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GBOU SPO "Yeisk Medical College"

"Diagnosis, treatment and prevention of human hereditary diseases"

1st year students

group 131(1)

specialty General Medicine

Vasilyeva Diana Nikolaevna

INTRODUCTION

According to the World Health Organization, about 2.5% of newborns are born with various malformations. At the same time, 1.5-2% of them are mainly due to unfavorable exogenous factors (the so-called teratogens), while the rest are predominantly of a genetic nature. Among the exogenous causes of malformations, biological (infectious diseases: rubella, herpes, toxoplasmosis, chlamydial infection, cytomegalovirus infection), physical (all types of ionizing radiation, radionuclides), chemical (all anticancer drugs, hormonal drugs, narcotic substances) should be mentioned.

Genetic factors of malformations reflect the so-called general genetic load of the population, which manifests itself in more than 5% of the world's population. Approximately 1% of the genetic burden is due to gene mutations, 0.5% to chromosomal mutations, about 3-3.5% corresponds to diseases with a pronounced hereditary component (diabetes, atherosclerosis, ischemic disease hearts, some tumors, etc.). If we add to this that about 40-50% of early infant (perinatal) mortality and disability from childhood are due to hereditary factors and about 30% of beds in children's hospitals are occupied by children with hereditary pathology, the unconditional need for a correct and rationally organized early diagnosis of congenital and hereditary diseases. The decisive role in this belongs to the institutes of the medical genetic service, and, first of all, to those subdivisions that provide prenatal diagnostics, which makes it possible not only to establish a diagnosis before birth, but also to prevent the birth of children with severe, unrepairable malformations, with socially significant fatal gene and chromosomal diseases.

Medical genetic assistance in Russia, as well as in the former USSR, is organized according to the territorial principle and includes, as a mandatory initial link, medical genetic consultations and offices, interregional (interregional) medical genetic centers and, as the highest level, federal medical genetic centers . Direct prenatal diagnostics is concentrated almost exclusively in regional, interregional and federal medical genetic centers.

Medical genetic counseling and prenatal diagnosis can reduce the risk of having a child with a hereditary disease, and therefore reduce the overall burden of pathological heredity.

Chapter 1. Diagnosis of genetic diseases

There are many methods for diagnosing hereditary diseases. Diagnosis can be carried out at any stage of the development of the baby, but it is best to find out about the presence of a predisposition to the disease in advance. For this purpose, a huge number of medical genetic consultations have been created.

If the baby has already begun to develop, then in this case, the diagnosis of hereditary diseases is made on the material that gives us the fetus. Such methods can be divided into invasive and non-invasive. The non-invasive method is the safest for the child. the invasive method involves the taking of tissues or cells of the fetus. This is associated with a small risk, but these are the most informative methods.

1.1 Diagnostics

1. Prenatal (intrauterine), i.e. by ultrasonic scanning, fetal x-ray, aminocetesis - analysis of amniotic fluid with desquamated fetal cells.

2. Postnatal (after birth) - based on dermatoglyphics (fingerprint) and morphological analysis (external signs)

3. Preclinical (presymptomatic)

4. Early postnatal diagnosis (identification) of hereditary diseases that can be treated.

Diagnosis of hereditary pathology is a complex and time-consuming process. Difficulties are caused by a large number of hereditary diseases (there are about 3.5 thousand of them), the variety of the clinical picture of each of them, and the rare occurrence of some forms. And also by the fact that hereditary diseases can proceed similarly to non-hereditary ones, accompany them.

Prenatal diagnosis (PD) of hereditary and congenital diseases is a relatively new area of ​​medical genetics that emerged in the 1980s at the intersection of such clinical sciences as obstetrics, gynecology, neonatology, medical genetics, on the one hand, pathophysiology, biochemistry, cytogenetics, molecular biology, human genetics - on the other.

At the present stage of development, prenatal diagnostics is acquiring the outlines of an independent scientific direction with its own tasks, methods and subject of research. The subject (object) of the scientific study of PD is the human embryo on different stages intrauterine development. The human embryo is now available for a wide variety of studies and diagnostics at almost any stage of development. It is advisable to divide the methods used in PD into indirect, when the object of the study is a pregnant woman, and direct, when the fetus itself is examined. The latter can be invasive (operative) and non-invasive.

1.2 Direct methods of prenatal diagnosis

1.2.1 Ultrasound Scan

The most common and most effective direct non-invasive method for examining the fetus is an ultrasound examination (scanning) - ultrasound diagnostics (USD). It is pleasant to note that almost all medical genetic centers in Russia are equipped with imported high-resolution ultrasound machines and up to 90% of all pregnant women in Moscow and St. Petersburg undergo ultrasound examinations during pregnancy. According to the City Medical Center of St. Petersburg, ultrasound diagnostics can detect up to 80% of fetuses with anatomical defects, that is this method today is the simplest and most effective way to diagnose anatomical defects. It is important to emphasize that the method has already been tested on tens, if not hundreds of millions of pregnant women, and its absolute harmlessness to the mother and fetus has been firmly proven. Unfortunately, it is not very informative in chromosomal and especially monogenic diseases, for the diagnosis of which it is necessary to use the cells of the fetus itself or its provisional organs (placenta, membranes), obtained under the control of ultrasound by surgical methods.

1.2.2 Invasive (surgical) methods of prenatal diagnosis

Sufficiently complete information about the karyotype of the embryo, the biochemical and genotypic features of its cells can only be obtained on the basis of appropriate studies of the tissues of the fetus itself or its provisional organs (placenta, chorion). Various invasive methods have been developed and widely used to obtain embryonic material at any stage of pregnancy. Thus, human embryos of pre-implantation stages of development, that is, during the first 7 days after fertilization, are actually available for research. By analyzing polar bodies or isolated cells (blastomeres) of crushing embryos obtained as a result of artificial insemination outside the mother's body by molecular or cytogenetic methods, it is possible to determine the sex of the fetus with sufficient confidence (which is important if there are X-linked diseases in the family), as well as conduct molecular diagnostics of some common hereditary diseases (cystic fibrosis, hemophilia, fragile X syndrome). In leading Western centers such pre-implantation diagnostics is already carried out and cases of healthy children born after such a procedure have been registered. However, in these centers pre-implantation diagnostics is still at the stage of scientific development. In Russia and the CIS countries, pre-implantation diagnosis of hereditary diseases is not yet available. At the same time, invasive methods for obtaining fetal material are widely used in many medical genetic centers of the country both in the first and second trimesters of pregnancy. It is significant that it was in Russia back in 1979 that V.S. Rozovsky and V.A. Bakharev performed some of the world's first chorion biopsies (obtaining placental tissue, or the villous membrane of the fetus) in order to prenatal diagnosis, which, however, did not gain popularity. Only in the 1980s, with the advent of high-resolution ultrasound machines, invasive methods for collecting fetal material began to be widely used.

Further progress in the field of invasive methods may concern the development of methods for biopsy of other fetal organs (muscles) and, finally, solving the problem of obtaining fetal cells floating in the mother's blood. Isolation of such cells in sufficient quantities from maternal peripheral blood opens up the possibility of fetal karyotyping and DNA diagnosis of gene diseases without invasive interventions. Active research in this direction is being carried out in advanced diagnostic centers in the United States, Western Europe, and also in Russia. However, they have not yet found wide practical application.

1.3 Diagnosis of chromosomal diseases

It is well known that all PD associated with chromosomal pathology accounts for the bulk (about 80-85%) of women in the groups high risk directed to PD using invasive methods. That is why such attention is paid to the development of convenient, efficient and reliable methods for chromosomal (cytogenetic) analysis of fetal cells. At present, the problem of reliable cytogenetic diagnosis of the human fetus at almost any stage of pregnancy has been successfully solved. Methodically, the most convenient for the diagnosis of chromosomal diseases in the fetus are the 10-12th weeks of pregnancy when, if necessary, a medical abortion is possible. Chromosomal preparations from the chorionic villi (placenta) are prepared by the direct method until the 19-20th week of pregnancy, and for more later dates prefer to obtain them from cultured cord blood lymphocytes. Karyotyping of cultured amniotic fluid cells is possible at 13-21 weeks of gestation.

Number chromosomal disorders detected in the early stages of pregnancy (first trimester), as a rule, is significantly higher than in the second. According to generalized world data, the effectiveness of PD of chromosomal diseases is on average 5%, and more than half of all chromosomal disorders are due to an excess of chromosome 21 - Down's disease. Simple mathematical calculations show that, even if all prenatal diagnostics were limited only to Down's disease, it would certainly be cost-effective from an economic point of view.

Further progress in the direction of PD of chromosomal diseases, apparently, will be achieved through the widespread use of methods and techniques of molecular cytogenetics, which make it possible to diagnose numerical disorders even on the nuclei of nondividing cells and to analyze structural rearrangements of chromosomes in more detail.

genetic treatment disease eugenic

1.4 DNA diagnostics of gene diseases

The number of monogenic diseases available for molecular diagnostics already exceeds 1000 and continues to grow rapidly. All new effective and fairly versatile methods of DNA diagnostics have been created and are constantly being improved, such as the polymerase chain reaction (PCR) method, the author of which, the American scientist Kay Mullis, was awarded the Nobel Prize in 1994, the blot hybridization method, which immortalized the name of its creator, Ed. Southern (1975), and DNA sequencing methods (analysis of the primary nucleotide sequence in a DNA chain) developed by P. Sanger.

DNA diagnostics in the country is carried out only in a few federal medical genetic centers in St. Petersburg, Moscow, Tomsk, and so far it concerns the most frequent, socially significant hereditary diseases, the number of which is increasing. It is also important to emphasize that DNA methods make it possible not only to diagnose gene diseases, but also to identify asymptomatic heterozygous carriers of mutations and, thus, to conduct effective disease prevention in high-risk families.

On the whole, the problem of DNA diagnostics of gene diseases, as well as chromosomal diseases, can in fact be considered solved in principle. Its further progress may concern not only increasing the number of diagnosed diseases, but also shifting the main burden of research into the early postnatal period to screen newborns for predisposition to multifactorial (polygenic) diseases, such as atherosclerosis, cardiac ischemia, diabetes, certain tumors and neuropsychiatric diseases. diseases.

1.5 Biochemical diagnostics

In recent years, the share of biochemical methods in the PD of hereditary and congenital diseases has noticeably decreased. The reason for this is the decisive advances in DNA diagnostics, which make it possible to analyze the gene itself, and not its products, and thus make it possible to diagnose on any fetal cells, and not just on those where the given gene works. Nevertheless, biochemical methods are widely used in PD of congenital defects of the nervous system (study of AFP and acetylcholinesterase in amniotic fluid), in some forms of mucopolysaccharide and lysosomal protein metabolism diseases, and even in PD of cystic fibrosis, the most common monogenic disease. However, it should be noted that as the nature of the mutant gene is clarified, its functions are understood, and a specific protein is identified, direct biochemical studies may also be effective, such as immunochemical analysis of the dystrophin protein in myofibrils in Duchenne myodystrophy or analysis of a specific protein in lymphocytes in Duchenne syndrome. fragile X chromosome. There are reasons to believe that cheaper biochemical methods available for mass use will find more and more widespread use in the screening of hereditary diseases.

Chapter 2. Treatment of hereditary diseases

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)

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. 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.

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 by means of the discovery of complex mutagens or by replacing a "sick" chromosome fragment in a cell with a "healthy" natural or artificial origin).

Chapter 3. Prospects for the treatment of hereditary diseases in the future

Today, scientists have managed to find out only the connection between violations of the chromosomal apparatus, on the one hand, with various pathological changes in the human body, on the other. Regarding the question of the future of medical genetics, we can say that the diagnosis and treatment of hereditary diseases will only develop. is of great practical interest for clinical medicine. Identification of the causes of initial disorders in the chromosome system, as well as the study of the mechanism of development of chromosomal diseases, is also a task for the near future, and a task of paramount importance, since the development of effective methods for the prevention and treatment of chromosomal diseases largely depends on its solution.

In recent years, thanks to the successful development of cytogenetics, biochemistry, and molecular biology, it has become possible to detect chromosomal and gene mutations in humans not only in the postnatal period, but also at different stages of prenatal development, i.e. prenatal diagnosis of hereditary pathology has become a reality. Prenatal (prenatal) diagnostics includes a set of measures aimed at preventing the appearance of a sick child in the family. The greatest success has been achieved in the prenatal diagnosis of chromosomal syndromes and monogenic diseases, while the prediction of a pathology characterized by polygenic inheritance is much more difficult. Methods of prenatal diagnosis are usually divided into invasive and non-invasive.

When using invasive methods, transabdominal (through the abdominal wall) or transcervical (through the vagina and cervix) sampling of fetal cells at various stages of pregnancy and their subsequent analysis (cytogenetic, molecular genetic, biochemical, etc.) are performed. Cytogenetic research methods make it possible to identify chromosomal aberrations in the fetus, using biochemical methods to determine the activity of enzymes or the concentration of certain metabolic products, molecular genetic analysis gives a direct answer to the question of whether the fetus has a pathological mutation in the gene under study. The use of invasive methods of prenatal diagnosis is the most effective, since their results allow us to judge with high accuracy the presence of a hereditary pathology in the fetus. The sampling of fetal material for prenatal diagnostics can be carried out at different stages of pregnancy under ultrasound control.

