to chromosomal syndromes, although their etiological factors are well known, or to diseases with a hereditary predisposition such as atherosclerosis and hypertension, although the individual mechanisms for the development of these diseases are more or less studied. The treatment of both is not specific, but symptomatic. Say, the main goal of therapy for chromosomal disorders is the correction of such phenotypic manifestations as mental retardation, slow growth, insufficient feminization or masculinization, underdevelopment of the gonads, and a specific appearance. For this purpose, anabolic hormones, androgens and estrogens, pituitary and thyroid hormones are used in combination with other methods of drug exposure. However, the effectiveness of treatment, unfortunately, leaves much to be desired.

Despite the lack of reliable ideas about the etiological factors of multifactorial diseases, their treatment with the help of modern medications gives good results. Without eliminating the causes of the disease, the doctor is forced to constantly carry out maintenance therapy, which is a serious drawback. However, the hard work of hundreds of laboratories studying hereditary pathology and methods of combating it will certainly lead to important results. The fatality of hereditary diseases exists only as long as their causes and pathogenesis are not studied.

EFFICIENCY OF TREATMENT OF MULTIFACTORIAL DISEASES
DEPENDING ON THE DEGREE OF HEREDITARY BURDENING IN PATIENTS

The main task of clinical genetics is currently the study of the influence of genetic factors not only on the polymorphism of clinical manifestations, but also on the effectiveness of the treatment of common multifactorial diseases. It was noted above that the etiology of this group of diseases combines both genetic and environmental factors, the features of the interaction of which ensure the implementation of a hereditary predisposition or prevent its manifestation. Once again, briefly recall that multifactorial diseases are characterized by common features:

1. high frequency in the population;
2. wide clinical polymorphism (from latent subclinical to pronounced manifestations);
3. significant age and sex differences in the frequency of individual forms;
4. the similarity of clinical manifestations in the patient and his immediate family;
5. the dependence of the risk of disease for healthy relatives on the overall incidence of the disease, the number of sick relatives in the family, on the severity of the disease in a sick relative, etc.

However, the above does not affect the features of the treatment of multifactorial pathology, depending on the factors of the hereditary constitution of the human body. Meanwhile, the clinical and genetic polymorphism of the disease should be accompanied by a large difference in the effectiveness of treatment, which is observed in practice. In other words, it is possible to put forward a position on the relationship between the effect of treating a particular disease and the degree of aggravation in a particular patient by the corresponding hereditary predisposition. Detailing this provision, we first formulated [Lil'in E. T., Ostrovskaya A. A., 1988], which on its basis can be expected:

1. significant variability in treatment outcomes;
2. pronounced differences in the effectiveness of various therapeutic methods depending on the age and sex of patients;
3. the similarity of the therapeutic effect of the same drugs in the patient and his relatives;
4. delayed therapeutic effect (with the same severity of the disease) in patients with a greater degree of hereditary burden.

All of these provisions can be studied and proven on the examples of various multifactorial diseases. However, since all of them logically follow from the main probable dependence - the severity of the process and the effectiveness of its treatment, on the one hand, with the degree of hereditary burden, on the other, it is this connection that needs a strictly verified proof on the appropriate model. This disease model must, in turn, satisfy the following conditions:

1. clear staging in the clinical picture;
2. relatively simple diagnosis;
3. treatment is carried out mainly according to a single scheme;
4. ease of registration of the therapeutic effect.

A model that sufficiently satisfies the conditions set is chronic alcoholism, the multifactorial nature of the etiology of which is currently not questioned. At the same time, the presence of a hangover and binge syndrome reliably indicates the transition of the process to the II (main) stage of the disease, a decrease in tolerance - to the transition to the III stage. Evaluation of the therapeutic effect by the duration of remission after therapy is also relatively simple. Finally, the unified treatment regimen for chronic alcoholism adopted in our country (aversion therapy by alternating courses) is used in most hospitals. Therefore, for further analysis, we studied the relationship between the degree of hereditary burden for chronic alcoholism, the severity of its course and the effectiveness of treatment in groups of people with the same age of onset of the disease.

