Monogenic diseases by organ system. Monogenic and polygenic diseases

We all know that along with acquired diseases, there are also congenital diseases caused by genetic disorders, in which a person is born already sick or is highly predisposed to developing this disease. Of all congenital diseases, monogenic diseases currently attract the most attention.

The increased interest in monogenically inherited diseases is caused by their huge diversity, despite their apparent rarity and, often, the severity of the disease, which sharply worsens the patient’s quality of life or is deadly.
Monogenic diseases are divided according to the type of inheritance:
autosomal dominant (that is, if at least one of the parents is sick, then the child will also be sick), for example
- Marfan syndrome, neurofibromatosis, achondroplasia
– autosomal recessive (a child can get sick if both parents are carriers of this disease, or one parent is sick, and the other is a carrier of gene mutations that cause it
disease)
– cystic fibrosis, spinal myoatrophy.
Close attention to this group of diseases is also due to the fact that, as it turns out, their number is much higher than previously thought. All diseases have completely different prevalence, which can vary depending on both geography and nationality, for example, Huntington's chorea occurs in 1 in 20,000 Europeans and is almost never found in Japan, Tay-Sachs disease is characteristic of Ashkenazi Jews and is extremely rare in other peoples.
In Russia, the most common monogenically inherited diseases are cystic fibrosis (1/12000 newborns), myoatrophy group (1/10000 newborns), hemophilia A (1/5000 newborn boys).
Of course, many monogenic diseases have been identified for a long time and are well known to medical geneticists.
Doctors of this specialty have a huge role to play in identifying families at risk of developing these diseases and tracking the transmission of diseases by inheritance.
Such couples are carefully examined in medical genetic centers, their “genetic tree” is compiled and the likelihood of having a sick child is determined.
The basis of such a “prediction” is the information content of the mutation pair, that is, the ability to determine which genes are changed. This is extremely important to know, because it is these mutations that can lead to the child being sick. Next, doctors expect parents from the risk group to be already pregnant and perform prenatal invasive diagnostics (chorionic villus biopsy) at 8-10 weeks of pregnancy. If the received material confirms the disease in the unborn child, then the pregnancy is terminated.
Despite its apparent simplicity, abortion is an operation that requires great skill from the doctor, because in this case the intervention is carried out at a fairly long stage of pregnancy, it is necessary not only to terminate the pregnancy, but also to prevent the development of complications that can significantly complicate the course postoperative period and cause harm to a woman’s health, lead to infertility or sharply reduce the likelihood of subsequent pregnancies. In addition, it is probably not worth mentioning how severe the psychological trauma of having to terminate a long-awaited pregnancy is.
Of course, in accordance with the classical laws of genetics on the transmission of monogenic diseases from generation to generation, the probability that the fetus will be sick is 25% for recessive inheritance, but, as life shows, cases of multiple abortions in the same couple are not uncommon , if both the second and third pregnancy ends up with a sick fetus.
At the same time, as the years go by, the chances of pregnancy become less and less, and with age, the likelihood of other genetic disorders increases, constant psychological stress also increases, the expectation of a subsequent pregnancy turns into the fear of a new “sick” pregnancy.

Monogenic diseases

A gene is a functionally indivisible unit of genetic material. This is a section of a DNA molecule that encodes the primary structure of a polypeptide. It is part of a genetic locus, which also includes introns separating exons and regulatory regions (promoters, enhancers).

Pretranscriptional stage - transcriptional stage - T-RNA processing - translational stage - posttranslational stage - abnormal cellular product or its absence - disturbance of neuroontogenesis.

A genotype is a set of genes of an organism that have a phenotypic manifestation

Gene properties:

Discretion - development various signs, controlled by various genes

Stability - the gene is transmitted unchanged

Specific effect - the absence of melanin has a specific effect in albinism

Dosage of actions - development of a trait in an amount characteristic of a given species

Allelic state

Genome - the amount of DNA contained in a haploid set of chromosomes / the complete genetic system of cells.

A trait is a phenotypic manifestation or the result of the interaction of genes and external and internal environmental factors. Determines the action of certain genes.

Phenotype is a set of characteristics of an organism determined by the interaction of the genotype and external and internal environmental factors. The difference between one organism and another based on some characteristic is a phenotypic difference.

Gene interaction:

1) Alelic

A) Dominance

B) Co-dominance - both allelic genes are active

C) Incomplete dominance - weakening of the action of a dominant gene under the influence of a recessive one

2) Non-allelic

A) Complementarity - a new sign may arise (often pathological)

B) Epistasis - suppression of one gene by another

C) The dependence of the manifestation of a gene on the genotype, as a system, is a position effect

Genome differences:

1) Unique sequence (60% of the genome) - structural genes in a single copy.