Chapter 4 Prevention

Prevention is an integral part of medicine. The social and preventive direction in the matter of protecting and strengthening the health of the people includes medical, sanitary, hygienic and socio-economic measures. The creation of a system for preventing diseases and eliminating risk factors is the most important socio-economic and medical task of the state. Allocate individual and social prevention. Depending on the state of health, the presence of risk factors for the disease or severe pathology in a person, 3 types of prevention are considered.

Primary prevention is a system of measures to prevent the occurrence and impact of risk factors for the development of diseases (vaccination, a rational regime of work and rest, rational high-quality nutrition, physical activity, environmental improvement, etc.).

Primary prevention includes socio-economic measures of the state to improve the lifestyle, environment, education, etc. Preventive activities are mandatory for all medical workers. It is no coincidence that polyclinics, hospitals, dispensaries, maternity are called health care facilities.

Secondary prevention is a set of measures to eliminate pronounced risk factors that, under certain conditions (reducing immune status, overstrain, adaptive breakdown) can lead to the onset, exacerbation or relapse of the disease. The most effective method of secondary prevention is medical examination as complex method early detection of diseases, dynamic monitoring, targeted treatment, rational consistent recovery.

A number of experts propose the term<третичная профилактика>as a set of measures for the rehabilitation of patients who have lost the opportunity to fully function. Tertiary prevention is aimed at social (formation of confidence in one's own social suitability), labor (the possibility of restoring work skills), psychological (restoration of the behavioral activity of the individual) and medical (restoration of the functions of organs and systems) rehabilitation.

The most important component of all preventive measures is the formation of medical and social activity among the population and attitudes towards a healthy lifestyle.

Medical genetic counseling. The tendency towards an increase in the weight of hereditary and hereditary 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. by the most best method cure of a hereditary disease would be the correction of a 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 unexplained 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 a medical genetic consultation, a patient is examined and a family tree is compiled. Based on the data obtained, the type of inheritance is assumed this disease. 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 harmful factors that provoke the development of the disease, is of great importance, especially with a high degree of predisposition. Diseases in which such preventive measures are effective, first of all, include hypertonic disease with its complications, ischemic heart disease and strokes, peptic ulcer, diabetes mellitus.

Almost all diseases depend on the hereditary predisposition of a person. In other words, depending on what signs a person has inherited from his parents, his chances of contracting certain diseases may vary. Among other diseases, there are those that are entirely (or almost completely) dependent on hereditary factors. These diseases are called hereditary. They can be prevented or less likely to occur if special measures are taken.

Chapter 5

According to the degree of threat (risk) of recurrence in the family of hereditary diseases, they are divided into 3 groups:

1. diseases with a high degree genetic risk (1: 4), which include diseases with autosomal dominant, autosomal recessive and sex-linked type of inheritance;

2. diseases with a moderate degree of genetic risk (less than 1:10); these include hereditary diseases caused by fresh mutations, as well as chromosomal diseases and diseases with a polygenic type of inheritance, that is, a significant part of congenital deformities and hereditary diseases that develop against a genetically unfavorable background;

3. diseases characterized by a low risk of recurrence or no risk at all.

Conclusion

Assessing the state of prevention of hereditary diseases in the world and in Russia, we can confidently state a decisive progress in this rapidly developing area of ​​medical genetics.

In practical terms, the following can be considered fundamentally resolved in our country: 1) effective ultrasound screening of pregnant women; 2) the problem of taking fetal material at all stages of pregnancy; 3) effective identification of women in high-risk groups for the birth of children with developmental defects; 4) problem effective methods diagnosis of chromosomal and gene diseases in the fetus.

At the same time, such problems as the lack of programs for mass screening of marker embryonic proteins in the blood serum of pregnant women are relevant for Russia; lack of operational computerized registries of hereditary diseases; poor medical genetic training of doctors; ineffective medical genetic counseling; poor awareness of doctors and the population of the country, especially women, about real opportunities prenatal diagnosis. The real needs of a particular region in molecular diagnostics, including prenatal diagnostics, are unknown, even for those hereditary diseases for which molecular studies already exist and are widely used. This often leads to unfortunate misunderstandings when high-risk families, having applied for help to foreign centers, receive a recommendation to conduct the necessary studies in Russia, where the requested diagnostics is not only quite feasible, but also free of charge.

Overcoming the noted shortcomings, largely due to insufficient funding for medical genetics, and prenatal diagnosis, in particular, will play a decisive role in the prevention of hereditary and congenital diseases, rational family planning, and the preservation of the gene pool of the Russian population.

Literature on the topic

1. Baranov V.S. Early diagnosis of hereditary diseases in Russia: Sovrem. state and prospects // Intern. honey. reviews. 1994. V. 2, No. 4. S. 236-243.

2. Bochkov N.P. Clinical genetics. Moscow: Medicine, 1997. 286 p.

3. Veltishchev Yu.P., Kazantseva L.Z. Clinical genetics: Significance for pediatrics, state and prospects // Motherhood and childhood. 1992. No. 8/9. pp. 4-11.

4. Gorbunova V.N., Baranov V.S. Introduction to molecular diagnostics and gene therapy of hereditary diseases. St. Petersburg: Spetsliterature, 1997. 286 p.

5. F.A. Samsonov, "Fundamentals of genetics and defectology"

6. L. Berg and S.N. Davydenkov "Heredity and hereditary human diseases"

7. N.D. Tarasova and G.N. Lushanova "What do you know about your heredity?"

8. N.I. Isaeva “On heredity. Human chromosomal diseases»

9. N.P. Sokolov "Hereditary human diseases"

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Due to the insufficient knowledge of the pathogenetic mechanisms of many hereditary diseases, and, as a result, the low effectiveness of their treatment, preventing the birth of patients with pathology is of particular importance.

Of paramount importance is the exclusion of mutagenic factors, primarily radiation and chemical ones, including the influence of pharmacological preparations. It is extremely important to lead a healthy lifestyle in broad sense of this word: regularly engage in physical culture and sports, eat rationally, exclude such negative factors as smoking, drinking alcohol, drugs, toxic substances. After all, many of them have mutagenic properties.

Prevention of hereditary diseases includes a whole range of measures both to protect the human genetic fund by preventing exposure to the genetic apparatus of chemical and physical mutagens, and to prevent the birth of a fetus that has a defective gene that determines a particular hereditary disease.

The second task is especially difficult. To conclude about the probability of the appearance of a sick child in a given couple, one should know the genotypes of the parents well. If one of the spouses suffers from one of the dominant hereditary diseases, the risk of having a sick child in this family is 50%. If a child with a recessive hereditary disease was born to phenotypically healthy parents, the risk of re-birth of an affected child is 25%. This is a very high degree of risk, so further childbearing in such families is undesirable.

The issue is complicated by the fact that not all diseases manifest themselves in childhood. Some begin in adult, childbearing life, such as Huntington's chorea. Therefore, this subject, even before the detection of the disease, could have children, not suspecting that among them there may be patients in the future. Therefore, even before marriage, it is necessary to know firmly whether this subject is a carrier of a pathological gene. This is established by studying the pedigrees of married couples, a detailed examination of sick family members to exclude phenocopies, as well as clinical, biochemical and electrophysiological studies. It is necessary to take into account the critical periods in which a particular disease manifests itself, as well as the penetrance of a particular pathological gene. To answer all these questions, knowledge of clinical genetics is required.

Basic principles of treatment: exclusion or restriction of products, the transformation of which in the body in the absence of the necessary enzyme leads to a pathological condition; replacement therapy with an enzyme deficient in the body or with a normal end product of a distorted reaction; induction of deficient enzymes. Great importance is attached to the factor of timeliness of therapy. Therapy should be started before the patient develops severe disorders in those cases when the patient is still born phenotypically normal. Some biochemical defects may partially compensate with age or as a result of intervention. In the future, great hopes are placed on genetic engineering, which means targeted intervention in the structure and functioning of the genetic apparatus, the removal or correction of mutant genes, replacing them with normal ones.

Consider the methods of therapy:

The first method is diet therapy: the exclusion or addition of certain substances to the diet. Diets can serve as an example: with galactosemia, with phenylketonuria, with glycogenoses, etc.

The second method is the replacement of substances not synthesized in the body, the so-called replacement therapy. In diabetes, insulin is used. Other examples of substitution therapy are also known: the introduction of antihemophilic globulin in hemophilia, gamma globulin in immunodeficiency states, etc.

The third method is the mediometosis effect, the main task of which is to influence the mechanisms of enzyme synthesis. For example, the appointment of barbiturates in Crigler-Nayar disease contributes to the induction of the synthesis of the enzyme glucuronyl transferase. Vitamin B6 activates the enzyme cystathionine synthetase and has therapeutic effect with homocystinuria.

The fourth method is the exclusion from the use of drugs, such as barbiturates for porphyria, sulfonamides for glucose-6-phosphate dehydrogenase.

The fifth method is surgical treatment. First of all, this applies to new methods of plastic and reconstructive surgery (cleft lip and palate, various bone defects and deformities).

Socio-legal aspect of the prevention of certain hereditary diseases and congenital malformations in humans

State policy in the field of prevention of certain hereditary diseases and congenital malformations in humans is an integral part public policy in the field of public health and is aimed at preventing, timely detection, diagnosis and treatment of phenylketonuria, congenital hypothyroidism, adrenogenital syndrome and congenital malformations of the fetus in pregnant women.

The state policy in the field of prevention of hereditary diseases and congenital malformations in humans specified in this law is based on the principles of public health protection established by law.

In the field of prevention of hereditary diseases and congenital malformations in humans, the state guarantees:

• a) availability for citizens to diagnose phenylketonuria, congenital hypothyroidism, adrenogenital syndrome, congenital malformations of the fetus in pregnant women;
• b) free carrying out of the specified diagnostics in the organizations of the state and municipal systems of health care;
• c) development, financing and implementation of targeted programs for the organization of medical genetic assistance to the population;
• d) quality control, efficiency and safety of preventive and treatment-diagnostic care;
• e) support scientific research in the development of new methods for the prevention, diagnosis and treatment of hereditary diseases and congenital malformations in humans;
• f) inclusion in the state educational standards for the training of medical workers of the issues of prevention of hereditary diseases and congenital malformations in humans.
• 1. Citizens in the implementation of the prevention of hereditary diseases and congenital malformations in humans specified in this law shall have the right to:
  • a) obtaining from medical workers timely, complete and objective information about the need for preventive and therapeutic and diagnostic care, the consequences of refusing it;
  • b) receiving preventive assistance in order to prevent the hereditary diseases specified in this law in offspring and the birth of children with congenital malformations;
  • c) keeping confidential information about the state of health, diagnosis and other information obtained during his examination and treatment;
  • d) free medical examinations and examinations in state and municipal institutions, healthcare organizations;
  • e) free drug supply with phenylketonuria.
• 2. Citizens are obliged:
  • a) take care of and be responsible for their own health, as well as for the health of their offspring;
  • b) if there are hereditary diseases in the genus or family that lead to disability and mortality, contact the medical genetic service in a timely manner;
  • c) comply with medical prescriptions and recommendations to prevent the birth of children with hereditary diseases.

Responsibilities of medical professionals

Medical professionals are required to:

• a) observe professional ethics;
• b) to keep confidential information about the patient's hereditary diseases;
• c) carry out activities for the diagnosis, detection, treatment of phenylketonuria, congenital hypothyroidism, adrenogenital syndrome in newborn children, clinical examination of newborns, as well as for the diagnosis of congenital malformations of the fetus in pregnant women.

LOAD OF HEREDITARY PATHOLOGY IN MEDICAL AND SOCIAL ASPECTS

Every family dreams of having healthy children. This becomes especially relevant after the birth of a sick child. The decrease in the number of children in families in developed countries makes the optimal outcome of each pregnancy extremely important. In this sense, the prevention of hereditary diseases should take a leading place both in the work of a doctor and in the health care system.

It is known that all hereditary pathology is determined by the load of mutations, newly emerging and inherited from previous generations. Effects of the Mutation Process for human populations are expressed in evolutionary-genetic, medical and social aspects. The evolutionary and genetic consequences of the mutation process (balanced polymorphism, lethality) are discussed in Chap. one.

Medical Consequences of Mutation Cargo - increased need for medical care and reduced life expectancy sick.

