Diseases belonging to the group of multifactorial conditioned. Multifactorial diseases of the nervous system

Introduction

The objectivity of the genetic classification of diseases is growing as the progress of molecular genetics and cytogenetics in the detection of defective genes that cause specific diseases. This applies to both hereditary diseases proper ( Mendelian, or monogenic), and multifactorial (multifactorial) diseases (MFD), in the occurrence and development of which both genetic and environmental factors are significant. However, until now the proportion of diseases that depend on known specific "pathological" genes remains very small. In the catalog of human hereditary traits for 1992, the chromosomal localization of genes and their primary products are indicated only for 322 of the 5710 described traits (that is, in only 5.6% of cases), and for 2.5 thousand cases only localization is indicated. The possible number of human hereditary diseases is much larger and amounts to 50 - 100 thousand. It is impossible to identify all such diseases and chromosomal syndromes, since violations of the structure of many proteins are incompatible with life and lead to early intrauterine death of the fetus; now more than 3,000 of them are known.

Thus, our knowledge of the molecular genetic basis of human diseases still concerns a relatively small number of them. At the same time, examples are known in clinical genetics that show the exceptional importance of this knowledge for diagnosis, early detection, effective treatment and prevention of specific hereditary diseases. Modern achievements in molecular genetics, or rather the “methodological revolution” of the 1970s, made it possible to isolate individual genes, chemical analysis of DNA nucleotide sequences, and functional study of gene expression and the molecular mechanisms of its regulation. All this created the prerequisites for the formation of new areas of applied molecular genetics - anatomy and pathological anatomy of the human genome, which are directly related to the problems of medicine. These areas are being developed most consistently within the framework of the Human Genome Project. The project operates in many countries and has proved its viability and effectiveness. It paves the way for the biology of the 21st century.

Multifactorial diseases

At the heart of monogenic (Mendelian) diseases are mutations of individual genes (dominant and recessive). Changes in the structure and number of chromosomes lead to chromosomal diseases. However, in many cases, human birth defects result from simultaneous appearance complex of different mutations. These are the already mentioned multifactorial diseases (MFD), or polygenic diseases. Multifactorial (polygenic) inheritance is responsible for many congenital malformations. MDs also include such widespread diseases as diabetes mellitus, hypertension, coronary disease, bronchial asthma, etc. They are the result of a complex interaction of many genetic and environmental factors.

(hereditarily predisposed, multifactorial, complex genetic disorders) is a large and nosologically diverse group of diseases, the development of which is determined by the interaction of certain hereditary factors (mutations or combinations of alleles) and environmental factors. The etiology and pathogenesis of these diseases are complex, multi-stage and in many ways still unclear and, of course, different for each disease.

Diseases with a hereditary predisposition occur in individuals with the corresponding genotype (a combination of "predisposing" alleles) with the provocative action of environmental factors,

With a certain degree of conditionality, multifactorial diseases can be divided into:

1) congenital malformations,

2) common mental and nervous diseases,

3) common diseases of "middle" age.

Congenital malformations of a multifactorial nature - cleft lip and palate, spinal hernia, pyloric stenosis, anencephaly and craniocerebral hernia, hip dislocation, hydrocephalus, hypospadias, clubfoot.

Bronchial asthma

Prevalence - from 4 to 8% among the general population, in the children's population - up to 10%.

Bronchial asthma is a disease based on chronic allergic inflammation of the bronchi, accompanied by their hyperreactivity and intermittent attacks of shortness of breath or suffocation as a result of widespread bronchial obstruction caused by bronchoconstriction, mucus hypersecretion, swelling of the bronchial wall.

The main predisposing factors - atopy and bronchial hyperreactivity - are genetically determined. Recent evidence suggests that three sets of traits (specific IgE level, total IgE level, and the presence of bronchial hyperreactivity) are inherited independently of each other. The genes that determine the production of specific IgE are localized on the short arm of chromosome 11 (11q13) and are associated with HLA class II alleles. The control of the basal level of total IgE is carried out by the gene cluster of the long arm of chromosome 5 (5q31.1). Bronchial hyperreactivity is associated with genetic markers of the same segment (5q31.1-q33). The same site contains genes for interleukins (IL-4, IL-9, etc.), which activate mast cells, the gene encoding the 2-adrenergic receptor.

Each of the genetic predisposition factors increases the likelihood of asthma, and their combination leads to a high risk of the disease with minimal involvement of environmental factors. The most significant of them are the pathological course of the prenatal period, prematurity, poor nutrition, pollutants and tobacco smoke, SARS.