2) Long repeats, short turns, satellite DNA. Their role is the DNA framework, regulators of the action of the gene system, DNA repair, and the formation of conformational structures.

Types of inheritance:

1. Monogenic (Mendelian) inheritance

1) Autosomal dominant

2) Autosomal recessive

3) X-linked dominant

4) X-linked recessive

5) Y-linked (holandric)

1. Mitochondrial type (non-nuclear)
2. Polygenic

1. Monogenic inheritance

1) autosomal dominant type: the mutant gene appears in homo and heterozygous states. It occurs easily or is detected later. The disease is constantly transmitted from generation to generation (with the exception of denova mutations). The risk of having a sick child is 50%. Both sexes are affected with equal frequency. The remaining family members remain healthy; sick children are born after marriage.

2) Autosomal recessive type: the disease begins early and is severe. Sick children from clinically healthy parents. The disease may be traced horizontally in relatives in the pedigree. The risk of having a sick child is 25%. Heterozygous carriage. Genetic isolate - a group of individuals isolated from the general population for national, religious, geographical or other reasons (Kostroma forests, bear corners).

3) X-linked dominant type: a sick father has all his daughters sick, but his sons are healthy. Mothers have an equal probability of having sick daughters

4) X-linked recessive: recessive, sex-linked. The disease occurs in men, relatives of the proband, and healthy women; there is no direct transmission from father to son. Daughters are direct carriers. Mostly men are affected (hemophilia, Duchenne-Becker disease).

5) Y-linked (holandric): transmitted from father to son (hypertrichosis of the auricles, syndactyly).

2. Mitochondrial (cytoplasmic): the disease is transmitted from a sick mother to all children, the disease is transmitted through the female line, girls are affected (myoclonal epilepsy, MERF, Libor disease). The gene is found in eggs.

3. Polygenic inheritance: segregation in families, predisposition depends on:

1) degree of relationship with the sick proband;

2) the number of sick relatives;

3) Severity of the disease;

5) Heritability of the disease. The more genes that cause a disease, the greater the likelihood of getting sick. Heritability of multifactorial diseases: schizophrenia 85%; bronchial asthma 80%.

Polygenic criteria:

If the concordance of monozygotic twins is 4 times greater than that of dizygotic twins, then this is polygenic inheritance.

Segregation ratio: if the proportion of siblings in families with 1 sick parent is 2.5 times or greater than the proportion of sick siblings and healthy parents, then this is a polygenic disease.

Types of gene mutations:

1. Missense - changing the meaning of a codon
2. Nonsense - mutation, with the formation of a terminator codon
3. Frame shift
4. Deletion
5. Inversion
6. Splicing disorder
7. Trinucleotide repeat expansion

Classification of monogenic diseases:

1. By type of inheritance
2. By organ and system type (diseases of the NS, GIT, CVS, STK and cells, codi and appendages, endocrine system)
3. By etiology

1) Diseases with an established primary defect (gene known)

2) Diseases with an unknown primary defect

1. According to the type of metabolic disorder (HBO - hereditary metabolic diseases - proteins, lipids, purines and pyrimidines, metals, parphyrin and bilirubin)

Classification of monogenic hereditary diseases:

1. Monogenic hereditary diseases of the central nervous system

1) MNB with predominant involvement of the extrapyramidal system

Hepatolinticular degeneration (Konovalov-Wilson disease). Autosomal recessive.

Huntington's chorea (autosomal dominant)

Torsion dystonia (autosomal recessive)

2) Hereditary spinocerebellar segeneration

Spinocerebellar atrophies with an autosomal dominant type of inheritance -

hereditary SCA type 1.

SCA with recessive inheritance, including Friedreich's disease

Ataxia - telangiectasia (Louis-Bar syndrome). Autosomal recessive.

3) Hereditary spastic paraplegia

Strumpel's spastic paraplegia. Dominant type of inheritance

2. Epilepsies and epilepsy syndromes

1) With a mapped gene

Juvenile myoclonic epilepsy

2) With polygenic inheritance

Familial temporal lobe epilepsy

3. Hereditary diseases of the neuromuscular system

1) Congenital structural myopathy and dystrophy

Diseases of the central core

2) Progressive muscular dystrophy

PMD Duchenne-Becker. Recessive, sex-linked.