Medical assistance to people with hereditary diseases in polyclinic conditions is provided 5-6 times more often than people without such a pathology. In children's general hospitals, from 10 to 20% of patients are children with hereditary pathology, which is 5-10 times higher than the frequency of such patients in the population. More frequent visits to the doctor of people with hereditary pathology is quite understandable, as well as their longer hospitalization. First, the disease itself requires a large amount of medical care, and sometimes permanent treatment. Secondly, a hereditary disease does not exclude burns, trauma, infectious diseases. On the contrary, they

* Corrected and supplemented with the participation of Ph.D. honey. Sciences T.I. Subbotina.

occur more frequently, proceed more severely and last longer due to less ability to maintain biochemical, immune and hormonal homeostasis in patients with hereditary pathology.

In a generalized form, the medical consequences of congenital malformations and hereditary diseases are presented in Table. 11.1.

Table 11.1. The consequences of congenital anomalies of various types in developed countries (according to the materials of the World Health Organization)

The life expectancy of patients with hereditary pathology depends not only on the disease itself, but also on the level of medical care. Although exact calculations have not yet been made, for countries with a well-developed health system it can be assumed with great certainty that at least 50% of all patients with hereditary diseases die in childhood. In Canada, a comprehensive assessment of life expectancy was carried out for all patients with hereditary pathology (with different age of onset of diseases and their different severity). It turned out to be 20 years less than the national average (50 years instead of 70).

The social and medical significance of the prevention of hereditary diseases is evidenced by the high level of disability of patients and the economic costs of their maintenance. For many years, such patients remain disabled, unable to take care of themselves. In boarding schools for disabled children, the average monthly expenses per child are equal to the average monthly salary in the country. Such children in boarding schools live on average up to 10 years. Of the 1 million newborns, approximately 5,000 are candidates for many years of severe disability since childhood.

Along with the medical and social significance of the prevention of hereditary diseases, it is equally important psychological aspects in a family with a sick child. The severity and progression of the course of the disease create, as observations show, psychological tension even in very close-knit families. Spouses or relatives find out (or suspect) who is to blame for the birth of a sick child. Family members have different opinions about the transfer of a child to a boarding school (refusal of a child), especially if he lived with his parents. Constant care for a sick child requires large material costs, moral and physical strength, which in one way or another leads to conflicts. Anxiety for a sick child is joined by fear for a possible illness in other children.

Although hereditary diseases, from a philistine point of view, are rare, the life of a particular family is concentrated on a sick child.

Finally, the need to prevent hereditary diseases is dictated by population patterns their distribution. With the improvement of medical care, patients will not only live longer, which automatically increases the number of patients with hereditary pathology in the population, but also pass mutations to the next generations. For example, over the past 100 years in England, the frequency of a mutant gene that causes congenital pyloric stenosis has increased. An operation to cut the pylorus muscle turned this anomaly from a death sentence into a scar on the abdominal wall. Carriers of the mutant gene (after the operation they are no longer sick in the strict sense) leave offspring, some of which also have the mutant gene, and additional cases of the disease appear in the population as a result of the mutation process.

In connection with the planned family size (as a rule, 1-3 children), the difference in the number of children in healthy and hereditarily burdened spouses is largely leveled (reproductive compensation). Natural selection ceases to regulate the number of offspring. There are more pregnancies in hereditarily burdened families (it is clear that some pregnancies end in the death of offspring at any stage of intrauterine development), but the number of live children is the same as in unburdened families. Some of these children are heterozygous, as a result, artificially supported elevated level reproduction of mutant alleles.

GENETIC BASES OF PREVENTION OF HEREDITARY PATHOLOGY

General provisions

From a preventive point of view, it is advisable to divide all hereditary pathology into 3 categories:

Newly emerging mutations (primarily aneuploidies and severe forms dominant mutations);

Inherited from previous generations (both genetic and chromosomal);

Diseases with hereditary predisposition. There are 3 types of prevention of hereditary pathology.

Primary prevention

Primary prevention is understood as actions that should prevent the conception of a sick child; it is the planning of procreation and the improvement of the human environment.

Planning for childbearing includes 3 main items:

The optimal reproductive age, which for women is 21-35 years (earlier or late pregnancies increase the likelihood of having a child with congenital pathology and chromosomal diseases) (see Fig. 5.29);

Refusal of childbearing in cases of high risk of hereditary and congenital pathology (in the absence of reliable methods of prenatal diagnosis, treatment, adaptation and rehabilitation of patients);

Refusal of childbearing in marriages with blood relatives and between two heterozygous carriers of a pathological gene.

Habitat improvement human should be directed mainly to the prevention of newly emerging mutations through strict control of the content of mutagens and teratogens in the environment. This is especially important for the prevention of the entire group of somatic genetic diseases (congenital malformations, malignant neoplasms, immunodeficiency states etc.).

Secondary prevention

Secondary prevention involves abortion with a high probability of fetal disease or prenatally

diagnosed disease. It is possible to terminate a pregnancy only within the established time limits and with the consent of the woman. The basis for the elimination of the embryo or fetus is a hereditary disease.

Termination of pregnancy is not the best solution, but so far it is the only method for the secondary prevention of most severe and fatal genetic defects.

Tertiary prevention

Under the tertiary prevention of hereditary pathology is understood correction of the manifestation of pathological genotypes. It can also be called normocopying, since with a pathological genotype they strive to obtain a normal phenotype.

Tertiary prevention is carried out both in hereditary diseases and (especially often) in diseases with a hereditary predisposition. With its help, you can achieve complete normalization of functions or reduce the severity of the pathological process. For some forms of hereditary pathology, it may coincide with therapeutic measures in the general medical sense.

It is possible to prevent the development of a hereditary disease (normcopying) in utero or after birth.

For some hereditary diseases, intrauterine treatment is possible (for example, with Rh incompatibility, some aciduria, galactosemia).

The development of the disease can currently be prevented by correction (treatment) after the birth of the patient. Typical examples of diseases for which tertiary prevention is effective are galactosemia, phenylketonuria, hypothyroidism (see below), etc. For example, celiac disease manifests itself with the start of complementary feeding. At the heart of the disease is gluten intolerance. The exclusion of this protein from food completely guarantees getting rid of the most severe pathology of the gastrointestinal tract.

Prevention of hereditary diseases and diseases with a hereditary predisposition should include several stages and be carried out at the population level. Modern ideas about hereditary pathology and methodological possibilities allow for prevention at different levels of ontogenesis. Their characteristics and target settings are presented in Table. 11.2.

Table 11.2. Characteristics of the main types of population-genetic preventive programs

As can be seen from Table. 11.2, preventive measures can be carried out before conception and end with a general population survey. In this case, it is desirable to use two fundamentally different approaches at the same time: family and population. Each of these approaches has its own resolutions and limitations.

The modern basis for the prevention of hereditary pathology is theoretical developments in the field of the molecular nature of hereditary diseases, the mechanisms and processes of their development in the pre- and postnatal periods, the patterns of conservation of mutations (and sometimes spread) in families and populations, as well as the study of the processes of occurrence and formation of mutations in germ and somatic cells.

In genetic terms, there are 5 approaches to the prevention of hereditary pathology, which are discussed below.

Controlling gene expression

In the middle of the 20s of the XX century. in experiments, the phenomena of penetrance and expressivity were discovered, which soon became the subject of study of medical genetics. It was noted above that

N.K. Koltsov formulated the concept of "euphenics", by which he understood the formation good qualities or correction of painful manifestations of heredity in a person by creating appropriate conditions (drugs, diet, education, etc.). These ideas began to be realized only in the 60s of the 20th century, when information was accumulated on the primary products of the pathological gene and the molecular mechanisms of the pathogenesis of hereditary diseases. Knowing the mechanisms of action of pathological genes, it is possible to develop methods for their phenotypic correction, in other words, manage penetrance and expressivity.

As science progresses, information is accumulated on methods for the prevention of hereditary pathology at different stages of ontogenesis - on therapeutic or dietary effects. A clinical example of gene expression control, which has already passed a long-term practical test, is the prevention of the consequences of phenylketonuria, galactosemia, and congenital hypothyroidism. The clinical picture of these diseases is formed in the early postnatal period, and therefore the principle of tertiary prevention is relatively simple. The disease must be diagnosed within a few days after birth in order to immediately apply prophylactic treatment that prevents the development of a pathological phenotype (clinical picture). Normcopying can be achieved by dietary (with phenylketonuria, galactosemia) or medicinal (with hypothyroidism) methods.

Correction of the manifestation of pathological genes can begin from the embryonic stage of development. The foundations of the so-called preconception and perinatal prevention of hereditary diseases(within a few months before conception and before delivery). For example, a hypophenylalanine diet for the mother during pregnancy reduces the manifestations of phenylketonuria in the postnatal period in a child. It is noted that congenital anomalies of the neural tube (polygenic nature of inheritance) are less common in children of women who receive enough vitamins. Further testing showed that if women are treated within 3-6 months before conception and during the first months of pregnancy with a hypervitamin (vitamins C, E, folic acid) diet, then the likelihood of developing neural tube anomalies in a child is significantly reduced. This is important for families that already have sick children, as well as for populations with a high frequency of pathological

genetic genes (for example, for congenital neural tube anomalies among the population of Ireland). For more information about the problems of preconception prevention of reproductive health, see the article by L.F. Smoked on CD.

In the future, new methods of intrauterine correction of the pathological expression of genes may be developed, which is especially important for families in which abortion is unacceptable for religious reasons.

Table 11.3 provides examples of congenital anomalies for which intrauterine treatments have already been developed.

Table 11.3. Examples of intrauterine treatment of congenital diseases

The experience of prenatal therapy of female fetuses with 21-hydroxylase deficiency can serve as a starting point for the development of methods for the treatment of other hereditary diseases. Treatment is carried out according to the following plan.

Pregnant women at risk of giving birth to a child with congenital adrenal hyperplasia are prescribed dexamethasone (20 mcg / kg) until the 10th week of pregnancy, regardless of the condition and sex of the fetus. Dexamethasone inhibits the secretion of androgens by the fetal adrenal glands. At the same time, it is necessary to conduct prenatal diagnosis of the sex of the fetus and DNA diagnosis of mutations in the gene (by either chorionic biopsy or amniocentesis). If it is found that the male or female fetus is not affected, then prenatal therapy is stopped, and if the fetus

females find mutations in the homozygous state, then treatment is continued until childbirth.

Prenatal treatment with low doses of dexamethasone is unlikely to cause side effects. When observing children under 10 years of age, no deviations were found. Women receiving dexamethasone experience minor side effects (mood swings, weight gain, high blood pressure, general discomfort), but they are willing to endure these inconveniences for the sake of their daughters' health. The positive results of treatment of female fetuses with 21-hydroxylase deficiency (adrenogenital syndrome) greatly outweigh the negative points.

Tertiary prevention based on the control of gene expression is especially important and effective for the prevention of diseases with a hereditary predisposition. The exclusion from the environment of factors contributing to the development of a pathological phenotype, and sometimes causing it, is a direct way to the prevention of such diseases.

All monogenic forms of hereditary predisposition can be prevented by exclusion from the habitat of the manifesting factors, primarily pharmacological agents in carriers of G6PD deficiency, abnormal pseudocholinesterase, mutant acetyltransferase. In these cases, we are talking about primary (congenital) drug intolerance, and not about acquired medicinal disease(see ch. 8).

For work in industrial conditions that provoke disease states in individuals with mutant alleles (for example, exposure to lead, pesticides, oxidizing agents), it is necessary to select workers in accordance with established principles (see Chapter 7).

Although the prevention of multifactorial conditions is more difficult, since they are caused by the interaction of several environmental factors and polygenic complexes, nevertheless, with the correct family history and molecular genetic analysis polymorphic markers of disease susceptibility genes can identify "weak" links in an individual's health and create favorable conditions for slowing down or stopping the development of a multifactorial disease (preventive medicine). Prevention of hypertension, atherosclerosis, and lung cancer is based on this principle.

Elimination of embryos and fetuses with hereditary pathology

The mechanisms of elimination of non-viable embryos and fetuses were worked out evolutionarily. In humans, these are spontaneous abortions and premature births. Of course, not all of them are due to the inferiority of the embryo or fetus; some of them are related to the conditions of gestation, i.e. with the state of the female body. However, definitely in at least 50% of cases of interrupted pregnancies, the fetuses have either congenital malformations or hereditary diseases.

Thus, the elimination of embryos and fetuses with hereditary pathology replaces spontaneous abortion as a natural phenomenon. Prenatal diagnosis techniques are evolving rapidly, so this preventive approach is gaining momentum. greater value. Establishing the diagnosis of a hereditary disease in the fetus is an indication for termination of pregnancy.

The procedure for prenatal diagnosis and especially termination of pregnancy must be carried out with the consent of the woman. As mentioned above, in some families, for religious reasons, pregnancy cannot be terminated.

Natural selection in humans during the prenatal period allowed the American embryologist J. Workany in 1978 to formulate the concept teratanasia. The term "teratanasia" refers to the natural process of sifting (or sifting) fetuses with congenital pathology. Teratanasia can be carried out by creating "intolerable" conditions for a fetus with pathology, although such conditions are quite acceptable for a normal fetus. These factors, as it were, reveal a pathological condition and at the same time cause the death of the fetus. Some experimental evidence in favor of this point of view already exists. Scientific developments can be directed to the search for methods of induced selective death of a fetus with a pathological genotype. Methods should be physiological for the mother and absolutely safe for a normal fetus.