Often AD is combined with atopic dermatitis, the main predisposing factor of which is also atopy. The risk of developing atopic disease in children (regardless of form) is 60-80% if both parents are sick and / or have a burdened heredity; up to 50% and above - on the mother's side; 25-30% - on the father's side.

peptic ulcer

Peptic ulcer is a chronic relapsing disease characterized by the formation of a stomach ulcer or duodenum due to a violation of the general and local mechanisms of the nervous and humoral regulation of the main functions of the gastroduodenal system and trophism, as well as the development of mucosal proteolysis.

From a genetic point of view, peptic ulcer can be divided into four main groups:

1. Peptic ulcer in general as a disease with a hereditary predisposition characteristic of multifactorial inheritance.

2. Peptic ulcer, which fits into a monogenic (usually autosomal dominant) type of inheritance.

3. Peptic ulcer as one of clinical manifestations several hereditary syndromes.

4. Ulcerative lesions of the gastroduodenal system in some somatic diseases.

Diabetes

Diabetes mellitus is a disease that is heterogeneous in nature, the etiology and pathogenesis of which involve both internal (genetic, immune) and external ( viral infections, intoxication), factors, the interaction of which leads to a violation of carbohydrate metabolism.

The role of genetic factors in the development of diabetes mellitus:

1. Diabetes mellitus, as well as impaired glucose tolerance, is a constant component of approximately 45 hereditary syndromes.

2. Various clinical manifestations and prevalence of diabetes mellitus in ethnic groups are not always explained only by differences in environmental conditions.

3. Among the sick diabetes There are groups of people with different dependence on insulin.

4. There is diabetes mellitus in adults, which is inherited monogenously in an autosomal dominant manner.

5. Various types of diabetes mellitus can be modeled on experimental animals.

The development of diabetes is affected by a mutation in one or more genes. Formation of a pathological phenotype, i.e. the development of clinical manifestations of diabetes mellitus in the presence of a hereditary predisposition occurs with the mandatory participation of environmental factors. In the etiology of diabetes mellitus, various stress factors, infections, injuries, and operations are of great importance. For insulin-dependent diabetes mellitus, certain viral infections (rubella, chicken pox, epidemic parotitis, coxsackie virus, epidemic hepatitis), toxic substances. For non-insulin-dependent diabetes mellitus, the risk factors are overweight, heredity burdened by diabetes, atherosclerosis, arterial hypertension, dyslipoproteinemia, decreased physical activity, and unbalanced nutrition.

High risk groups for diabetes:

1. Monozygotic twin of a patient with diabetes mellitus;

2. A person in whom one or both parents are sick or had diabetes;

3. A woman who gave birth to a child weighing more than 4.5 kg, as well as a dead child with hyperplasia of the pancreatic islet apparatus.

Irrational drug therapy is one of the most important risk factors for the development of diabetes.

Drugs acting on carbohydrate metabolism: adrenaline, chlorpromazine, caffeine, salbutamol, surosemide, corticosteroids, thyroxine, growth hormone, ACTH, dopegit, clonidine, trental, PASK, salicylates, butadione, sulfonamides.

Hereditary syndromes accompanied by impaired glucose tolerance or insulin resistance:

Genetic: Louis Bar syndrome, cystic fibrosis, Fanconi anemia, glucose-6-phosphate dehydrogenase deficiency, type I glycogenosis, gout, hemochromatosis, Huntington's chorea, Lawrence-Moon-Barde-Biedl syndrome, Prader-Willi syndrome.

Chromosomal: Down syndrome, Klinefelter syndrome, Shereshevsky-Turner syndrome.

Given the various mechanisms that affect the development and course of the disease, it is not possible to trace clear patterns of transmission of the disease from generation to generation. The analysis of pedigrees in multifactorial diseases is not based on Mendel's laws, as with monogenic traits, but on empirically obtained data. As a result of long-term observations, the following features were identified that are characteristic of this form of pathology.

1. The probability of manifestation of the disease depends on the degree of relationship with the affected family member, since this determines the number of common genes (see Table 1).
2. The number of sick relatives determines the prognosis for the proband (Fig. 14). For example, in diabetes mellitus, the risk for proband siblings, depending on the number of sick relatives, will be as follows:
   • if the parents are healthy, the probability is 5-10%;
   • if one of the parents is sick, the risk is 10-20%;
   • if both parents are sick, the risk rises to 40%. The risk for the children of the proband, depending on the susceptibility of his parents, will be either 10% or 20% (Fig. 15).
3. The genetic prognosis depends on the severity of the disease of the affected relative, since the severity in multifactorial diseases is determined by the total action of several genes. Thus, a person who has received 4 genes on which arterial hypertension depends will have more severe form diseases and, of course, a greater likelihood of transmitting a pathological gene to offspring.
4. The degree of hereditary burden for a proband increases if its sick parent belongs to a rarely affected sex. For example, in the case of peptic ulcer of the stomach and duodenum in each family burdened with this disease, the probability of gene transfer to offspring is the same. However, the probability of getting sick is always greater for males and if female relatives of the proband are affected. In the pedigree shown in Fig. 16, the risk for children of the proband to develop duodenal ulcer increases as a result of two factors: a) they are both males (peptic ulcer refers to diseases with a predominant lesion only of males) and b) the mother of the proband suffers from peptic ulcer, i.e. in this case, the affected parent belongs to the less frequently affected sex.