Limb-lumbar forms with a dominant type of inheritance

Limb-lumbar forms with a recessive type of inheritance (including

Erbra type)

Distal myopathy

3) Myotonia

Generalized form (Thomson's disease). Autosomal dominant.

Atrophic (Cushman-Batette disease). Autosomal dominant.

4) Denervation amyotrophy (secondary, neurogenic PMD)

Spinal (Werdnig-Hoffmann type 1; Kugelberg-Gelander type 3)

Hereditary neuropathies

5) Hereditary paroxysmal myopathies

Neural amyotrophy of Charcot-Marie. 1 type Autosomal dominant.

Hypokalemic form. Autosomal dominant.

Hyperkalemic form. Autosomal dominant.

4. Phakomatoses

Tuberous sclerosis

Neurofibromatosis of Recklinghausen

Encephalotrigeminal

5. Hereditary metabolic diseases affecting the NS.

Lipidosis (gangliosidosis, Gaucher disease)

Leukodystrophies (Crabbe's disease, Alexander's disease)

Mucopolysaccharidoses

Mucolipidoses

A disease caused by a disorder of amino acid metabolism (phenylketonuria, etc.)

Prevention of hereditary diseases:

Primary prevention is a set of measures that prevents the appearance of a sick child (prevents conception)

Secondary prevention is correction of the manifestation of the pathological genotype.

Prevention Approaches:

1. Control of gene expression ( dietary food, medicinal measures).
2. Preconception prophylaxis (G-6-PD deficiency - sulfonamide drugs - hemolysis of erythrocytes; sensitivity to ditilin - ditilin - prolonged respiratory arrest)
3. Elimination of embryos and fetuses (premature births, spontaneous abortions)
4. Genetic engineering approaches - operations are performed at the embryonic level (introduction of a normal gene into abdominal cavity fetus 12 weeks pregnant. Nowadays it is possible to rejoice at the level of the egg and sperm.
5. Family planning. If the risk of the disease is high, the family is advised not to have children.
6. Refusal of consanguineous marriage
7. Refusal to marry heterozygous carriers
8. Refusal to give birth to a child by a woman after 30-35 years
9. Environmental protection
10. Medical genetic consultations (a structural unit that is formed within a constituent entity of the Russian Federation)

Indications for medical genetic counseling:

Birth of a child with a congenital malformation

Established or suspected hereditary disease in the family

Delayed physical and mental development.

Repeated spontaneous abortions, miscarriages, stillbirths

Consanguineous marriages

Exposure to teratogens in the first trimester of pregnancy

Unfavorable pregnancy (currently only 25% are favorable)

pregnancies)

A geneticist diagnoses hereditary diseases and makes a prognosis for the birth of children (diagnosis - prognosis - conclusion - advice)

Prenatal diagnostic methods:

1. Screening

Medical genetic counseling

Determination of AFP level in blood serum of pregnant women

Determination of hCG

Unconjugated estriol

Acetylcholinesterase

Before and during pregnancy from 16 to 20 weeks.

2. Non-invasive

Ultrasound (6-24 weeks)

3. Invasive

Chorionic villus biopsy (9-11 weeks)

Placentobiopsy (11-22 weeks)

Anticentesis (15-17 weeks)

Cordocentesis (18-22 weeks)

Skin biopsy (14-16 weeks)

Muscle biopsy (18-22 weeks)

Fetoscopy (18-22 weeks)

Congenital malformations:

CNS- ancephaly, encephalocele

Limbs - reduction

Heart - vices

Kidneys - renal agenesis, polycystic disease

Gastrointestinal tract - duodenal atresia

Cytogenetic study(fetal lymphocytes, chorion cells) - woman’s age is 35 years, the presence of chromosomal mutations in one of the parents, low level AFP, ultrasound results.

Molecular genetic or immunological studies(chorion, blood, amniotic cells) - high risk birth of a child with a genetic disease, heterozygous carriage, diagnosis of fetal infections, immunodeficiency.

Pathological examination- high risk of having a child with a severe genetic disease.

Fetoscopy - clarifying the diagnosis of congenital malformations

These diseases include monogenic conditioned pathological conditions inherited in accordance with Mendel's laws.

Depending on the functional significance of the primary products of the corresponding genes, gene diseases are divided into hereditary disorders of enzyme systems (enzymopathies), defects of blood proteins (hemoglobinopathies), defects of structural proteins (collagen diseases) and gene diseases with an unclear primary biochemical defect.

Enzymopathies. Enzymopathy is based on either changes in enzyme activity or a decrease in the intensity of its synthesis. In heterozygous carriers of the mutant gene, the presence of the normal allele ensures the preservation of about 50% of the enzyme activity compared to the normal state. Therefore, hereditary enzyme defects are clinically manifested in homozygotes, and in heterozygotes, insufficient enzyme activity is revealed by special studies.