Genetic engineering at the germ cell level

Prevention of hereditary diseases can be most complete and effective if a gene is inserted into the zygote that replaces the mutant one in function. Elimination of the cause of a hereditary disease (namely, this is the most fundamental aspect of

prevention) means quite serious manipulation of genetic information in the zygote. These can be: the introduction of a normal allele into the genome by transfection, the reverse mutation of a pathological allele, the inclusion of a normal gene in the work, if it is blocked, the deactivation of a mutant gene. The complexities of these problems are obvious, but intensive experimental developments in the field of genetic engineering testify to the fundamental possibility of solving them. Genetic engineering prevention of hereditary diseases has become no longer a utopia, but a prospect, albeit not a close one.

The prerequisites for the correction of human genes in germ cells have already been created. They can be summarized as the following provisions.

The decoding of the human genome has been completed, especially at the level of sequencing of normal and pathological alleles. Functional genomics is rapidly developing, thanks to which intergene interactions will be known.

It is not difficult to obtain any human genes in pure form on the basis of chemical or biological synthesis. Interestingly, the human globin gene was one of the first artificially produced genes.

Methods have been developed for incorporating genes into the human genome with different vectors or in pure form by transfection.

Methods of directed chemical mutagenesis allow to induce specific mutations in a strictly defined locus (obtaining reverse mutations - from a pathological allele to a normal one).

In experiments on different animals, evidence of transfection of individual genes at the zygote stage (Drosophila, mouse, goat, pig, etc.) was obtained. The introduced genes function in the recipient organism and are inherited, although not always according to Mendel's laws. For example, the gene for rat growth hormone, introduced into the genome of mouse zygotes, functions in born mice. Such transgenic mice are much larger in size and body weight than conventional ones.

Genetic engineering prevention of hereditary diseases at the level of zygotes is still poorly developed, although the choice of methods for gene synthesis and methods for their delivery to cells is already quite wide. The solution of the issues of transgenesis in humans today rests not only on genetic engineering difficulties, but also on ethical problems. After all we are talking about the composition of new genomes that are not created by evolution

lucy, but a man. These genomes will join the human gene pool. What will be their fate from a genetic and social point of view, will they function as normal genomes, is society ready to accept the consequences of unsuccessful outcomes? Today it is difficult to answer these questions, and without answering them one cannot begin clinical trials because there will be irreversible interference with the human genome. Without an objective assessment of the evolutionary consequences of genetic engineering, these methods cannot be applied to humans (even with medical purposes at the zygote stage). Human genetics is still far from a complete understanding of all the features of the functioning of the genome. It is not clear how the genome will work after the introduction of additional genetic information into it, how it will behave after meiosis, reduction in the number of chromosomes, in combination with a new germ cell, etc.

All of the above gave grounds for biomedical ethicists at the international level [WHO (World Health Organization), UNESCO (United Nations Educational, Scientific and Cultural Organization), Council of Europe] to recommend temporarily refraining from conducting experiments, and even more so from clinical trials. germ cell transgenesis trials.

Family planning

With a high (more than 20%) risk of having a sick child and the absence of prenatal diagnostics, it is recommended refusal to have children. It is clear that such a recommendation should be given after a qualified medical genetic consultation, when there are no methods of prenatal diagnostics or termination of pregnancy is unacceptable for the family for various reasons.

As you know, consanguineous marriages increase the likelihood of having a child with hereditary disease. Refusal of consanguineous marriages or restriction of childbearing in them can be considered as a method of prevention of hereditary pathology. This is evidenced by the following facts.

Consanguineous marriages at the level of cousin siblings are preferred by at least 20% of the world's population. At least 8.4% of children are born to relatives. This custom is common in the Eastern Mediterranean and South India, as well as among many populations that have been tribal for thousands of years.

In the USA, Canada, Russia, most European countries, in Australia, New Zealand, the frequency of consanguineous marriages is less than 1%, in the Central Asian republics, Japan, North India, South American countries - 1-10%, in the countries of North Africa, the Middle East, South India - from 10 to 50%.

The custom of consanguineous marriages in the past supported the woman and the family. However, this is reflected in the frequency of birth of children with recessive diseases. For unrelated parents, the overall risk of stillbirth, infant and child mortality, or serious congenital malformations is approximately 2.5%, the risk of mental retardation is another 3%. In total, these risks approximately double for children of married couples - cousins. If infant mortality in the region is high, then this effect is hardly noticeable, and if it is low, then the effect of consanguinity in the form of congenital malformations and chronic disabling diseases becomes apparent.

In populations with a high incidence of any disease in which the diagnosis of carriage is carried out, it is possible rejection of marriages of heterozygous carriers.

For women after 35 years, the probability of having a child with chromosomal diseases increases significantly (see Chapter 5), for men - with gene diseases (Table 11.4).

Table 11.4. Mean age of fathers at birth of children with autosomal dominant disorders (sporadic cases)

The difference in the age of fathers of probands and fathers in the control sample is 5 years on average. The reasons for this phenomenon are unclear, but for the prevention of hereditary diseases it must be taken into account.

Thus, end of childbearing before age 35 and even earlier is one of the factors in the prevention of hereditary diseases. When planning the birth of 2-3 children, this period is quite enough for most families.

environmental protection

Human hereditary variability is constantly replenished with new mutations. Newly emerging spontaneous mutations generally determine up to 20% of all hereditary pathology. For some severe dominant forms, new mutations are responsible for 90% or more of hereditary diseases. Hereditary diseases caused by newly emerging mutations cannot actually be predicted. These are random events, rare for each gene.

So far, there are no prerequisites to intervene in the process of spontaneous mutagenesis in humans, although intensive studies of antimutagenesis and antiteratogenesis may lead to the creation of new methods for the prevention of hereditary diseases and congenital malformations.

Along with spontaneous mutagenesis, induced mutagenesis (radiation, chemical, biological) is possible in humans. The universal nature of induced mutagenesis at all levels of heredity organization for all living beings is beyond doubt. Naturally, induced mutagenesis can serve as an additional source of hereditary diseases. From the point of view of the prevention of hereditary diseases, it should be completely excluded.

It should be emphasized that the induced mutation process is dangerous not so much for an individual prognosis as for a population one. Hence it follows that exclusion of mutagenic factors from the human environment is a method of population prevention of hereditary diseases.

Methods for testing external factors for mutagenicity have been developed, they can be introduced into hygienic regulations for environmental protection. This question is very important, because the mutagenic effects of environmental factors do not appear in the exposed population, but in the offspring in several generations.

The protection of the human environment also includes exception from her factors causing ecogenetic pathological reactions

tions. For example, for individuals with xeroderma pigmentosa (homozygotes), contact with ultraviolet rays should be excluded, for individuals with protease inhibitor deficiency - with dust, for carriers of the porphyrin gene mutation - with barbiturates, etc.

MEDICAL GENETIC COUNSELING

General provisions

Medical genetic counseling - a specialized type of medical care - is the most common method of preventing hereditary diseases.

Its essence lies in determining the prognosis for the birth of a child with a hereditary pathology based on an updated diagnosis, explaining the likelihood of this event to the counselors and helping the family to decide on further childbearing.

Back in the late 20s of the twentieth century. S.N. Davidenkov was the first in the world to organize a medical genetic consultation at the Institute of Neuro-Psychiatric Prevention. He clearly formulated the tasks and methods of medical genetic counseling. However, the development of this area of ​​prevention and human genetics as a whole slowed down in the 30s in almost all developed countries. This was due to the fact that in Nazi Germany they used genetic concepts to justify genocide and introduced forced sterilization as a method of "healing the race." Eugenic sterilization has been widely practiced in the USA, Denmark, Sweden and other countries. Largely in connection with eugenics, as well as for political reasons, the Medicogenetic Institute was closed in Moscow (1936).

Although in the United States medical genetic consultations (offices) began to be organized already in the 40s, the really intensive development of such assistance in different countries(including in Russia and Germany) began in the 60-70s. By this time, there was a big breakthrough in the study of chromosomal pathology and hereditary metabolic diseases.

Term "medical genetic consultation" defines two concepts: a medical opinion of a geneticist and a specialized healthcare institution (both independent and as part of an association).

Indications for medical genetic counseling:

The presence of an established or suspected hereditary disease in the family;

The birth of a child with a congenital malformation;

Delayed mental or physical development of the child;

Repeated spontaneous abortions, miscarriages, stillbirths;

High risk of fetal pathology according to the results of biochemical screening of marker serum proteins of a pregnant woman;

The presence of ultrasound markers of a hereditary disease in the fetus;

The age of the pregnant woman is 35 years and older;

closely related marriages;

Exposure to teratogens in the first 3 months of pregnancy.

In principle, it is desirable for every couple to undergo medical genetic counseling before planning a childbearing (prospectively) and, of course, it is necessary after the birth of a sick child (retrospectively).

Functions of a geneticist

The geneticist performs two main functions. First, with the help of other "narrow" specialists makes a diagnosis, using special genetic methods in differential diagnosis; second, he determines health prognosis future (or already born) offspring. The doctor always faces medical, genetic and deontological problems; at different stages of counseling, one or the other predominates.

Medical genetic consultation includes 4 stages: diagnosis, prognosis, conclusion, advice. Communication between a geneticist and the patient's family should be trusting and friendly.

Diagnostics

Counseling always begins with a clarification of the diagnosis of a hereditary disease, since an accurate diagnosis remains a necessary prerequisite for any consultation. Before referring a patient to a medical genetic consultation, the attending physician should, using the methods available to him, clarify the diagnosis as much as possible and determine the purpose of the consultation. If it is necessary to additionally apply genealogical, cytogenetic, biochemical and other special genetic methods (for example, to determine the linkage of genes or use molecular genetic methods, etc.), then the patient is referred for a medical genetic consultation,

and the geneticist assists the attending physician in establishing the diagnosis. In this case, it may be necessary to refer the patient or his relatives for additional examination. For his part, a geneticist can set other specialists (neuropathologist, endocrinologist, orthopedist, ophthalmologist, etc.) a specific task - to recognize the symptoms of a suspected hereditary disease in a patient or his relatives. The geneticist himself cannot have such universal knowledge to fully provide clinical diagnosis several thousand hereditary diseases.

At the first stage of counseling, a geneticist faces many purely genetic tasks (genetic heterogeneity of a disease, inherited or newly emerged mutation, environmental or genetic conditionality of a given congenital disease, etc.).

The diagnosis is clarified in a medical genetic consultation using genetic analysis. For this purpose, a geneticist uses clinical genealogical, cytogenetic and molecular genetic methods, as well as gene linkage analysis, methods of somatic cell genetics. Of the non-genetic methods, biochemical, immunological and other paraclinical methods are widely used to help establish an accurate diagnosis.

Clinical and genealogical method subject to careful collection of pedigree gives certain information for the diagnosis of a hereditary disease. The clinical and genealogical method allows us to describe the first encountered, new form of the disease. If the type of inheritance is clearly traced in the pedigree, then counseling is possible even with an undetermined diagnosis (the features of using the clinical and genealogical method and its resolving capabilities are discussed above). In medical genetic consultation, this method is used in all cases without exception.

cytogenetic study, as evidenced by the experience of many consultations, it is used in at least 10% of cases. This is due to the need for prognosis for offspring with an established diagnosis of chromosomal disease and the need to clarify the diagnosis in unclear cases with congenital malformations. These problems are often encountered in counseling practice. As a rule, not only probands are examined, but also parents.

Biochemical, immunological and other paraclinical methods are not specific to genetic counseling, but are as widely used as in the diagnosis of non-hereditary diseases. In hereditary diseases, the same tests are often used not only for the patient, but also for other family members (compiling a biochemical or immunological "pedigree").

In the process of genetic counseling, there is often a need for an additional paraclinical examination. In such cases, the patient or his relatives are sent to the appropriate specialized institutions.

Ultimately, in a medical genetic consultation, the diagnosis is clarified by genetic analysis of all the information received, including (if necessary) data on the linkage of genes or the results of a study of cultured cells. A geneticist must be a highly qualified specialist in various fields of medical genetics.

Prognosis for offspring

After the diagnosis is clarified, the prognosis for the offspring is determined. A geneticist formulates a genetic problem, the solution of which is based either on theoretical calculations using the methods of genetic analysis and variation statistics, or on empirical data (empirical risk tables). It is clear that the usual training of a general practitioner does not allow such a prognosis to be qualified. A doctor's mistake with an incorrect prognosis for a family can be fatal: a seriously ill child will be born again or the family will unlawfully refuse to bear children.

If prenatal diagnosis is used, the solution of the genetic problem is not required. In such cases, the birth of a child with the disease is not predicted, but the disease is diagnosed in the fetus.