Thus, we note that the variety of types of hereditary transmission of traits fully demonstrates the complexity of establishing the type of inheritance. A practitioner who does not have the skills in compiling and analyzing a pedigree should not take the liberty of making a final conclusion. He should refer the patient and his relatives for medical genetic counseling. At the same time, it should be emphasized that for a general practitioner, the most elementary use of the clinical genealogical method (but no less effective) can be a full-fledged collection of data from a seemingly well-known family history. Meanwhile, even today, many doctors underestimate the importance of a family history, do not have a clear idea of ​​what to ask the subject, how to evaluate the information received and why it is needed. Therefore, if a doctor collects family history data, he often confines himself to individual random questions, noting, for example, that there were cases of pneumonia, tuberculosis, and diabetes among relatives, leaving the information received without further analysis and evaluation.

All this is of particular importance at the present time, when the task of ensuring the general medical examination of the population has been set before the Soviet public health service. During clinical examination, diseases penetrating in adulthood and old age are of particular interest. In these cases, an analysis of the family history may prompt the doctor to need a detailed clinical or biochemical study in order to detect early symptoms (preclinical stage) of a hereditary pathology not only in a particular individual, but also in his relatives. That is why the anamnesis should contain information that allows assessing the risk of disease for healthy members of a hereditarily burdened family. This risk may be due to varying degrees of predisposition, late penetration, or low expressivity of the genotype.

Let us dwell on the minimum of questions that the doctor should ask the subject (the patient or during a medical examination).

During the medical examination, the majority of the examined are people who do not present any complaints. Therefore, the doctor must first of all, observing the principles of deontology, explain to the subject that the purpose of the questions is to clarify the predisposition of his family members to diseases of certain systems and organs in order to prevent the possibility of their development. Here is a sample list of questions.

First, the doctor should ask the individual what chronic diseases his relatives (parents, brothers, sisters, uncles, aunts, nephews, etc.) suffered from. If a person cannot accurately name diseases, he may know the profile of clinics (or hospital departments) in which his relatives were treated, or the main symptoms of diseases. The usual answer is to list diseases of the elderly and senile age, and even then contains some useful information. However, the collection of anamnestic data should not be limited to information about diseases of the elderly. Equally important, and sometimes even more important, are data on diseases of relatives in adulthood, youth and childhood, including congenital physical and mental anomalies. Information about the causes of death of relatives (heart attack, stroke, malignant tumor, trauma, tuberculosis, diabetes, etc.) and their age at the time of death (young, elderly, old) can also be significant. Women are, as a rule, aware of spontaneous abortions and stillbirths of their relatives, of certain malformations in their children, which is also important. Further, it should be clarified whether the cases of diseases detected in the family were single (sporadic) or they were repeated in other relatives. In this case, it is necessary to indicate the degree of relationship with the subject (father, mother, sister, uncle, nephew, etc.).

The recurrence of the disease in the family may also be due to unfavorable external factors, the role of which must be confirmed or excluded. So, when relatives work in the same production, occupational hazards can be the cause of their illness. Medicinal effects on the fetus, as well as a number of infectious agents (especially on early stages development), can cause malformations that copy hereditary pathology - phenocopies. It is imperative to get answers to some specific "genetic" questions: about the consanguinity of the proband's parents or their origin from the same locality, the approximate sex ratio among sick relatives, etc. This will allow us to assume with a certain probability the type of inheritance of this pathology in the family being examined.

Let's move on to the features of collecting family history data from patients, the analysis of which in the future should also contribute to the characterization of the general genetic background in the family, the identification of other diseases and predisposition to them among relatives. These features primarily include the ability to communicate with the relatives of the patient themselves, which allows you to significantly clarify the information received from him. This is especially important in those cases when, guided by certain considerations, patients try to hide from the doctor the information known to them. The second feature is the possibility of conducting a survey of those relatives for whom a high risk of developing a particular disease has been established. For example, when a violation of glucose tolerance is detected in relatives of a patient with diabetes mellitus, it is advisable to conduct appropriate preventive actions without waiting for the clinical manifestation of the disease.

Only a geneticist can quantify the risk, using an arsenal of genetic techniques for this purpose, including drawing up pedigrees and determining the type of inheritance. But every doctor should be able to qualitatively assess the risk as significant, moderate or small for the relatives of the patient or the person undergoing medical examination.