Table data analysis. 9 shows that the average age of the first alcoholization significantly differs in groups with different degrees of hereditary aggravation. The higher the degree of aggravation, the earlier alcoholization begins. It is natural to assume that the average age at the time of the onset of all other symptoms will also be different. The results presented below confirm this. However, the difference, for example, between patients of the two extreme groups in terms of the average age of the first alcoholization and the onset of episodic drinking is 2.5 years, while the difference between them in terms of the average age of the onset of systematic drinking is 7 years, in terms of the average age of the onset of the hangover syndrome is 10 years, and for the median age of onset of psychosis, 13 years. The intervals between the onset of episodic drinking and the transition to systematic drinking, the duration of systematic drinking before the onset of hangover syndrome and alcoholic psychosis, is the shorter, the higher the degree of hereditary burden. Therefore, the formation and dynamics of these symptoms are under genetic control. This cannot be said about the average duration of the interval from the first alcoholization to the onset of episodic alcohol consumption (in all groups it is 3.5 years) and the average duration of the interval from the formation of a hangover syndrome to the patient's registration (in all groups it is 4 years), which, Naturally, they depend solely on environmental factors.

Turning to the results of the study of the relationship between the effectiveness of the treatment of chronic alcoholism and the degree of hereditary aggravation of patients, we note that in patients there was a significant trend towards a decrease in the duration of remission with a greater degree of aggravation. The difference in the two extreme groups (without hereditary burden and with maximum burden) is 7 months (respectively 23 and 16 months). Consequently, the effectiveness of ongoing therapeutic measures is also associated not only with social, but also with biological factors that determine the pathological process.

Thus, the results obtained allow us to conclude that there is a real relationship between the severity of the course and the effectiveness of the treatment of chronic alcoholism with the degree of hereditary burden. Consequently, the analysis of hereditary aggravation and its tentative assessment according to the scheme given in Chapter 2 should help the family doctor in choosing the optimal treatment tactics and predicting the course of various multifactorial diseases as the relevant data accumulate.

TREATMENTS IN DEVELOPMENT

Consider the possibilities of treatment methods that have not yet left the walls of laboratories and are at one stage or another of experimental verification.

Analyzing the principles of substitution therapy above, we mentioned that the spread of this method of combating hereditary pathology is limited due to the impossibility of targeted delivery of the necessary biochemical substrate to organs, tissues, or target cells. Like any foreign protein, introduced "drug" enzymes cause an immunological reaction leading, in particular, to the inactivation of the enzyme. In this regard, they tried to introduce enzymes under the protection of some artificial synthetic formations (microcapsules), which did not have much success. Meanwhile, the protection of the protein molecule from the environment with the help of an artificial or natural membrane remains on the agenda. For this purpose, in recent years, liposomes have been studied - artificially created lipid particles consisting of a framework (matrix) and a lipid (ie, not causing immunological reactions) membrane-shell. The matrix can be filled with any biopolymer compound, for example, an enzyme, which will be well protected from contact with immunocompetent cells of the body by the outer membrane. After being introduced into the body, liposomes penetrate into cells, where, under the action of endogenous lipases, the shell of liposomes is destroyed and the enzyme contained in them, which is structurally and functionally intact, enters into an appropriate reaction. The same goal - the transport and prolongation of the action of the protein necessary for the cells - is also devoted to experiments with the so-called erythrocyte shadows: the patient's erythrocytes are incubated in a hypotonic medium with the addition of a protein intended for transport. Next, the isotonicity of the medium is restored, after which a part of the erythrocytes will contain the protein present in the medium. Protein-loaded erythrocytes are introduced into the body, where it is delivered to organs and tissues with simultaneous protection.