Conclusion of medical genetic counseling and advice to parents

The conclusion of medical genetic counseling and advice to parents can be combined. The conclusion of a geneticist must be written, because family members may return to thinking about the situation. Along with this, it is necessary to verbally explain the meaning of the genetic risk in an accessible form and help the family make a decision.

The final stages of counseling require the closest attention. No matter how the methods of calculating risk (empirical or theoretical) are improved, no matter how fully the achievements of medical genetics are introduced into the work of consultations, counseling will be ineffective if patients misunderstand the explanation of a geneticist. Contact with a family doctor whom the spouses trust also helps, so the coordination of the actions of the family (attending) doctor and the geneticist is very important. For example, even if the fetus is diagnosed in the prenatal period, not all women decide to terminate the pregnancy. With severe chromosomal diseases (trisomy 13, 18, 21), 83% of women terminate pregnancy, with neural tube defects - 76%, with Turner's syndrome - 70%, with other forms of chromosomal abnormalities - 30%.

To achieve the goal of counseling, when talking with patients, one should take into account their level of education, the socio-economic situation of the family, the personality structure and the relationship of spouses. Many patients are not prepared to perceive information about hereditary diseases and genetic patterns. Some tend to feel guilty for the misfortune that has happened and suffer from an inferiority complex, others quite seriously trust the stories of acquaintances, others come to the consultation with unrealistic requests or expectations, due to the fact that they were incorrectly aware of the possibilities of genetic counseling (including sometimes by attending physicians). ). It must be borne in mind that almost all counseling spouses want to have a child (otherwise they would not have sought counseling). This significantly increases the professional responsibility of both the attending physician and the geneticist. Each inaccurate word can be interpreted in the direction in which the spouses are set. If the spouses are very afraid of having a sick child and want to give birth to a healthy one, then each careless phrase of the doctor about the danger increases fear, although in reality the risk may be small. On the contrary, the desire to have a child is so strong that even at high risk, the spouses decide to have children, because the doctor said about some probability of birth healthy child.

The risk statement should be individually tailored to each case. In some cases, we should talk about a 25% probability of having a sick child, in others - about a 75% probability of having a healthy child. However, one must always convince the patient

ents in the random distribution of hereditary factors in order to eliminate the feeling of guilt for the birth of a sick child. Sometimes this feeling is very strong.

It is advisable to send spouses for medical genetic counseling not earlier than 3-6 months after the diagnosis of a hereditary disease is established, since during this period adaptation to the situation in the family takes place, and earlier any information about future children is perceived poorly.

The tactics of a geneticist in helping patients make decisions have not been finally determined. Of course, it depends on the specific situation. Although the decision is made by the patients themselves, the doctor's role in making the decision for the family may be active or limited to explaining the meaning of the risk. In our opinion, a geneticist and an attending physician (especially a family physician) should help with advice in making a decision, since with the current level of knowledge in the field of genetics among the population, it is difficult for those consulting to make an adequate decision on their own.

The medical tasks of counseling are easier to solve than social and ethical problems. For example, with the same disease, with the same probability of having a sick child, different family situations (wealth, relationships between spouses, etc.) require different approaches to explaining the risk. In any case, the decision to have children remains with the family.

Organizational matters

When organizing medical genetic consultations as structural units, it is necessary to rely on the healthcare system that has developed in the country and take into account the degree of development of medicine in general, including the level of knowledge of genetics among doctors. Consultations function as a link in the existing system of medical care for the population.

In most foreign countries with developed healthcare, the counseling system is 3-step: in simple cases, the prognosis for offspring is determined by the family doctor; more difficult cases get to a genetics doctor working in a large medical center; counseling in complex genetic situations is carried out in special genetic consultations. In order to implement this generally effective system, it is necessary that each family doctor or attending physician has a good understanding

clinical genetics, and the organization of medical care for the population should be adequate.

Medico-genetic consultations as structural units of medical institutions can be both general and specialized.

Probands turning to general consultation according to the nosological principle, they have a very different pathology. Since the work on clarifying the diagnosis in the consultation occupies a large place, the diverse profile of the diseases of the probands makes it necessary to examine both the probands and relatives. In this regard, it is advisable to create genetic consultations on the basis of large multidisciplinary medical institutions of republican or regional subordination. The patient and his relatives in this case can get advice from specialists and, if necessary, be hospitalized. In addition, the consultation should be able to send for a specialized (tomography, hormonal profile, etc.) examination to other institutions, if the hospital on the basis of which the consultation operates does not have such capabilities. Close contact with other departments and their correct subordination is an important principle of the general medical genetic consultation.

Specialized medical genetic consultations can be organized at large specialized hospitals, in which a geneticist gains experience in consulting on hereditary diseases of one profile. In difficult cases, general consultations may refer patients to a specialized consultation.

Two consultations - general and specialized - can function in parallel, but independently.

General consultation staff should include geneticists, cytogenetics and biochemists-genetics. A geneticist who conducts reception of the population must have comprehensive genetic training, since he has to solve a wide variety of genetic problems. The object of study of the geneticist is the family, and the proband is only the starting person in this study. Any consultation requires the collection of information about relatives, and sometimes their examination. The conclusion of a geneticist about the repeated risk of the disease is intended directly for the family who applied for help, so the meaning of the conclusion must be explained in an accessible form

(often several family members). All this takes much more time than the reception of the patient by any other specialist. It takes from 1 to 1.5 hours for the initial examination of the proband and his parents, as well as for the collection of a family history. Thus, one geneticist can see no more than 5 families during a working day.

Of all special studies, the greatest need arises for cytogenetic analyzes (average 1 study per 1 family). The great need for the use of the cytogenetic method is due to the referral to medical genetic counseling, primarily of patients with chromosomal pathology, congenital malformations and obstetric pathology. In this case, as a rule, not 1 person is examined, but 2 or 3.

Biochemical studies are needed in approximately 10% of patients who seek advice. This is a pretty high number. However, with a wide variety of hereditary metabolic diseases reuse the same biochemical methods in consultation is very rare. In large cities, it is expedient to create specialized biochemical laboratories with wide methodological possibilities for examining patients with various metabolic disorders.

Thus, genetic counseling as a structural subdivision is a link in the polyclinic service, consisting of a geneticist's office, a procedural room (blood sampling) and a laboratory for cytogenetic and screening biochemical studies. Clinical, paraclinical, molecular genetic, biochemical, immunological and other studies are carried out in specialized laboratories and medical institutions, to which the consultation is attached. Such consultations in hospitals do not exclude the organization of highly specialized medical genetic centers with all the necessary departments.

Analysis of referrals to medical genetic counseling

Until now, only a small number of families (hardly more than 10%) who need the advice of a geneticist seek such specialized help. At the same time, more than 50% of the direction

nyh on consultation of persons have incorrect indications for its carrying out. This discrepancy is associated with the insufficient level of medical genetic knowledge among doctors and the public and with the insufficient understanding by healthcare organizers of the importance of medical genetic counseling as a method of preventing hereditary diseases.

Since the main conductor of the idea of ​​medical genetic counseling is a general practitioner, the referral to such a consultation depends on his knowledge and understanding of the tasks of consultations. The population's awareness of the issues of hereditary diseases also affects the appeal to medical genetic counseling. However, the validity of appeals depends entirely on the competence of the doctor.

The ratio of patients referred by doctors and self-referral to the consultation fluctuates greatly. In various consultations, the proportion of those who applied on their own ranged from 10 to 80%. It depends on who (doctors or the public) was targeted by propaganda, which to a large extent determines the validity of appeals, i.e. accurate diagnosis and correct indications for consultation.

The distribution of those who applied for consultation by disease groups should correspond to the relative frequency of such diseases in human populations. However, the analysis of nosological referrals in consultations of different countries shows deviations from the theoretically expected distribution.

Most often, families with children with chromosomal diseases, congenital malformations and neuropsychiatric diseases turn to consultations.

The social characteristics of patients in different consultations are of the same type. Most of the patients are university educated and well off. The motives for seeking counseling are the desire to have a healthy child (about 90% of respondents) and the desire to cure a sick child (about 10% of cases). In 50% of families, there are conflicting relationships between spouses.

The effectiveness of medical genetic consultations

The goal of genetic counseling in the general population sense is to reduce the burden of pathological heredity, and the goal of a separate consultation is to help the family to adopt

the right decision on family planning, treatment and prognosis of the patient's health. Consequently, the criterion for the effectiveness of medical genetic counseling in a broad sense is the change in the frequency of pathological genes, and the result of the work of a separate consultation is a change in the behavior of spouses who turn to counseling on childbearing.

With the widespread introduction of medical genetic counseling, it is possible to achieve some reduction in the frequency of hereditary diseases, as well as a decrease in mortality (especially for children). Calculations show that out of every 100 consulted families, 3-5 do not have sick children (without consultation, they would have been born), despite the fact that 25-30% of the consulted do not follow the advice of a geneticist. If the attending (or family) doctors helped the spouses to follow such recommendations, then the effectiveness of medical genetic counseling would be even higher.

The population effects of medical genetic counseling are expressed in a change in the frequency of pathological alleles. This indicator will change little, because the main contribution to the frequency of genes in populations is made by heterozygous carriers, and their frequency as a result of counseling will practically not change. If counselees follow the advice of a geneticist, only the number of homozygous carriers will decrease. The reduction in the frequency of severe dominant diseases in populations as a result of genetic counseling will not be significant, because 80-90% of them are the result of new mutations.

Cabinets of medical genetic counseling should be organized in all regional and large city hospitals. The volume of medical genetic counseling, of course, depends on the level of medical care in the country.

With developed health care, the real needs for medical genetic counseling are quite large. For example, all families where children with congenital and hereditary pathologies were born (about 5% of them) require medical genetic assistance. Consequently, in Russia, with an estimated number of 1,500,000 births per year, there will be 75,000 such families. Women over 35 who decide to have a baby need medical genetic counseling. More than 70,000 women over 35 years of age give birth in Russia every year. Other estimates of consultations for early forms of cardiovascular disease

diseases, cancer, nervous, mental and other diseases show that every 5-10th family needs general or specialized medical genetic counseling.

PRENATAL DIAGNOSIS

General issues

The term "prenatal diagnosis" refers to the totality of all methods of examination of the state of the embryo or fetus, aimed at identifying congenital malformations, hereditary diseases and any other forms (infectious, traumatic) diseases that develop in utero. The purpose of such diagnostics is to prevent the birth of children with congenital and hereditary diseases. Prenatal diagnostics as a scientific and practical direction arose in the 70s of the last century and progressed rapidly, based on the successes of genetics and clinical disciplines. The number of prenatal diagnostic procedures currently runs into the tens of millions per year.

Prenatal diagnosis of hereditary diseases is a complex, rapidly developing area of ​​medicine that uses both ultrasound and surgical techniques (chorion biopsy, amnio- and cordocentesis, fetal muscle and skin biopsy), and laboratory methods (cytogenetic, biochemical, molecular genetic).

Family concern for the health of the unborn child (and sometimes unreasonable concern) requires not only an assessment of genetic and environmental risk factors for the outcome of pregnancy (medical genetic counseling), but also the use of prenatal diagnostic methods.

When organizing and developing a system of prenatal diagnostics, the following conditions must be met.

Physicians, when determining indications for research, must be aware of the likelihood of false positive and false negative diagnoses, or, in other words, the limitations of the method.

Prenatal diagnosis should include two stages:

The first stage is the identification and selection of women (more precisely, families) with an increased risk of a genetically unfavorable outcome of pregnancy during medical genetic counseling.

vaniya or primary examination of pregnant women, including using methods of screening diagnostics; the second stage is a clarifying prenatal diagnosis. Any methods of clarifying diagnostics (invasive or non-invasive, laboratory, expensive, labor-intensive) are used only in women with risk factors.

Specialists in prenatal diagnostics (obstetrician-gynecologist, geneticist, laboratory geneticist) should not know the diagnostic limitations of the method in general, but specifically in their laboratory (ultrasound technology, the possibility of taking samples of tissues and cells of the fetus, etc.). It should be taken into account that appropriate laboratory diagnostics may be unavailable or limited.

Specialists must strictly adhere to the standards for determining indications and performing procedures and laboratory tests, carry out ongoing quality control of work, and also have statistics on pregnancy outcomes and discrepancies in diagnoses (control after abortion or after birth).

The importance of observing all the above conditions is associated not only with medical, but also with deontological considerations: all these issues are exacerbated in the family in anticipation of a child.

Methods prenatal diagnosis is divided into indirect and direct.

Indirect Methods- obstetric-gynecological, serological examination, as well as the analysis of embryo-specific markers. The listed markers form the essence of the so-called sifting laboratory methods.

Direct Methods- non-invasive or invasive examination of the fetus. Non-invasive research is practically limited to ultrasound, although in rare cases X-rays, etc. are used. Invasive methods include chorion and placentobiopsy, amnio- and cordocentesis, biopsy of fetal tissues.

For each method there are indications and contraindications, allowing possibilities and complications. The choice of method and all tactics of prenatal diagnosis should be strictly individualized in accordance with the specific situation in the family and the condition of the pregnant woman.