Depending on the nature of the metabolic disorder in cells, the following forms are distinguished among enzymopathies.

1. Hereditary defects in carbohydrate metabolism (galactosemia - a disorder of the metabolism of milk sugar - lactose; mucopolysaccharide rhidosis - a violation of the breakdown of polysaccharides).

2. Hereditary defects in lipid and lipoprotein metabolism (sphingolipidoses - impaired breakdown of structural lipids; disorders of blood plasma lipid metabolism, accompanied by an increase or decrease in blood cholesterol and lecithin).

3. Hereditary defects in amino acid metabolism (phenylketonuria - a disorder of phenylalanine metabolism (see section 4.1); tyrosinosis - a disorder of tyrosine metabolism; albinism - a disorder of the synthesis of melanin pigment from tyrosine, etc.).

4. Hereditary defects in vitamin metabolism (homocystinuria - develops as a result of a genetic defect in the coenzyme of vitamins B 6 and B 12, inherited in an autosomal recessive manner).

5. Hereditary defects in the metabolism of purine and pyrimidine nitrogenous bases (Lesch-Nayan syndrome, associated with deficiency of the enzyme that catalyzes the conversion of free purine bases into nucleotides, is inherited in an X-linked recessive type).

6. Hereditary defects in hormone biosynthesis ( adrenogenital syndrome associated with mutations in genes that control androgen synthesis; testicular feminization, in which androgen receptors are not formed).

7. Hereditary defects of erythrocyte enzymes (some hemolytic non-spherocytic anemia, characterized by a normal hemoglobin structure, but a violation of the enzyme system involved in the anaerobic (oxygen-free) breakdown of glucose. Inherited both in an autosomal recessive and X-linked recessive type).

Hemoglobinopathies. This is a group of hereditary diseases caused by a primary defect in the peptide chains of hemoglobin and the associated violation of its properties and functions. These include methemoglobinemia, erythrocytosis, sickle cell anemia, thalassemia (see § 4.1).

Collagen diseases. The occurrence of these diseases is based on genetic defects in the biosynthesis and breakdown of collagen, the most important structural component of connective tissue. This group includes Ellers-Danlos disease, characterized by large genetic polymorphism and inherited in both an autosomal dominant and autosomal recessive manner, Marfan disease, inherited in an autosomal dominant pattern, and a number of other diseases.

Hereditary diseases with an unknown primary biochemical defect. The vast majority of monogenic hereditary diseases belong to this group. The most common are the following.

1. Cystic fibrosis - occur with a frequency of 1:2500 newborns; are inherited in an autosomal recessive manner. The pathogenesis of the disease is based on hereditary damage to the exocrine glands and glandular cells of the body, their secretion of thick secretion, altered in composition, and the associated consequences.

2. Achondroplasia - a disease in 80-95% of cases caused by a newly emerging mutation; inherited in an autosomal dominant manner; occurs with a frequency of approximately 1:100,000. This disease skeletal system, in which anomalies in the development of cartilage tissue are observed mainly in the epiphyses of tubular bones and bones of the base of the skull (Fig. 6.23).

3. Muscular dystrophies(myopathies) - diseases associated with lesions of striated and smooth muscles. Various shapes characterized by different types of inheritance. For example, progressive pseudohypertrophic Duchenne myopathy is inherited in an X-linked recessive manner and appears predominantly in boys at the beginning of the first decade of life. Pseudohypertrophic muscular dystrophy is known, inherited in an autosomal recessive manner, which begins to develop in the second half of the first decade of life and occurs with equal frequency in both sexes. Muscular dystrophy of the shoulder and pelvic girdle: inherited in an autosomal dominant manner, etc.

Genetic diversity of gene diseases. The study of hereditary diseases in humans indicates that often a similar phenotypic manifestation of a disease is caused by several different mutations. This phenomenon was first described in the 30s. S. N. Davidenkov and named genetic heterogeneity of hereditary diseases. Genetic heterogeneity of hereditary diseases can be caused by mutations in different genes encoding enzymes of the same metabolic pathway, as well as mutations of the same gene, leading to the appearance of its different alleles.

Among the hereditary diseases discussed above, mucopolysaccharidoses are distinguished by a particularly high degree of genetic polymorphism, the genetic heterogeneity of which is explained by multiple mutations in 11-12 genes associated common function breakdown of polysaccharides. The congenital autosomal recessive form of deafness is characterized by great genetic heterogeneity, in which at least 35 genetically different variants with phenotypically similar manifestations are distinguished.