Among other developed methods for the treatment of hereditary diseases, genetic engineering attracts special attention not only medical, but also the general public. We are talking about a direct influence on the mutant gene, about its correction. By biopsy of tissues or blood sampling, it is possible to obtain cells of the patient, in which, during cultivation, the mutant gene can be replaced or corrected, and then these cells can be autoimplanted (which would exclude immunological reactions) into the patient's body. Such a restoration of the lost function of the genome is possible with the help of transduction - the capture and transfer by viruses (phages) of a part of the genome (DNA) of a healthy donor cell into an affected recipient cell, where this part of the genome begins to function normally. The possibility of such correction of genetic information in vitro with its subsequent introduction into the body was proved in a number of experiments, which led to exceptional interest in genetic engineering.

At present, as noted by V. N. Kalinin (1987), two approaches to the correction of hereditary material are emerging, based on genetic engineering concepts. According to the first of them (gene therapy), a clone of cells can be obtained from the patient, into the genome of which a DNA fragment containing the normal allele of the mutant gene is introduced. After autotransplantation, one can expect the production of a normal enzyme in the body and, consequently, the elimination of the pathological symptoms of the disease. The second approach (genosurgery) is associated with the fundamental possibility of extracting a fertilized egg from the mother's body and replacing an abnormal gene in its nucleus with a cloned "healthy" one. In this case, after autoimplantation of the egg, a fetus develops, not only practically healthy, but also deprived of the possibility of transmitting pathological heredity in the future.

However, the prospects for using genetic engineering to treat hereditary metabolic diseases are very remote, once we consider some of the emerging problems. We list the problems that do not require special genetic and biochemical knowledge [Annenkov G. A., 1975], the solution of which is still a matter of the future.

The introduction of "healthy" DNA into a recipient cell without simultaneous removal of a "damaged" gene or DNA segment will mean an increase in the DNA content in this cell, i.e. its excess. Meanwhile, excess DNA leads to chromosomal diseases. Will an excess of DNA affect the functioning of the genome as a whole? In addition, some genetic defects are realized not at the cellular, but at the organism level, i.e., under the condition of central regulation. In this case, the successes of genetic engineering achieved in experiments on an isolated culture may not be preserved when the cells are "returned" to the body. The lack of methods for precise control over the amount of genetic information introduced can lead to an "overdose" of a particular gene and cause a defect with the opposite sign: for example, an extra insulin gene in diabetes will lead to the development of hyperinsulinemia. The introduced gene should not be built into any, but into a certain place on the chromosome, otherwise intergenic bonds may be broken, which will affect the reading of hereditary information.

The metabolism of a cell with pathological heredity is adapted to atypical conditions. Therefore, the built-in "normal" gene, or rather, its product - a normal enzyme - may not find in the cell the necessary metabolic chain and its individual components - enzymes and cofactors, not to mention the fact that the production of a normal cell, but in fact " "foreign" protein can cause massive autoimmune reactions.

Finally, in genetic engineering, no method has yet been found that would correct the genome of germ cells; this means the possibility of a significant accumulation of harmful mutations in future generations with phenotypically healthy parents.

These are, in brief, the main theoretical objections to the use of genetic engineering for the treatment of hereditary metabolic disorders. The vast majority of hereditary metabolic diseases are the result of extremely rare mutations. The development of an appropriate genetic engineering method for each of these often unique situations is not only an extremely "cumbersome" and economically unprofitable business, but also doubtful in terms of the timing of the start of a specific treatment. For most of the common inborn "mistakes" of metabolism, dietary therapies have been developed that, when used correctly, give excellent results. We are by no means trying to prove the futility of genetic engineering for the treatment of hereditary diseases or to discredit it as a method for solving many general biological problems. The foregoing concerns, first of all, the remarkable successes of genetic engineering in the prenatal diagnosis of hereditary diseases of various origins. The main advantage in this case is the determination of a specific violation of the DNA structure, i.e., "detection of the primary gene that is the cause of the disease" [Kalinin VN, 1987].