Screening of pregnant women based on the determination of biochemical markers (sieving methods)

Such methods allow to identify women who have an increased risk of having a child with a hereditary or congenital disease. Methods should be available for wide application and inexpensive.

Of course, genetic counseling of families screens them for prenatal diagnosis. The best option screening for the prevention of hereditary pathology through prenatal diagnosis would be medical genetic counseling with a genealogical analysis of all families planning childbearing. In this case, apparently, about 10% of women would need a deeper examination. During medical genetic counseling, women are referred for prenatal diagnosis according to the following indications:

Age 35 years and older (men 45 years and older);

The presence in the family or in the population of a prenatally detected hereditary disease;

Adverse obstetric history (repeated spontaneous abortions or the birth of a child with congenital malformations);

Diabetes;

Epilepsy;

Infections in a pregnant woman;

drug therapy;

Contacts with teratogenic factors.

Screening methods that determine the need for invasive prenatal diagnosis include fetal ultrasound and the determination of substances in the blood serum of a pregnant woman, called maternal serum markers:

AFP concentrations;

HCG level;

The level of unbound estriol;

PAPP-A.

α -fetoprotein produces the yolk sac and liver of the fetus. This protein is excreted in the urine into the amniotic fluid, from where it enters the blood of the pregnant woman through the fetal membranes and placenta. Its content changes during pregnancy. Each laboratory should establish standards in terms of median content.

protein for each week of pregnancy, because AFP concentrations fluctuate among representatives of different races and in different geographical areas, and the distribution of concentrations does not follow the law of normal distribution. Deviation from the average (normal) level of the indicator (indicated in IOM units - multiples of median) is estimated by the ratio of the amount of AFP in the blood of a particular woman to the average value (median) of the content of this protein in many women with the same period of normal pregnancy. This method allows you to suspect congenital defects of the neural tube and abdominal wall. With such a pathology, the concentration of AFP in the blood serum of a pregnant woman in the II trimester is significantly higher than normal (Fig. 11.1). An increase in the level of AFP is also recorded in gastroschisis, omphalocele, and kidney anomalies.

Because neural tube anomalies are several times more common than average in some populations, it is necessary to determine the AFP concentration in all pregnant women in such populations. An indication for this study is also a burdened pedigree, i.e. the presence in it of a patient with an anomaly of the neural tube within the III degree of kinship in both lines of spouses.

The concentration of AFP is reduced from the 15th to the 18th week of pregnancy in the blood of women carrying a fetus with Down's disease (Fig. 11.2) or other chromosomal diseases.

Rice. 11.1 The concentration (along the abscissa) of α-fetoprotein (AFP) in the blood serum of a pregnant woman during the bearing of a normal fetus and a fetus with a congenital neural tube defect: 1 - unaffected; 2 - open spina bifida; 3 - anencephaly

Rice. 11.2. The concentration (along the abscissa) of α-fetoprotein (AFP) in the blood serum of a pregnant woman during the bearing of a fetus with Down syndrome: 1 - Down syndrome; 2 - unaffected

The mechanism of this association is not clear, but its existence is not in doubt. Such a survey of pregnant women can detect up to 20% of cases of Down's disease.

There are no medical contraindications for determining the concentration of AFP. A woman with an altered AFP level is sent for an additional examination. If the protein concentration is elevated, then to clarify the diagnosis of an anomaly of the neural tube, ultrasound is performed and the concentration of AFP in the amniotic fluid is determined. If the protein concentration is low, then a cytogenetic study of the cells (amniocytes or lymphocytes) of the fetus is prescribed.

To increase the effectiveness of the screening diagnosis of Down's disease by analyzing AFP allows the determination serum hCG levels future mother. Normally, the content of hCG decreases to low values ​​​​after the first trimester of pregnancy. In 68% of women carrying a fetus with a chromosomal disease, this indicator remains elevated until delivery. The median concentration of hCG in Down syndrome is increased by 2 times or more (Fig. 11.3). False positive results are rare.

Introduction to the sifter detection program content of unconjugated estriol in the blood serum of a pregnant woman further expands the diagnostic capabilities of the method, however, this significantly increases the relative number of false positive responses. The concentration of this hormone is much lower

Rice. 11.3. The concentration (along the abscissa) of human chorionic gonadotropin (hCG) in the blood serum of a pregnant woman when carrying a fetus with Down syndrome: 1 - unaffected; 2 - Down syndrome

Rice. 11.4. The concentration (along the abscissa) of unconjugated estriol in the blood serum of a pregnant woman during gestation with a fetus with Down syndrome: 1 - Down syndrome; 2 - unaffected

when carrying a fetus with Down's disease (Fig. 11.4).

The greatest diagnostic possibilities are provided by a combination of the three described tests (Fig. 11.5).

In recent years, the possibility of using some other maternal serum markers (for example, PAPP-A) has been actively discussed, the change in which also closely correlates with trisomy in the fetus already in the first trimester.

Computer programs allow you to compare the results and use the obtained indicators with a sufficient degree of reliability. Ways to improve the efficiency of biochemical screening can be found in the article of the same name by T.K. Kashcheeva on CD.

Rice. 11.5. Combination of the results of screening biochemical diagnostics of congenital neural tube anomalies and Down's syndrome: abscissa - gestational age; along the y-axis - analytical concentration; A - low risk; B - high risk; NE - unconjugated estriol

Although the possibility of a reliable non-invasive prenatal determination of the pathology or sex of the fetus by peripheral blood through preliminary enrichment of cells or DNA is not in doubt, due to the high cost, the use of these methods remains within the limits of scientific research, see the article by A.V. Lavrova "Fetal cells and free fetal DNA in maternal blood in non-invasive prenatal diagnostics" on CD.

Non-invasive methods include ultrasound. Radio or radiography was used 20-30 years ago (and even then not very widely) at the initial stages of prenatal diagnosis. In recent years, the use of MRI for fetal imaging has gradually become possible. Despite the high resolution, the value of the method is significantly reduced due to the low speed of image formation (seconds and tens of seconds), which, due to the mobility of the fetus, can lead to incorrect results.

Ultrasound can detect both congenital malformations and the functional state of the fetus, placenta, umbilical cord, membranes. The timing of ultrasound in Russia is determined by the order of the Ministry of Health. These are the 10-13th, 20-22nd and 30-32nd weeks of pregnancy. Ultrasound can also be used to detect embryonic or fetal growth retardation from the 6th to 8th week of pregnancy.

Ultrasound can be used both as a sifting and as a clarifying method. In some countries, ultrasound is done for all pregnant women. This makes it possible to prevent the birth of 2-3 children with serious congenital malformations per 1000 newborns, which is approximately 30% of all children with such a pathology. For a detailed repeated ultrasound as a clarifying diagnostic procedure, the following indications can be distinguished:

Identification of abnormalities (markers of pathology) or malformations of the fetus during screening ultrasound;

Mismatch between the size of the fetus and the gestational age;

Birth of a previous child with congenital malformations;

Diseases in a woman (diabetes mellitus, epilepsy, alcoholism, etc.), which increase the risk of having a child with congenital malformations;

Exposure to a teratogenic factor (radiation, chemicals, infections) in the first 10 weeks of pregnancy;

Congenital malformations in one of the spouses (or in relatives of the I-III degree of kinship along the lines of both spouses).

A brief list of congenital malformations diagnosed by ultrasound in approximately 80-90% of cases is presented in Table. 11.5. The range of defects recognized by this method is quite wide. Every doctor should have this information. You can learn about the possibilities of prenatal diagnosis of congenital heart defects in the article of the same name by I.M. Volkova et al. on CD.

Table 11.5. Congenital malformations diagnosed by ultrasound

End of table 11.5

Invasive methods

Initially, only fetoscopy belonged to invasive methods. Now cells and tissues of the embryo, fetus and provisional organs are obtained by invasive methods in any period of gestation. The development of methods for taking material was stimulated by the emergence of more advanced methods for the laboratory diagnosis of hereditary diseases. Invasive methods are improving in several directions: earlier obtaining of samples for research, more wide range samples, safer methods of sampling for the pregnant woman and the fetus.

To date, in the world practice there is sufficient experience (millions of examined) in the use of chorion and placentobiopsy, obtaining amniotic fluid (amniocentesis), biopsy of fetal tissues, taking fetal blood (cordocentesis).

Chorion- and placentobiopsy are used to obtain a small amount of chorionic villi or pieces of the placenta in the period from the 7th to the 16th week of pregnancy. The procedure is carried out transabdominally or transcervically under ultrasound control (Fig. 11.6, 11.7). There is no fundamental difference between the indications for the use of these two biopsy methods. The effectiveness of the procedure depends on which method the specialist knows better. Although chorionbiopsy is technically simple, sufficient experience and continuous technical improvement are required. Good results are obtained by obstetricians who make at least 200-400 chorionbiopsies per year, failures are 1%. Based on a large amount of material (several million cases), conclusions were drawn about complications after chorionbiopsy. After transcervical chorion biopsy, about 10-30% of women experience a slight

Rice. 11.6.Transabdominal chorion or placentobiopsy

Rice. 11.7.Transcervical chorion or placentobiopsy

bleeding, very rarely - uterine infection, after the transabdominal method, 2.5% of women may have a threat of abortion.

One of the complications of chorionbiopsy is spontaneous abortion (miscarriage). The total loss of the fetus after chorionbiopsy averages 2.5-3%, these figures also include the frequency of spontaneous miscarriages. Actually chorionbiopsy induces, obviously, no more than 2% of cases of abortion.

Any disturbances of the placenta, fetal growth, the appearance of congenital malformations and an increase in perinatal mortality after chorionbiopsy are not observed. Some centers noted that early chorionbiopsy (before 8 weeks of gestation) can induce transverse congenital limb amputations, the so-called reduction defects. In this regard (since 1992) chorion biopsy is recommended after the 8th week of pregnancy, and after the 11th week placentobiopsy is performed.

Samples of the chorion (villi) are subject to cytogenetic, molecular genetic, biochemical studies in order to identify hereditary pathology. When chorionic villi are aspirated, cells of the decidua of the uterus can enter the material, which can lead to diagnostic errors. It is believed that in 4% of cases, laboratory diagnosis of chorion biopsies gives false positive results (for example, in 1.5% of analyzes, chromosomal mosaicism is noted, which is mosaicism of the chorion, and not the embryo), and sometimes (although extremely rarely) - false negative results. The accuracy of the analyzes largely depends on the qualifications of the genetics laboratory assistant.

Amniocentesis- puncture of the fetal bladder in order to obtain amniotic fluid with amniocytes in it. Used for prenatal diagnosis since the early 1970s. We have accumulated vast experience in this procedure. The diagnostic significance of the method is beyond doubt. Usually the procedure is carried out at the 15-18th week of pregnancy, early amniocentesis is performed at the 12-15th week of pregnancy. The risk of pregnancy complications with amniocentesis is less than with chorionbiopsy, according to some authors, only 0.2%. For this reason, many prenatal diagnosis centers prefer to do amniocentesis rather than chorionbiopsy. In the event of a failed analysis of chorion biopsies, prenatal diagnosis is repeated using amniocentesis.

Amniocentesis is performed through the anterior abdominal wall (transabdominally) of a woman under ultrasound control (Fig. 11.8). Transcervical amniocentesis is possible but rarely used. From the amniotic cavity extract 3-30 ml of fluid.

Rice. 11.8. Amniocentesis

Previously proposed biochemical and virological studies of amniotic fluid are not very informative for prenatal diagnosis.

Of the biochemical parameters of the fluid, only the concentration of AFP is diagnostically significant. The level of AFP is significantly increased in neural tube anomalies and defects in the anterior abdominal wall.

Cells are the main diagnostic material for amniocentesis. They must be cultivated (it takes 2-4 weeks) for both cytogenetic and biochemical studies. Only molecular genetic variants of PCR diagnostics do not require cell culture.

Cordocentesis- intrauterine puncture of the umbilical cord vessels to obtain fetal blood (Fig. 11.9). Timing cordocentesis - 18-22 weeks of pregnancy. Blood samples are used for cytogenetic (lymphocytes are cultivated), molecular genetic and biochemical diagnostics of hereditary diseases.

Rice. 11.9. Cordocentesis

Cordocentesis is used to diagnose chromosomal diseases, hereditary blood diseases (hemoglobinopathies, coagu-

spatula, thrombocytopenia), immunodeficiencies, hematological status with Rh sensitization, intrauterine infections.

According to a multicenter study, the incidence of complications during cordocentesis in total for 16 Russian centers for prenatal diagnosis did not increase.

raises 2%. The first attempt to obtain material is successful in 80-97% of cases. The advantage of cordocentesis over amniocentesis is that blood is more convenient to study than amniotic fluid cells. Lymphocytes are cultured faster (2-3 days) and more reliably than amniocytes. Molecular methods of rapid karyotyping in prenatal diagnosis can be found on the CD in the article of the same name by V.A. Timoshevsky and I.N. Lebedev.