An objective indicator of the risk of having a pathological gene can be the degree of relationship with the patient or patients in the family. The first degree of kinship includes the parents, brothers and sisters of the subject. In hereditary diseases associated with a defect in one gene (monogenic), in this case, the probability of having a pathological gene is 1/2 (50%). The second degree of kinship includes the grandfather (grandmother) of the subject, his uncles and aunts. In this case, the probability of having a pathological gene is 1/4 (25%). With the III degree of kinship (cousins) the probability is 1/8 (13%). The risk should be considered significant in case of illness of relatives of the I and II degree of kinship. If there are cases of the disease among relatives of the third degree of kinship, the risk can be considered as moderate. Single, sporadic cases of the disease among relatives of IV and more distant degrees of kinship indicate a low degree of risk.

With multifactorial diseases, the theoretical calculation of risk is impossible, since both the pathology itself and the possibility of its manifestation are due to the complex interaction of many genes and environmental factors. However, here again, the degree of relationship with patients and repeated cases of pathology in the family are of great importance. For example, in schizophrenia, if one of the parents is ill, the probability of the patient being ill is 8-12%, and if both parents are ill, 40%.

What kind practical implications the doctor can and should do by collecting and evaluating family history data.

If the risk of predisposition to family pathology is assessed as small, the doctor may recognize the anamnesis as favorable. But if the risk is assessed as moderate and even more so as significant, this indicates the need for diagnostic and preventive measures. When identified, these individuals, even if they are quite healthy, should be assigned to a high-risk group, registered and further under regular medical supervision. Particular attention should be paid to prophylaxis, which should be carried out in people who do not yet have clinical manifestations of the disease, but are "threatened" for this disease, for example, when the main "risk factors" are found. coronary disease hearts in relatives of the I degree of kinship of the proband with this pathology; in persons with high levels of uric acid in family members who have a patient with gout, etc. Identification of persons "threatened" for various hereditary diseases is carried out during preventive examinations of the population, in population studies as a result of total and selective screening. However, the use of the clinical and genealogical method will allow solving this problem more effectively. At the same time, it is advisable, depending on the type of possible hereditary pathology, to attribute people to certain risk groups (for monogenic and chromosomal diseases, for diseases with a hereditary predisposition).

RISK GROUP FOR CHROMOSOMAL PATHOLOGY

A child is at risk for chromosomal diseases when:

• mother's age is more than 36 years; her risk of having a child with Down syndrome is almost 40 times higher than that of a 20-year-old woman;
• there are children with chromosomal diseases in the family;
• the mother has a burdened obstetric and family history (miscarriages, stillbirths, children with multiple malformations, with an undetermined diagnosis, especially if the mother has microanomalies or congenital malformations, which may be a sign of mosaicism with chromosomal aberration);
• the mother (father) has chromosomal mosaicism or chromosomal aberration, previously established;
• parents were in contact with mutagenic factors.

RISK GROUP IN MONOGENIC DISEASES

A child is at risk of a genetic pathology if the parents, siblings or other relatives are diagnosed with a hereditary disease.

The risk group includes persons who, due to their close relationship with the proband, have an increased risk of heterozygous carriage of the mutant gene. So, parents and children of homozygotes for the recessive gene will be heterozygous. For example, in phenylketonuria, the patient's parents and future children are heterozygous carriers of this gene. In dominant diseases with incomplete penetrance, carriers of the pathological gene are all persons who have sick children and sick parents at the same time.

In diseases linked to chromosome X, all the daughters of the patient (for example, with hemophilia) and all the mothers of patients become heterozygous "conductors".

In the case of determining heterozygosity by the clinical genealogical method, other methods are not used, and carriers of the pathological gene must be registered. If heterozygosity is probabilistic based on genealogical analysis (for example, the sister of an individual with an X-linked recessive disease), clinical and paraclinical methods should be used (Fig. 17). If possible heterozygous carriers marry, then the likelihood of heterozygosity of the future spouse should be determined and the family should be informed of the results of the genetic risk calculation. Possible heterozygous carriers are also advised to avoid consanguineous marriages, as this increases the risk of having an affected child.

RISK GROUP FOR MULTIFACTORIAL DISEASES

In case of multifactorial diseases, individuals should be included in the high-risk group, taking into account the magnitude of hereditary burden, which depends on the severity of the disease, the degree of relationship with the patient and the number of patients in the family.

Identification of risk groups using the genealogical method will effectively carry out early treatment and prevention measures for individuals genetically predisposed to various diseases. So, in the presence of hypertension in one of the parents, it is necessary to control the blood pressure of the child, recommend a sparing regimen. In these families, it is necessary to promote as early as possible and constantly go in for sports, observe the regime of work and rest, and limit the consumption of table salt. If such habits are developed from childhood, they can have a preventive effect. The local doctor should have close contact with the patient's family, and, apparently, the "family" approach to disease prevention should be started by him. At the first fix high blood pressure persons with burdened heredity should be taken to the dispensary.