The principles of DNA diagnostics are relatively easy to understand. The first of the procedures (blotting) consists in the possibility, with the help of specific enzymes - restriction endonucleases, to divide the DNA molecule into numerous fragments, each of which may contain the desired pathological gene. At the second stage, this gene is detected using special DNA "probes" - synthesized nucleotide sequences labeled with a radioactive isotope. This "probing" can be carried out in various ways, described, in particular, D. Cooper and J. Schmidtke (1986). To illustrate, let's focus on just one of them. Using genetic engineering methods, a small (up to 20) normal nucleotide sequence is synthesized that overlaps the site of the proposed mutation, and it is labeled with a radioactive isotope. This sequence is then attempted to hybridize with DNA isolated from the cells of a particular fetus (or individual). Clearly, hybridization will succeed if the DNA being tested contains the normal gene; in the presence of a mutant gene, i.e., an abnormal nucleotide sequence in the isolated DNA chain, hybridization will not occur. The possibilities of DNA diagnostics at the present stage are shown in Table. 10-13 taken from D. Cooper and J. Schmidtke (1987).

Thus, in a number of issues of medical practice, genetic engineering, as it develops and improves, will certainly achieve even more impressive success. Theoretically, it remains the only method of etiological treatment of various human diseases, in the genesis of which heredity is "represented" in one way or another. In the fight against mortality and disability from hereditary diseases, all the forces and means of medicine must be used.

PREVENTION OF CONGENITAL PATHOLOGY IN WOMEN FROM HIGH RISK GROUP

The problem of combating human congenital pathology in connection with its medical and socio-economic significance attracts exceptionally great attention of specialists. The continuing increase in the frequency of birth defects (up to 6-8% among newborns, including mental retardation) and, above all, those that drastically reduce a person's viability and the possibility of his social adaptation, led to the creation of a number of fundamentally new methods for the prevention of these disorders.

The main way to combat congenital diseases is their prenatal diagnosis using special expensive methods and termination of pregnancy in the event of a disease or defect. It is quite obvious that, in addition to the serious psychological trauma that is inflicted on the mother, this work requires significant material costs (see below). At present, it is generally recognized abroad that, from all points of view, it is much more “profitable” not so much to diagnose pregnancy with an abnormal fetus in time, but to prevent such a pregnancy from occurring at all. To this end, a number of international programs are being implemented to prevent the most severe types of congenital anomalies - the so-called neural tube defects - the absence of a brain (anencephaly), spina bifida with a herniated spinal cord (spine bifida) and others, the frequency of which in different regions of the world ranges from 1 up to 8 per 1000 newborns. It is very important to emphasize the following: from 5 to 10% of mothers who gave birth to such children have abnormal offspring from a subsequent pregnancy.

In this regard, the main task of these programs is to prevent the recurrence of abnormal children in women who already had a child with malformations in a previous pregnancy. This is achieved by saturating the woman's body with some physiologically active substances. In particular, studies conducted in some countries (Great Britain, Czechoslovakia, Hungary, etc.) have shown that taking vitamins (especially folic acid) in various combinations before conception and in the first 12 weeks of pregnancy reduces the frequency of re-birth of children with neural tube defects from 5 -10% to 0-1%

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3.4. Treatment and prevention of certain human hereditary diseases

The increased interest of medical genetics in hereditary diseases is explained by the fact that in many cases knowledge of the biochemical mechanisms of development makes it possible to alleviate the suffering of the patient. The patient is injected with enzymes that are not synthesized in the body. For example, diabetes mellitus is characterized by an increase in the concentration of sugar in the blood due to insufficient (or complete absence) production of the hormone insulin by the pancreas in the body. This disease is caused by a recessive gene. Back in the 19th century, this disease almost inevitably led to the death of the patient. Getting insulin from the pancreas of some pets has saved the lives of many people. Modern methods of genetic engineering have made it possible to obtain much higher quality insulin, absolutely identical to human insulin, on a scale sufficient to provide insulin to every patient and at a much lower cost.

Now hundreds of diseases are known, in which the mechanisms of biochemical disorders have been studied in sufficient detail. In some cases, modern methods of microanalysis make it possible to detect such biochemical disorders even in individual cells, and this, in turn, makes it possible to diagnose the presence of such diseases in an unborn child by individual cells in the amniotic fluid.