Fetal tissue biopsy as a diagnostic procedure is carried out in the II trimester of gestation under ultrasound control.

For the diagnosis of severe hereditary skin diseases (ichthyosis, epidermolysis), fetal skin biopsy with pathomorphological (and sometimes with electron microscopic) examination of the material. Morphological criteria of hereditary skin diseases make it possible to establish an accurate diagnosis or confidently reject it.

For the diagnosis of Duchenne muscular dystrophy at the intrauterine stage, an immunofluorescent method has been developed. For this, they produce fetal muscle biopsy. The biopsy specimen is treated with monoclonal labeled antibodies to the dystrophin protein, which is not synthesized in patients. Appropriate fluorescent treatment highlights the protein. When inheriting a pathological gene, there is no luminescence. This technique is an example of diagnosing a hereditary disease at the level of the primary gene product. In the case of Duchenne myopathy, this method gives more accurate results than molecular genetic diagnosis.

Conclusion

A general practitioner needs to have an idea about the methods of prenatal diagnosis, their capabilities and limitations, and indications for referral for research. The specific timing of its implementation and the choice of method (and sometimes methods) is determined by the group (team) of prenatal diagnostics (geneticist, obstetrician-gynecologist and laboratory geneticist), based on the state of health of the pregnant woman, the course of pregnancy, the psychological readiness of the woman for the procedure. The volume and possibilities of secondary prevention of hereditary diseases by eliminating embryos and fetuses after prenatal diagnosis are summarized in Table. 11.6-11.8.

Table 11.6.

Table 11.7. Comparative characteristics of prenatal diagnostic methods using the transabdominal sampling technique (according to the materials of the World Health Organization)

End of table 11.7

Table 11.8. Indications for the use of different methods of invasive prenatal diagnosis

PRE-IMPLANTATION DIAGNOSIS

Thanks to the development of methods of assisted reproductive technologies [in vitro fertilization, intracytoplasmic sperm injection into the oocyte (ICSI)], on the one hand, and the improvement of laboratory diagnostic methods for hereditary diseases, on the other hand, pre-implantation diagnosis was born in the late 90s of the last century. material for

pre-implantation diagnostics are polar bodies or individual blastomeres obtained from blastocysts using a micromanipulator.

Such diagnostics refers to the methods of primary prevention of hereditary diseases. Its advantage lies in the fact that it helps to avoid repeated abortions after routine prenatal diagnosis in families with a high risk of hereditary pathology.

Pre-implantation diagnosis is successful under the following conditions:

Obtaining an embryo at the pre-implantation stage of development (up to 5-7 days after fertilization);

Availability of diagnostic (analytical) micromethods at the level of one or several cells;

Microsurgical technique (microbiopsy) to take the minimum number of cells without damaging the germinal vesicle;

Accurate medical indications from the family for diagnosis.

Obtaining pre-implantation embryos is possible by non-surgical uterine lavage and in vitro fertilization.

Via mother lavage it is possible to obtain a not yet implanted embryo within 90-130 hours after fertilization. By this time, the embryo descends from the fallopian tube into the uterus. This procedure is painless and safe. Appropriate devices (catcher, guidewire and catheter) have already been tested. The procedure does not affect subsequent ovarian cycles and does not interfere with future pregnancies.

After replanting the embryo into the uterus, normal pregnancy occurs in 50% of cases.

In vitro fertilization and intracytoplasmic sperm injection into the oocyte(ICSI) have proven themselves in obstetric practice. These methods are used to overcome various types of infertility.

The microsurgical procedure for cell isolation for laboratory diagnostics is carried out using a micromanipulator (Fig. 11.10). From the embryo at the stage of 8-16 cells, 1-2 cells can be separated. Sometimes the study is limited to the secondary polar body (it carries the genome of the egg). germ retain

under deep-freeze conditions (or the embryo continues to develop under artificial conditions) while the cell is being analyzed.

Replanting after freezing is possible during any other ovarian cycle.

Diagnosis at the level of one or several cells is currently feasible in many diseases. It is carried out using PCR, monoclonal antibodies, ultramicro analytical methods. There have already been reports of successful diagnosis at the pre-implantation stage of Marfan's syndrome, myotonic dystrophy, Huntington's chorea, familial polypous colon cancer, cystic fibrosis,

OM2 gangliosidosis (Tay-Sachs disease), Lesch-Nyhan syndrome, thalassemia, spinal muscular atrophy, Duchenne muscular dystrophy, mental retardation with a fragile X chromosome, phenylketonuria.

Rice. 11.10. Using a micromanipulator, one cell (with a nucleus) is removed from a human embryo at the 12-cell stage. Photo from video

To date, pre-implantation diagnosis is available for about 50 nosological forms of monogenic and chromosomal nature.

It can be hoped that in the coming years the methodological possibilities of pre-implantation diagnostics will expand both in the field of obtaining diagnostic material and analytical methods (cultivation of pre-implantation embryos and their blastomeres, micromanipulation, cryopreservation).

Pre-implantation diagnosis is an extremely important direction in the system of new reproductive technologies, because, for unknown reasons, the frequency of aneuploidy in human embryos, according to Russian researchers, is very

high: 30-50% of abnormal embryos when assessing aneuploidy for chromosomes 13, 16, 18, 21, 22, X and Y. More information about pre-implantation diagnosis can be found in the article by A.V. Svetlakova et al. "Problems and prospects of pre-implantation genetic diagnosis" on CD.

PRECLINICAL DIAGNOSIS,

SCREENING PROGRAMS AND PREVENTIVE TREATMENTS

Idea screening (screening) was born in the USA at the beginning of the 20th century. (examination of schoolchildren, preventive examinations for the detection of tuberculosis, regular examinations of workers, etc.). These techniques have confidently entered the practice of world health care. Screening involves a mass and unselected examination, a preventive focus and a two-stage (at least) diagnosis.

Screening(screening) can be defined as the identification of unrecognized diseases through rapid tests. This ensures the selection of persons with a probable disease. They are re-examined using clarifying diagnostic methods, allowing either to reject the diagnosis assumed at the first stage, or to confirm it.

The idea of ​​a mass examination of newborns for a hereditary disease began to be tested in the 60s of the twentieth century. To date, the main provisions of the mass diagnosis of hereditary diseases at the preclinical stage (criteria for the selection of hereditary diseases for screening and diagnostic methods) have finally taken shape.

Mass screening of newborns for hereditary diseases is carried out if they:

Without timely preventive treatment, they significantly reduce viability, lead to disability and the need for special assistance to the patient;

Amenable to accurate biochemical or molecular genetic diagnosis at the preclinical stage;

Amenable to effective preventive treatment;

They have a frequency of 1:10,000 or more. Only in a few countries, with a research team, screening of newborns

nyh is carried out for diseases that occur with a frequency of 1: 20,000-1: 40,000. Diagnostic methods of mass screening of newborns must meet the following criteria.

Profitability. Methods should be technically simple and cheap in mass studies.

Diagnostic value. There should be practically no false negative results, and the ratio of true positives and false positives should be at least 1:5. This can be called the sensitivity and specificity of the method.

reliability or reproducibility. The results of the survey should be equally reproduced in the work of different researchers.

Availability biological material. The method should be adapted to the analysis of biological material that is easily obtained in small quantities, well preserved (at least for several days) and acceptable for shipment to a centralized laboratory.

The main goal of the programs of mass screening of newborns for hereditary diseases is the early detection of the disease at the preclinical (presymptomatic) stage and the organization of treatment. The program must include the following steps:

Taking biological material for research from all newborns and delivering the material to the diagnostic laboratory;

Laboratory screening diagnostics;

Clarifying diagnosis of all cases with positive screening results;

Treatment and clinical examination of patients with monitoring of the course of treatment;

Medical genetic counseling of the family.

Thus, mass screening programs for hereditary diseases amenable to preventive treatment can only be established within the framework of federal or regional (including city) health care. This requires the organization of a special link in the structure of health care and considerable economic costs, which on a national scale are compensated by a decrease in the number of disabled people since childhood. Numerous studies conducted in different countries have shown that the economic efficiency of screening programs (preserving the health of treated individuals) provides the state with a 5-10-fold economic benefit.

The first program to screen newborns for phenylketonuria was established in the United States about 25 years ago. Since then, programs for more than 10 hereditary metabolic diseases have also been tested in different countries. As a result, the above criteria for the mass diagnosis of hereditary diseases were worked out. Ultimately, countries with developed health care began to carry out mass screening of newborns for only a few diseases, the characteristics of which are presented in table. 11.9. It should be noted that these recommendations are valid for Caucasian populations. For other races, and sometimes populations, the frequency of these diseases may be lower, and then there will be no indications for their mass diagnosis.

Table 11.9. Characteristics of diseases for which mass screening of newborns is carried out

Since 2006, neonatal screening of five hereditary diseases has been carried out in Russia: adrenogenital syndrome, galactosemia, congenital hyperthyroidism, cystic fibrosis, phenylketonuria - with the aim of their early detection, timely treatment, prevention of disability, development of severe clinical consequences, reducing child mortality.

For neonatal screening, blood samples are taken from the heel of a newborn on the 4th day of life (in full-term ones) and on the 7th day in preterm infants 3 hours after feeding. Blood sampling is carried out on special filter test forms, which are issued by a medical genetic consultation.

healthcare institutions providing medical care to women during childbirth. The results, problems and prospects of neonatal screening can be found in the article of the same name by L.P. Nazarenko et al. on CD.

Phenylketonuria

In Russia, in recent decades, a federal screening program based on fluorometric quantitative method determination of phenylalanine in the blood. Different countries use different methods. The essence of the diagnosis of phenylketonuria is to quantify the concentration of phenylalanine in the blood. Experience has shown that missed cases of phenylketonuria are not errors in laboratory methods, but are the result of dishonesty or carelessness when taking blood in maternity hospitals.

In the case of a positive screening result in children, a clarifying biochemical diagnosis is carried out. This is a more complex, sometimes multi-stage procedure. Firstly, it is necessary to confirm hyperphenylalaninemia, and secondly, it is necessary to understand its cause. It can be caused by typical phenylketonuria (phenylalanine hydroxylase deficiency), variant or atypical forms of this disease, hereditary hyperphenylalaninemia (benign), and other forms of metabolic disorders.

When the diagnosis of phenylketonuria is confirmed, the child is transferred to an artificial non-phenylalanine diet.

Table 11.10 lists the names of formulas for feeding children with phenylketonuria.

Table 11.10. Non-phenylalanine formulas

Vitamins and mineral salts are given in the form of pharmacological preparations. Over time, the diet is expanded. Children older than 1 year tolerate food phenylalanine more easily. Treatment with a diet is carried out under regular biochemical control of the concentration of phenylalanine in the blood: 2 times a week in the 1st month (usually a period of hospitalization), weekly until 6 months of age, 2 times a month at the age of 6 months - 1 year and monthly thereafter . This control allows you to determine the adequacy of therapy.

With the timely start of treatment with a non-phenylalanine diet in the first months after birth, children homozygous for the phenylalanine hydroxylase deficiency gene do not show any clinical signs of mental or physical developmental delay. From the age of 9-11 years, the diet of such patients can be significantly expanded, but they remain under the supervision of a geneticist. This is especially true for women with phenylketonuria, since during pregnancy an increased level of phenylalanine and its derivatives in the serum of a woman is toxic to a genetically healthy fetus. This requires special preventive measures.

congenital hypothyroidism

Under the name "congenital hypothyroidism" is understood the sum of hereditary and non-hereditary pathologies: thyroid agenesis, ectopia of the thyroid gland, dyshormonogenesis (hereditary diseases), autoimmune processes. The main clinical manifestations: mental retardation, a sharp lag in growth, swelling of the skin, and with dyshormonogenesis, the development of goiter. For all forms of the disease, the same mass sieving program is acceptable, since the biochemical markers are a decrease in plasma thyroxine and an increase in thyroid-stimulating hormone (TSH). The diagnostic significance of screening is fully manifested in the determination of both markers, but for economic reasons they often stop at the determination of TSH.

Radioimmune and enzyme immunoassay (immunofluorescent) methods of screening diagnostics are used. Their sensitivity and specificity are about the same. The ELISA method is preferable for technical reasons. Thyroxine and TSH are determined in blood samples

newborns dried on special filter paper (see above).

At a positive result the diagnosis must be confirmed by an endocrinologist in a clinical setting and the result of a laboratory analysis of blood serum for thyroxine, TSH and other hormones.

Replacement therapy with levothyroxine sodium (L-thyroxine  ) should be started in children with a positive screening test before the diagnosis is finally confirmed. The effectiveness of therapy is quite high, but treatment started after the 2nd month of life is ineffective, although by this age the disease is clinically manifested only in 4% of patients. This makes early diagnosis especially important.