Particular attention should be paid to families whose members are predisposed to diseases such as diabetes mellitus, epilepsy, schizophrenia, peptic ulcer disease, hypertension, etc. So, if one of the parents is sick, then the risk of having a child with diabetes is 10% . Therefore, there is a real risk of development this disease. Members of such families must be registered with the dispensary, periodically conduct preventive examinations using additional methods.

Therapeutic and preventive measures can be divided into two groups:

1. prophylaxis for persons without clinical manifestations of the disease, but with genetic risk factors, aimed at preventing the development of pathology (risk group based on family background);
2. genetic prophylaxis - prevention of cases of recurrent diseases in families.

Genetic prophylaxis is carried out by doctors of the medical genetic consultation and is aimed at preventing the birth of a sick child. Most effective method genetic prevention is the prenatal diagnosis of hereditary diseases. Currently, it is possible for all chromosomal diseases, X-linked diseases, and for some hereditary fermentopathies. If prenatal diagnosis is not possible, a genetic risk calculation is performed.

Medico-genetic counseling for multifactorial diseases is often not aimed at preventing the birth of sick children, but at preventing the disease in persons "threatened" by this disease.

Genetic diseases are called heterogeneous in clinical manifestations of a group of diseases that occur under the influence of mutations at the gene level. A group of diseases that arise and develop against the background of a defect in the hereditary apparatus of cells and the influence of adverse environmental factors should be considered separately.

What are multifactorial hereditary diseases

Specifically, this group of diseases has one clear difference from gene diseases. Multifactorial diseases begin to manifest themselves in unfavorable environments. Some scientists suggest that a genetic predisposition may never manifest itself unless environmental factors arise.

The etiology and genetics of multifactorial diseases is very complex, the origin has a multi-stage structure and may be different in the case of each specific disease.

Varieties of multifactorial pathologies

Conditionally multifactorial can be divided into:

• native malformations;
• mental and nervous diseases;
• age-related diseases.

Depending on the number of genes involved in pathology, there are:

• Monogenic diseases - have one mutant gene, which creates a person's predisposition to a particular disease. In order for the disease to begin to develop in this case, it will be necessary to influence one specific factor. environment. It can be physical, chemical, biological, or medicinal. If a specific factor has not arisen, even if the mutant gene is present, the disease will not develop. If a person does not have a pathogenic gene, but is exposed to an external environmental factor, the disease will not occur either.
• Polygenic hereditary diseases or multifactorial diseases are determined by pathologies in many genes. The action of multifactorial signs can be discontinuous or continuous. But any of the diseases can only arise through the interaction of many pathogenic genes and environmental factors. Normal human characteristics such as intelligence, height, weight, coloration skin, are continuous multifactorial features. Isolated (cleft lips and palate), congenital heart disease, neural tube defects, polyrostenosis, hypertension, peptic ulcer and some others have a higher incidence in close relatives than in the general population. Multifactorial diseases, examples of which are mentioned above, are "intermittent" multifactorial features.

MFZ diagnostics

Diagnosis of multifactorial diseases and the role of genetic inheritance help different kinds research. For example, a family study, thanks to which the concept of an “oncological family” appeared in the practice of doctors, that is, a situation where repeated cases of malignant diseases occur in relatives within the same pedigree.

Doctors often resort to the study of twins. This method, like no other, allows you to operate with reliable data on the hereditary nature of the disease.

Studying multifactorial diseases, scientists pay a lot of attention to the study of the relationship between the disease and the genetic system, as well as to the analysis of the pedigree.

IHF-Specific Criteria

• The degree of relationship directly affects the likelihood of manifestation of the disease in relatives, that is, the closer the relative is to the patient (in genetic terms), the greater the likelihood of the disease.
• The number of patients in the family affects the risk of the disease in relatives of the patient.
• The severity of the disease of the affected relative affects the genetic prognosis.

Diseases related to multifactorial

Multifactorial diseases include:

Bronchial asthma is a disease based on chronic allergic inflammation of the bronchi. It is accompanied by hyperactivity of the lungs and the periodic occurrence of attacks of shortness of breath or suffocation.

Peptic ulcer, which is a chronic relapsing disease. It is characterized by the formation of ulcers in the stomach and duodenum due to disturbances in the general and local mechanisms of the nervous and humoral systems.

Diabetes mellitus, in the process of occurrence of which both internal and external factors causing disturbances in carbohydrate metabolism. The occurrence of the disease is strongly influenced by stress factors, infections, injuries, operations. Risk factors can be viral infections, toxic substances, overweight, atherosclerosis, decreased physical activity.