3.5. Medical genetic counseling

Knowledge of human genetics makes it possible to predict the probability of the birth of children suffering from hereditary ailments, when one or both spouses are sick or both parents are healthy, but the hereditary disease occurred in the ancestors of the spouses. In some cases, it is possible to predict the probability of having a second healthy child if the first one was affected by a hereditary disease.

As the biological and especially genetic education of the general population increases, married couples who do not yet have children are increasingly turning to geneticists with a question about the risk of having a child affected by a hereditary anomaly.

Medical genetic consultations are now open in many regions and regional centers of our country. The widespread use of medical genetic counseling will play an important role in reducing the frequency of hereditary ailments and save many families from the misfortune of having unhealthy children.

Currently, in many countries, the method of amniocentesis is widely used, which allows the analysis of embryonic cells from the amniotic fluid. Thanks to this method, a woman at an early stage of pregnancy can obtain important information about possible chromosomal or gene mutations in the fetus and avoid the birth of a sick child.

Conclusion

So, the paper outlined the key concepts of genetics, its methods and achievements in recent years. Genetics is a very young science, but the pace of its development is so high that at the moment it occupies the most important place in the system of modern sciences, and, perhaps, the most important achievements of the last decade of the past century are connected with genetics. Now, at the beginning of the 21st century, prospects are opening up before humanity that fascinate the imagination. Will scientists be able to realize the gigantic potential inherent in genetics in the near future? Will humanity receive the long-awaited deliverance from hereditary diseases, will a person be able to extend his too short life, gain immortality? At present, we have every reason to hope so.

According to the forecasts of geneticists, by the end of the first decade of the 21st century, genetic vaccines will replace the usual vaccinations, and doctors will have the opportunity to permanently end such incurable diseases as cancer, Alzheimer's disease, diabetes, and asthma. This area already has its own name - gene therapy. She was born just five years ago. But soon it may lose its relevance due to gene diagnostics. According to some forecasts, exceptionally healthy children will be born around 2020: already at the embryonic stage of fetal development, geneticists will be able to correct hereditary problems. Scientists predict that in 2050 there will be attempts to improve the human species. By this time, they will have learned to design people of a certain specialization: mathematicians, physicists, artists, poets, and maybe geniuses.

And closer to the end of the century, the dream of man will finally come true: the aging process, of course, can be controlled, and there it is not far from immortality.

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Heredity and genes, Science and Life, March 1999

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The set of linked genes of one chromosome that control the allogroup is called a haplotype. Meaning: 1) study of the causes and dynamics of genotypic variability, which forms the basis of evolutionary genetics; 2) clarification of the origin of individual animals; 3) definitions of mono- and dizygotic twins; 4) construction of genetic maps of chromosomes; 5) the use of biochemical systems as genetic ...

Today, the number of hereditary diseases, even taking into account the constant development of medicine, does not stop growing and makes up a significant share in the list of common human pathologies. Doctors of all specializations have to deal with the treatment of such diseases, although it is not always possible to determine the genetic characteristics of a particular disease in a clinical setting. And this is understandable, because diagnosing pathologies of a hereditary type is not always so simple, it is a rather labor-intensive process.

Difficulties in diagnosis are due to the variety of various nosological forms of genetic diseases. Some diseases are extremely rare, so it is important for the attending physician to consider the main principles that can help identify uncommon pathology and make an accurate diagnosis.

Diagnosis of the patient is carried out taking into account several points. The clinical picture, the results of laboratory tests and genetic testing are taken into account. It is important to know that any hereditary disease can develop, hiding, for example, behind the signs of a somatic disease. Therefore, only a competent doctor should deal with the diagnosis of diseases.