Congenital adrenal hyperplasia

This clinical form combines 9 hereditary disorders of enzymatic processes in three interrelated metabolic pathways of steroidogenesis. The most common deficiency of 21-hydroxylase, on the basis of which the methods of screening diagnostics in newborns have been developed. These methods reveal a biochemical marker of the disease - an increase in the content of 17-α-hydroxyprogesterone in the blood. Radioimmune and enzyme immunoassay methods have been developed to clearly detect elevated levels of 17-α-hydroxyprogesterone. The sensitivity of both methods is quite high, but for technical reasons, the ELISA method is preferable.

Clinical diagnosis requires laboratory confirmation.

Treatment is hormone replacement therapy, usually successful.

Galactosemia

In Russia, since 2006, screening for galactosemia has been carried out. This disease is a consequence of mutations in enzymes involved in the metabolism of galactose. Due to the insufficiency of these enzymes, toxic metabolites (galactose and galactose-1-phosphate) accumulate in the body, which negatively affect internal organs(liver, brain, kidneys, intestines). In addition, galactosemia is characterized by inhibition of leukocyte activity, which most often leads to sepsis. The disease manifests itself in the 1st-2nd week of life. Children without treatment live no longer than six months.

Screening of newborns is carried out on the 4th-5th day in full-term babies and on the 7th day in premature babies. It is important that the child is breastfed or fed with galactose-containing mixtures.

There are several approaches to detecting galactosemia. In our country, the level of metabolites and galactose in the serum of newborns is assessed using tandem mass spectrometry. At a galactose level of >7 mg% in the serum of a newborn, the test is repeated, at a level of >10 mg%, it is considered positive. At the same time, enzyme analysis is carried out by the fluorometric method. The main advantage of enzyme analysis is the ability to detect deficiencies, regardless of the nature of the diet. However, this method makes it possible to detect only homozygotes for the mutation of galactose-1-phosphate uridyltransferase (in the gene GALT), while heterozygotes and homozygotes for mutations in other enzymes (galactokinase and UDP-galactose-4-epimerase) may be missed.

The main disadvantage of biochemical screening of newborns for galactosemia is a large number of false positive results. This is due to the fact that the conditions of obtaining, transporting and storing the material (temperature, humidity) can lead to a decrease in the activity of the enzyme.

The diagnosis is confirmed by molecular genetic methods. More than 180 different mutations have already been found in the gene galt, but the most common are Q188R and K285N. Together, they account for about 70% of cases of the classical form of galactosemia. The N314D mutation in the same gene has also been described, leading to Duarte's galactosemia. This type of galactosemia is characterized by a relatively mild course, the level of the enzyme decreases slightly, which leads to an erased clinic. Duarte's galactosemia can most often only be detected by screening.

Until now, the introduction of newborn screening for galactosemia is considered a controversial issue, since this disease does not meet all the WHO criteria for mass screening: the disease is rare, it can manifest even before the results of screening, treatment does not always completely stop all symptoms. Therefore, recently more and more often they talk about selective screening for galactosemia, including metabolic studies together with molecular genetic studies in risk groups. This is how false positives can be ruled out.

screening results and determine the type of galactosemia, which will significantly increase the effectiveness of treatment.

Treatment of galactosemia involves the exclusion of galactose from the diet. This allows you to reduce and prevent the development of complications from the internal organs. However, early initiation of treatment does not affect the occurrence of long-term effects. Patients with galactosemia often have delayed mental and speech development, develop endocrinological and neurological disorders, and deviations from the genital organs. You can learn more about galactosemia in the article by E.Yu. Zakharova et al. "Galctosemia type I: clinical manifestations, diagnosis and treatment" on CD.

cystic fibrosis

Neonatal screening for cystic fibrosis is based on a significant increase in the concentration of immunoreactive trypsin in the blood of newborns suffering from this disease. The CF screening protocol includes 4 steps.

Primary test for immunoreactive trypsin. If the level of immunoreactive trypsin is greater than or equal to 70 ng/ml, then the 2nd stage is carried out.

Retest for immunoreactive trypsin is carried out on the 21-28th day. If the level of immunoreactive trypsin is greater than or equal to 40 ng/ml, then proceed to the 3rd stage.

Sweat test - determination of chlorides in sweat by a biochemical method. If the chloride content is 60-80 mmol/l (boundary result), then the 4th stage is carried out. If more than 80 mmol / l, then the screening for cystic fibrosis is considered positive.

DNA diagnostics (molecular genetic examination is performed if the sweat test has questionable results or at the request of the parents).

Molecular genetic confirmation is available only in some regions of Russia, so the key screening step is a sweat test, which is usually done twice.

Early treatment and rehabilitation measures, including enzyme replacement therapy, lead to an improvement in the nutritional status, which leads to an improvement in the condition and a slowdown in irreversible processes in the bronchopulmonary system, and therefore, determines a higher life expectancy. Early

identification of patients with cystic fibrosis contributes to the prevention of this disease through prenatal diagnosis.

So, it is possible to prevent the clinical manifestations of hereditary pathology by prophylactic treatment of the disease at the presymptomatic stage. The progress of molecular and clinical medicine allows us to go further along the path of normocopying pathological genetic conditions. Methods are already being developed prenatal treatment(see table. 11.3), and there is experience in the treatment of methylmalonic aciduria in utero with large doses of vitamin B 12 . Carboxylase deficiency is treated prenatally with biotin. Treatment with dexamethasone for congenital 21-hydroxylase deficiency can be started from the 9th week of pregnancy if prenatal diagnosis has been made. Women with phenylketonuria who are heterozygous for the phenylketonuria gene are recommended a diet low in phenylalanine during pregnancy.

Recently developing preconception prevention hypothesis. The period of such prevention includes several months before conception and early development of the embryo. It is assumed that the preparation of a woman's body (a complete fortified diet, antioxidant therapy, immunity correction, absence of stress) before conception and in the early stages of embryonic development (up to the 10th week) helps to reduce the frequency of congenital malformations of a multifactorial nature. This is especially clearly shown for neural tube anomalies (various types of spinal hernias) and congenital heart defects. The frequency of re-birth of a child with such a defect is on average 4.6%, and in women who took folic acid and vitamin C, - 0.7%.

KEY WORDS AND CONCEPTS

Genetic engineering and primary prevention

Load of hereditary pathology (medical consequences)

Laboratory prenatal diagnostics

Medical genetic counseling

Methods of prenatal diagnosis

Methods of screening prenatal diagnosis

Primary, secondary and tertiary prevention of hereditary diseases

Preconception prophylaxis Indications for prenatal diagnosis Preimplantation diagnosis Prenatal treatment Prenatal health prognosis

Screening programs for the diagnosis of metabolic diseases for newborns

Preventive treatment Teratanasia

Ultrasound diagnosis of congenital malformations Phenotypic correction Functions of a geneticist

Lavrov A.V. Fetal cells and free fetal DNA in maternal blood in non-invasive prenatal diagnostics // Medical genetics. - 2009. - T. 8. - No. 7. - S. 3-8.

Prenatal diagnosis of hereditary and congenital diseases / ed. E.K. Ailamazyan, V.S. Baranov. - M.: MEDpressinform, 2006. - 416 p.

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 directions have to deal with the treatment of such diseases, although it is not always possible to determine genetic features one or another disease is possible in clinical conditions. And this is understandable, because diagnosing pathologies hereditary type It's not always that easy, it's 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, volume are measured chest and other patient related information. 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 set out 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.

The most common and effective approach to the prevention of hereditary diseases is a medical genetic consultation. From the point of view of healthcare organization, medical genetic counseling is one of the types of specialized medical care. The essence of counseling is as follows: 1) determining the prognosis for the birth of a child with a hereditary disease; 2) explaining the likelihood of this event to the consultants; 3) assistance to the family in making a decision.

With a high probability of the birth of a sick child, two recommendations can be correct from a preventive point of view: either abstinence from childbearing, or prenatal diagnosis, if it is possible with this nosological form.

The first cabinet for medical genetic counseling was organized in 1941 by J. Neil at the University of Michigan (USA). Moreover, back in the late 50s, the largest Soviet geneticist and neuropathologist S. K. Davidenkov organized a medical genetic consultation at the Institute of Neuro-Psychiatric Prevention in Moscow. Currently, there are about a thousand genetic consultations worldwide.

The main reason that makes people turn to a geneticist is the desire to know the prognosis of the health of future offspring regarding hereditary pathology. As a rule, families with a child with a hereditary or congenital disease(retrospective counseling) or its appearance is expected (prospective counseling) due to the presence of hereditary diseases in relatives, consanguineous marriage, age of parents (over 35-40 years), radiation exposure and other reasons.

The effectiveness of the consultation depends mainly on three factors: the accuracy of the diagnosis, the accuracy of the calculation of the genetic risk, and the level of understanding of the genetic conclusion by the counselors. Essentially, these are three stages of counseling.

The first stage of counseling always begins with a clarification of the diagnosis of a hereditary disease. An accurate diagnosis is a prerequisite for any consultation. It depends on the thoroughness of clinical and genealogical research, on knowledge of the latest data on hereditary pathology, on special studies (cytogenic, biochemical, electrophysiological, gene linkage, etc.).

Genealogical research is one of the main methods in the practice of medical genetic counseling. All studies must be supported by documentation. Information is obtained from at least three generations of relatives in ascending and lateral lines, and data must be obtained on all family members, including those who died early.

In the course of genealogical research, it may be necessary to refer the object or its relatives for additional clinical examination in order to clarify the diagnosis.

The need for constant acquaintance with the new literature on hereditary pathology and genetics is dictated by diagnostic needs (several hundred new genetic variations, including anomalies, are discovered annually) and preventive ones in order to select the most modern methods prenatal diagnosis or treatment.

Cytogenetic examination is used in at least half of the consulted cases. This is due to the assessment of the prognosis of offspring with an established diagnosis of a chromosomal disease and to clarify the diagnosis in unclear cases with congenital malformations.

Biochemical, immunological and other clinical methods are not specific to genetic counseling, but are used as widely as in the diagnosis of non-hereditary diseases.

The second stage of counseling is the determination of the prognosis of the offspring. Genetic risk is determined in two ways: 1) by theoretical calculations based on genetic patterns using methods of genetic analysis and variation statistics; 2) using empirical data for multifactorial and chromosomal diseases, as well as for diseases with an unclear mechanism of genetic determination. In some cases, both principles are combined, that is, theoretical corrections are made to the empirical data. The essence of genetic prognosis is to assess the likelihood of a hereditary pathology in future or already born children. Consulting on the prognosis of the offspring, as mentioned above, is of two types: prospective and retrospective.

Prospective counseling is the most effective type of prevention of hereditary diseases, when the risk of having a sick child is determined before the onset of pregnancy or in its early stages. Most often, such consultations are held in the following cases: in the presence of consanguinity of the spouses; when cases of hereditary pathology have occurred along the line of a husband or wife; when one of the spouses is exposed to harmful environmental factors shortly before the onset of pregnancy or in its first weeks (therapeutic or diagnostic exposure, severe infections, etc.)

Retrospective counseling is counseling after the birth of a sick child in the family regarding the health of future children. This is the most common causes consultation requests.

Methodically, the prognosis of offspring in diseases with different types of inheritance differs. If for monogenic (Mendelian) diseases the theoretical foundations for assessing genetic risk are quite clearly developed, then for polygenic diseases, and even more so multifactorial ones, counseling is often based on pure empiricism, reflecting the insufficient genetic knowledge of this pathology.

In mendelian diseases, the task is mainly to laboratory identification or probabilistic assessment in counselors of a certain discrete genotype underlying the disease.

In non-Mendelian diseases, it is currently impossible to isolate specific and discrete pathological genotypes that determine the development of the disease, since many genetic and environmental factors that are nonspecific in their effects can participate in its formation, i.e., the same effect (disease) can be caused different genes and/or environmental factors. This creates numerous difficulties in the genetic analysis of non-Mendelian traits and diseases.

The third stage of counseling is the final one. After making a diagnosis in an object, examining relatives, solving a genetic problem to determine the genetic risk, the geneticist explains to the family in an accessible form the meaning of the genetic risk or the essence of prenatal diagnosis and helps her in making a decision.

It is customary to consider the specific genetic risk up to 5% low, up to 10% - increased in mild degree, up to 20% - medium and above 20% - high. It is possible to neglect the risk, which does not go beyond the increased to a mild degree, and not consider it a contraindication to further childbearing. Only a moderate genetic risk is regarded as a contraindication to conception or as an indication for the termination of an existing pregnancy if the family does not want to be at risk.

From a social point of view, the goal of genetic counseling in general is to reduce the frequency of pathological genes in human populations, and the goal of a specific consultation is to help the family decide on the possibility of childbearing. With the widespread introduction of genetic counseling, some reduction in the frequency of hereditary diseases, as well as mortality, especially among children, can be achieved. However, the reduction in the frequency of severe dominant diseases in populations as a result of medical genetic counseling will not be significant, because 80-90% of them are new mutations.

The effectiveness of medical genetic counseling depends on the extent to which the counselors understand the information they have received. It also depends on the nature of the legal laws in the country relating to termination of pregnancy, welfare of the sick, etc.