Hearts are the result of a shortened or total absence myocardial blood supply. This happens due to pathological processes in the coronary vessels.

Prevention of multifactorial diseases

Types of prophylaxis that prevent the occurrence and development of hereditary and congenital diseases can be primary, secondary and tertiary.

The primary type of prevention is aimed at preventing the conception of a sick child. This can be realized in planning childbearing and improving the human environment.

Secondary prevention is aimed at terminating the pregnancy if the likelihood of the disease in the fetus is high or the diagnosis has already been established prenatally. The basis for making such a decision may be a hereditary disease. Occurs only with the consent of the woman in a timely manner.

The tertiary type of prevention of hereditary diseases is aimed at combating the development of the disease in an already born child and its severe manifestations. This type Prevention is also called normoping. What it is? This is the development of a healthy child with a pathogenic genotype. Normcopying with the appropriate medical complex can be done in utero or after birth.

Prevention and its organizational forms

Prevention of hereditary diseases is implemented in the following organizational forms:

1. Medical genetic counseling is a specialized health care. Today, one of the main types of prevention of hereditary and genetic diseases. For medical genetic counseling, contact:

• healthy parents who gave birth to a sick child, where one of the spouses has a disease;
• families with practically healthy children, but who have relatives with hereditary diseases;
• parents seeking to make a prognosis for the health of brothers or sisters of a sick child;
• pregnant women who have an increased risk of having a child with abnormal health.

2. Prenatal diagnosis is the prenatal determination of a congenital or hereditary pathology of the fetus. In general, all pregnant women should be examined to exclude hereditary pathology. For this, ultrasound examination, biochemical studies of the serum of pregnant women are used. Indications for prenatal diagnosis may be:

• the presence in the family of an accurately diagnosed hereditary disease;
• mother's age exceeding 35 years;
• previous spontaneous abortions in a woman, stillbirths with unclear causes.

Importance of prevention

Every year it improves and gives more and more opportunities to prevent most hereditary diseases. Each family with health problems is given full information about what they are at risk and what they can expect. Raising the genetic and biological awareness of the general population, promoting healthy lifestyle at all stages of human life, we increase the chances of humanity to have healthy offspring.

But at the same time, polluted water, air, food products with mutagenic and increase the prevalence of multifactorial diseases. If the achievements of genetics are applied in practical medicine, then the number of children born with hereditary genetic diseases will be reduced, early diagnosis and adequate treatment of patients will be available.

Multifactorial diseases (hereditarily predisposed, multifactorial, "Complex genetic disorders") are a large and nosologically diverse group of diseases, the development of which is determined by
the interaction of certain hereditary factors (mutations or combinations of alleles) and environmental factors. The etiology and pathogenesis of these diseases are complex, multi-stage and in many ways still unclear and, of course, different for each disease.
The wide genetic polymorphism of human populations ensures the genetic uniqueness of each individual, which is expressed not only in physical differences, abilities, character, but also in the body's reactions to pathogenic environmental factors.
Diseases with a hereditary predisposition occur in individuals with the corresponding genotype (a combination of "predisposing" alleles) with the provocative action of environmental factors. Hereditary predisposition to the disease can have a polygenic and monogenic basis. The relative role of genetic and environmental factors is different not only for a given disease, but also for each patient.
With a certain degree of conditionality, multifactorial diseases can be divided into:

1. congenital malformations, 2) common mental and nervous diseases,
2. common diseases of the "middle" age.

Congenital malformations of a multifactorial nature - cleft lip and palate, spinal hernia, pyloric stenosis, anencephaly and craniocerebral hernia, hip dislocation, hydrocephalus, hypospadias, clubfoot. The frequency data is given in the previous chapter.

Bronchial asthma
Prevalence - from 4 to 8% among the general population, in the children's population - up to 10%.
Bronchial asthma is a disease based on chronic allergic inflammation of the bronchi, accompanied by their hyperreactivity and intermittent attacks of shortness of breath or suffocation as a result of widespread bronchial obstruction caused by bronchoconstriction, mucus hypersecretion, swelling of the bronchial wall.
The main predisposing factors - atopy and bronchial hyperreactivity - are genetically determined. Recent evidence suggests that three sets of traits (specific IgE level, total IgE level, and the presence of bronchial hyperreactivity) are inherited independently of each other. Genes that predetermine the production of specific IgE are localized on the short arm of chromosome 11 (11q13) and are associated with HLA class II alleles. The control of the basal level of total IgE is carried out by the gene cluster of the long arm of chromosome 5 (5q31.1). Bronchial hyperreactivity is associated with genetic markers of the same segment (5q31.1-q33). The same site contains the genes for interleukins (IL-4, IL-9, etc.), which activate mast cells, and the gene encoding the 2-adrenergic receptor.
Each of the genetic predisposition factors increases the likelihood of asthma, and their combination leads to a high risk of the disease with minimal involvement of environmental factors. The most significant of them are the pathological course of the prenatal period, prematurity, poor nutrition, pollutants and tobacco smoke, SARS.
Often AD is combined with atopic dermatitis, the main predisposing factor of which is also atopy. The risk of developing atopic disease in children (regardless of form) is 60-80% if both parents are sick and / or have a burdened heredity; up to 50% and above - on the mother's side; 25-30% - on the father's side.
peptic ulcer
Peptic ulcer is a chronic relapsing disease characterized by the formation of a stomach or duodenal ulcer due to a violation of the general and local mechanisms of the nervous and humoral regulation of the main functions of the gastroduodenal system and trophism, as well as the development of mucosal proteolysis.
From a genetic point of view, peptic ulcer can be divided into four main groups:

1. Peptic ulcer disease in general as a disease with a hereditary predisposition characteristic of multifactorial inheritance.
2. Peptic ulcer that fits into a monogenic (usually autosomal dominant) type of inheritance.
3. Peptic ulcer as one of the clinical manifestations of several hereditary syndromes.
4. Ulcerative lesions of the gastroduodenal system in some somatic diseases.

Diabetes
Diabetes mellitus is a heterogeneous disease in nature, in the etiology and pathogenesis of which both internal (genetic, immune) and external (viral infections, intoxications) factors are involved, the interaction of which leads to a violation of carbohydrate metabolism.
The role of genetic factors in the development of diabetes mellitus:

1. Diabetes mellitus, as well as impaired glucose tolerance, is a constant component of approximately 45 hereditary syndromes.
2. Different clinical manifestations and prevalence of diabetes mellitus in ethnic groups are not always explained only by differences in environmental conditions.
3. Among patients with diabetes, there are groups of people with different dependence on insulin.
4. There is diabetes mellitus in adults, which is inherited monogenically in an autosomal dominant manner.
5. Various variants of diabetes mellitus can be modeled on experimental animals.
6. The development of diabetes is affected by a mutation in one or more genes. Formation of a pathological phenotype, i.e. the development of clinical manifestations of diabetes mellitus in the presence of a hereditary predisposition occurs with the mandatory participation of environmental factors. In the etiology of diabetes mellitus, various stress factors, infections, injuries, and operations are of great importance. For insulin-dependent diabetes mellitus, risk factors are some viral infections (rubella, chicken pox, mumps, coxsackie virus, epidemic hepatitis), toxic substances. For non-insulin-dependent diabetes mellitus, the risk factors are overweight, heredity burdened by diabetes, atherosclerosis, arterial hypertension, dyslipoproteinemia, decreased physical activity, and unbalanced nutrition.

High risk groups for diabetes:

1. Monozygotic twin of a diabetic patient;
2. A person in whom one or both parents are sick or had diabetes;
3. A woman who gave birth to a child weighing more than 4.5 kg, as well as a dead child with hyperplasia of the pancreatic islet apparatus.
4. Irrational drug therapy is one of the most important risk factors for the development of diabetes mellitus.

Drugs acting on carbohydrate metabolism: adrenaline, chlorpromazine, caffeine, salbutamol, surosemide, corticosteroids, thyroxine, growth hormone, ACTH, dopegit, clonidine, trental, PASK, salicylates, butadione, sulfonamides.
Hereditary syndromes accompanied by impaired glucose tolerance or insulin resistance:

• genetic: Louis Bar syndrome, cystic fibrosis, Fanconi anemia, glucose-6-phosphate dehydrogenase deficiency, type I glycogenosis, gout, hemochromatosis, Huntington's chorea, Lawrence-Moon-Barde-Biedl syndrome, Prader-Willi syndrome.
• chromosomal: Down syndrome, Klinefelter syndrome, Shereshevsky-Turner syndrome.

Ischemic heart disease (CHD)
IHD occurs as a result of a decrease or cessation of blood supply to the myocardium due to a pathological process in the coronary vessels. The main part of IHD is a multifactorial pathology characterized by the formation of the disease in the process of interaction of genetic and environmental factors that lead to the direct causes of IHD: I) spasm of the coronary arteries; 2) atherosclerosis coronary vessels. The main pathophysiological mechanism of coronary artery disease is a discrepancy between myocardial oxygen demand and the ability of coronary blood flow to satisfy them.
Genetically determined risk factors for coronary artery disease include:

• gender of the proband: in women, clinical manifestations occur 10-15 years later, this is due to hormonal differences and morphological features of the structure of the collateral vessels of the coronary arteries;
• body type: more cardiovascular diseases associated with atherosclerosis are found in individuals with a hypersthenic body type;
• personality traits: personality type “A” is described (energy, accelerated pace of work, desire to achieve goals, people are emotional, subject to stress factors), in which the frequency of coronary artery disease is observed 2 times more often than in type "B".
• a certain structure of the coronary vessels;
• elevated level total cholesterol in the blood; high blood levels of low and very low density lipoproteins (LDL and VLDL); low concentration of high density lipoproteins (HDL);
• low activity of LDL receptors;
• disorders in the blood coagulation system (increase in fibrinogen in the blood serum, hereditary deficiency of fibrinolytic activity);
• arterial hypertension;
• diabetes.