Before making a diagnosis, the specialist will necessarily conduct a general clinical examination of the patient and, at the slightest suspicion of any hereditary disease, will perform a differential diagnosis. Also of paramount importance is the questioning of a sick person. Properly collected anamnesis is already half the success. For example, if the problem concerns children, then the doctor will thoroughly study the data on pregnancy, childbirth, and the period of feeding. Information about the diseases that the baby has had at an early age is also important. The obstetric history also plays a role, which the doctor will also study when making a diagnosis.

By interviewing the parents of a sick child, the doctor learns about their state of health, chronic diseases, age, and even profession. For example, if Down syndrome or another chromosomal abnormality is suspected, the age of the mother matters. The age of the father is important if Marfan syndrome or, for example, Shereshevsky-Turner syndrome is suspected, when a chromosomal disease develops, which is characterized by anomalies in physical development.

If a patient develops rare symptoms of a specific type, then the doctor will in any case suspect the presence of hereditary pathologies.

When a partial or complete dislocation of the lens of the eye is diagnosed, the development of several syndromes can be assumed, in particular Weyl-Marchesani.

• Problems relating to sexual development are characteristic of chromosomal diseases.
• Enlargement of the liver to a huge size can develop due to galacto-, fructosemia, etc.
• Amenorrhea - with Shereshevsky-Turner syndrome.
• A sunken bridge of the nose - with mucopolysaccharidosis.
• Muscular aplasia of the hands - with Edwards syndrome.

When diagnosing hereditary diseases, anthropometry is performed before prescribing drugs. Head circumference, arm and leg length, weight and height, skull shape, chest volume and other information related to the patient are measured. If chromosomal diseases are suspected, the doctor can apply dermatoglyphics, during which the skin is examined, or rather, patterns on the soles of the feet, palms of the hands and flexion areas of the fingers.

As for paraclinical studies, the whole range of methods is used in the diagnosis of hereditary diseases. Here one can single out immunological, clinical, biochemical, and radiological options. For example, clinical and biochemical methods are indispensable for suspected phenylketonuria and cystic fibrosis.

Immuno- and cytogenetic methods, screening studies are also used.

A century ago, many hereditary diseases were a kind of sentence. But thanks to modern genetics, many diseases of this type can now be treated, that is, they are amenable to complex therapy under the strict supervision of a physician.

Unfortunately, it is impossible to describe in detail in written material the therapeutic principles and lists of drugs for all hereditary diseases, because such diseases are diverse in their clinical manifestations, type of mutations, and other features.

In this case, we can only highlight the general data. For example, genetic diseases, as well as well-studied diseases, are divided into 3 groups according to the type of possible therapy: those requiring symptomatic treatment, etiological and pathogenetic. Only the attending physician can prescribe medications, taking into account the age of the patient, the characteristics of the pathology, the clinical picture of the manifestation of the disease and the presence of concomitant diseases.

Today, pathogenetic therapy is actively formed due to the achievements of biochemical and molecular genetics. Treatment with drugs is carried out by direct intervention in the pathogenesis of the disease.

In any case, the use of drugs for hereditary pathologies is a complex procedure. But such methods of influence in any case should be carried out on an ongoing basis.

There are three types of prevention of hereditary diseases:

• Primary prevention is a process aimed at preventing the birth of a sick child. Such prevention includes planning for a healthy pregnancy, the ideal female age for which is between 21 and 35 years.
• Secondary prevention is the termination of a pathological pregnancy, in which the disease is diagnosed in the fetus even in the prenatal period.
• The tertiary type of prevention is corrective manipulations aimed at the pathological genotype. It is thanks to such actions that it is possible to obtain normalization and a steady decrease in the level of severity of the pathological process. For example, for some diseases, drugs are prescribed even during the period of gestation. Also, a certain effectiveness is demonstrated by the prescription of drugs at the preclinical stage of the development of a hereditary disease.

1. Treatment of hereditary diseases:

1. Symptomatic and pathogenetic - impact on the symptoms of the disease (the genetic defect is preserved and transmitted to offspring):

1) diet therapy, which ensures the intake of optimal amounts of substances in the body, which relieves the manifestation of the most severe manifestations of the disease - for example, dementia, phenylketonuria.

2) pharmacotherapy (introduction of the missing factor into the body) - periodic injections of missing proteins, enzymes, Rh factor globulins, blood transfusion, which temporarily improves the condition of patients (anemia, hemophilia)

3) surgical methods - removal of organs, correction of damage or transplantation (cleft lip, congenital heart defects)

2. Eugenic measures - compensation for natural human deficiencies in the phenotype (including hereditary), i.e. improving human health through phenotype. They consist in treatment with an adaptive environment: prenatal and postnatal care for offspring, immunization, blood transfusion, organ transplantation, plastic surgery, diet, drug therapy, etc. It includes symptomatic and pathogenetic treatment, but does not completely eliminate hereditary defects and does not reduce the amount of mutant DNA in the human population.

3. Etiological treatment - impact on the cause of the disease (should lead to a cardinal correction of anomalies). Not currently developed. All programs in the desired direction of fragments of genetic material that determine hereditary anomalies are based on the ideas of genetic engineering (directed, reverse induced mutations through the discovery of complex mutagens or by replacing a "sick" chromosome fragment in a cell with a "healthy" natural or artificial origin)

2. Prevention of hereditary diseases:

Preventive measures include medical genetic consultations, prenatal diagnostics and clinical examination. Specialists in many cases can indicate to parents the likelihood of a child with certain defects, chromosomal disease or metabolic disorders caused by gene mutations.

Medical genetic counseling. The trend towards an increase in the weight of hereditary and hereditarily caused pathology is quite clearly expressed. The results of population studies in recent years have shown that, on average, 7-8% of newborns have any hereditary pathology or malformations. The best method of curing a hereditary disease would be to correct the pathological mutation by normalizing the chromosomal or gene structure. Experiments on "back mutation" are carried out only in microorganisms. However, it is possible that in the future genetic engineering will correct the mistakes of nature in humans as well. So far, the main ways to combat hereditary diseases are changes in environmental conditions, as a result of which the development of pathological heredity becomes less likely, and prevention through medical genetic counseling of the population.

The main goal of medical genetic counseling is to reduce the frequency of diseases by limiting the appearance of offspring with hereditary pathology. And for this it is necessary not only to establish the degree of risk of having a sick child in families with a burdened heredity, but also to help future parents correctly assess the degree of real danger.

The following are subject to referral to medical genetic counseling:

1) patients with hereditary diseases and members of their families;

2) members of families in which there are repeated cases of illness of an unknown cause;

3) children with malformations with suspected chromosomal disorders;

4) parents of children with established chromosomal disorders;

5) spouses with repeated spontaneous abortions and infertile marriages;

6) patients with impaired sexual development

7) persons wishing to marry if one of them or one of their relatives suffers from hereditary diseases.

In the medical genetic consultation, the patient is examined and the family tree is compiled. Based on the data obtained, the type of inheritance of this disease is assumed. In the future, the diagnosis is specified either by examining the chromosome set (in the cytogenetic laboratory), or with the help of special biochemical studies (in the biochemical laboratory).

In diseases with a hereditary predisposition, the task of medical genetic counseling is not to predict the disease in offspring, but to determine the possibility of developing this disease in the patient's relatives and develop recommendations if treatment or appropriate preventive measures are necessary. Early prevention, aimed at eliminating the harmful factors that provoke the development of the disease, is of great importance, especially with a high degree of predisposition. The diseases in which such preventive measures are effective include, first of all, hypertension with its complications, coronary heart disease and strokes, peptic ulcer, and diabetes mellitus.

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3. The value of diagnosis and treatment of hereditary diseases
4. REALITIES AND PROSPECTS FOR THE TREATMENT OF HEREDITARY DISEASES
5. HEREDITY AND PATHOLOGY - GENE DISEASES. CHROMOSOMAL DISEASES. METHODS FOR STUDYING HUMAN HEREDITY
6. Prevention and treatment of isoserological incompatibility depending on the degree of risk of developing hemolytic disease of the fetus