Monogenic forms of lipid metabolism disorders are described in Section 4. Phenocopies of hyperlipidemia associated with impaired lipid metabolism may be due to the action of such environmental factors as:

• smoking (mortality from coronary artery disease among smokers is 2-5 times higher than among non-smokers);
• physical inactivity (the risk of death from coronary artery disease in physically inactive people is 3 times higher);
• unbalanced diet; change in the mineral composition of water - long-term use of soft water, poor mineral salts(Ca, Mg, lithium, zinc);
• exposure to negative psychosocial factors;
• taking contraceptive steroids

This is a science that studies the role of heredity and variability in the occurrence of human diseases.

object is a person with a hereditary pathology.

Subject are all pathologies and their causes.

Tasks of medical genetics:

The study of hereditary variability: genomic, chromosomal and gene mutations and their role in causing human diseases

Study of the mechanisms of development and features of clinical manifestations of hereditarily determined diseases

Development of effective mechanisms for the correction of hereditary diseases

Prevention of hereditary diseases

1. Approaches to the classification of hereditary diseases.

Classification of human diseases

hereditary diseases

Genetic and etymological factor - mutations (gene and chromosomal)

The role of environmental factors - only in severity, affects the course of these diseases.

Phenylketonuria and Down syndrome (translocation mechanism)

Diseases with a hereditary arrangement of a monogenic type

The presence of a mutated gene.

Environmental factors are required for gene expression

Padagra (some forms) and diabetes

Multifactorial diseases

Several genes combined with environmental factors.

About 90% of all human diseases.

Diseases caused by the action of only environmental factors

Occur only under the influence of environmental factors, genetic factors can also influence the course (Injuries, burns, etc.)

1. General characteristics of genetic diseases.

Genetic diseases are a group of diseases that are heterogeneous in clinical manifestations and are caused by mutations at the gene level.

Frequency 1-2%

Peculiarities:

The etiological factor acts constantly;

The mutant gene is persistently passed on from generation to generation;

The pathogenesis of gene diseases can be due to: abnormal protein synthesis;

an excess of a gene product;

deficiency or absence of the product;

the amount of the product is sufficient, but its activity is impaired.

Phenylketonuria

Marfan syndrome

1. Types of inheritance of gene diseases. Examples.

Diseases with autosomal dominant inheritance are characterized by the fact that for their development it is enough to inherit the mutant allele from one parent. Most diseases of this type are characterized by such pathological conditions that do not cause serious damage to human health and in most cases do not affect his ability to have offspring. Diseases with autosomal recessive inheritance appear in individuals only in the homozygous state. Heterozygotes do not differ phenotypically (clinically) from healthy individuals with two normal alleles. Diseases with X-linked dominant inheritance. Features of the inheritance of these diseases are due to the fact that women have 2 X chromosomes, and men have 1 X chromosome. Therefore, a woman, having inherited a pathological allele from one of her parents, is heterozygous, and a man is hemizygous. Diseases with X-linked recessive inheritance are rare. At the same time, women are almost always heterozygous, i.e. are phenotypically normal (healthy) and are carriers. Only men are sick. The characteristic features of diseases of this type are different depending on the violation of reproduction. Y-linked inheritance type. For a long time it was believed that the Y chromosome contains only heterochromatic regions (without genes). The latest research has made it possible to detect and localize a number of genes on the Y chromosome, a gene that determines the development of the testicles, is responsible for spermatogenesis (azoospermia factor), controls the intensity of growth of the body, limbs and teeth, etc. Hairiness of the auricle is controlled by a gene located on the Y chromosome. On this sign, one can see the characteristic features of the Y-linked transmission type. The trait is passed on to all boys. Naturally, pathological mutations affecting testis formation or spermatogenesis cannot be inherited because these individuals are sterile. For mitochondrial inheritance the following signs are characteristic (it must be remembered that mitochondria are transmitted with the cytoplasm of oocytes; sperm do not have mitochondria, since the cytoplasm is eliminated during the maturation of male germ cells): the disease is transmitted only from the mother; both girls and boys are sick; sick fathers do not pass the disease on to their daughters or sons.