Great prospects for deciphering the hereditary heterogeneity of genetic diseases are opening up in connection with the use of molecular genetic methods for their direct analysis using DNA probes.

Clinical diversity of hereditary diseases. The diversity of the clinical picture of hereditary diseases is manifested in the difference in the time of onset of the disease, in the spectrum and severity of symptoms, in the course and outcome in different patients. For example, Huntington's chorea, inherited in an autosomal dominant manner, which affects the basal ganglia of the brain, clinically begins to manifest itself in the form of involuntary movements in the at different ages, but more often at 40-45 years old. The severity of the disease is also related to the time of onset of clinical manifestation (see 6.4.1.4).

We can talk about clinical polymorphism only in relation to a genetically determined hereditary form. The causes of clinical polymorphism can be both genetic and environmental. Genetic reasons include the effect of modifier genes on the manifestation of a pathologically altered gene and a complex system of various interactions between it and other genes. In addition, the variety of clinical manifestations of hereditary diseases may depend on environmental factors in which the organism develops and which influences the expression of pathologically altered genes.

Monogenic diseases

Monogenic diseases are divided according to the type of inheritance:
1. autosomal dominant (that is, if at least one of the parents is sick, then the child will also be sick), for example, Marfan syndrome.
2. autosomal recessive (a child can get sick if both parents are carriers of this disease, or one parent is sick and the other is a carrier of gene mutations that cause this disease)
3. cystic fibrosis, spinal myoatrophy.

Early diagnosis allows you to begin preventive treatment and prevent pathology from manifesting itself. For example, in phenylketonuria, mutations disrupt the functioning of the gene that controls the conversion of the amino acid phenylalanine to tyrosine. The disease develops when a child receives a damaged gene from both parents. If one of a pair of genes is normal, the person remains healthy.

Most of these mutations are passed on from generation to generation, remaining in the population. Each nation has its own spectrum of characteristic mutations.

The same can be said about the autosomal recessive disease - Wilson-Konovalov disease. Due to mutations in a gene associated with copper metabolism, copper accumulates in the body and, as a result of its toxic effects, the liver and brain are affected. The disease occurs latently for a long time, early manifestations are very diverse, which makes it difficult to identify.

The study of the molecular causes of monogenic diseases and hereditary predisposition in groups with different genetic structure is one of the important problems of medical genetics. The results of such studies can serve as a theoretical and methodological basis for accurate diagnosis and prevention of a number of hereditary pathologies in a particular region.

Chromosomal diseases are complexes of multiple congenital malformations caused by numerical (genomic mutations) or structural (chromosomal aberrations) changes in chromosomes visible under a light microscope.

Chromosomal aberrations and changes in the number of chromosomes, like gene mutations, can occur at different stages of organism development. If they arise in the gametes of the parents, then the anomaly will be observed in all cells of the developing organism (complete mutant). If an anomaly occurs during the process embryonic development when the zygote is fragmented, the karyotype of the fetus will be mosaic. Mosaic organisms may contain several (2, 3, 4 or more) cell clones with different karyotypes. This phenomenon may be accompanied by mosaicism in all or in individual organs and systems. With a small number of abnormal cells, phenotypic manifestations may not be detected.

The etiological factors of chromosomal pathology are all types of chromosomal mutations and some genomic mutations (changes in the number of chromosomes). Only 3 types of genomic mutations occur in humans: tetraploidy, triploidy and aneuploidy. Of all the variants of aneuploidy, only trisomy on autosomes, polysomy on sex chromosomes (tri-, tetra- and pentasomy) are found, and among monosomies - only monosomy X.

All types of chromosomal mutations have been found in humans: deletions, duplications, inversions and translocations. A deletion (lack of a region) in one of the homologous chromosomes means partial monosomy for this region, and duplication (doubling of a region) means partial trisomy.

Multifactorial.

Diseases whose development depends on the interaction of many factors, both hereditary and environmental, include diabetes, ischemic disease heart disease, essential hypertension, bronchial asthma, alcoholic psychosis, drug addiction. Pathogenic mutations in these genes do not necessarily lead to the disease, but the risk of developing it is increased. Predisposition to such multifactorial diseases occurs when genetic abnormalities disrupt the regulation of nervous processes, metabolism (for example, lipids or carbohydrates) or the operation of systems for neutralizing foreign substances (xenobiotics).

Once in the body, they decompose in two stages: first they undergo enzymatic modification, and only then the intermediate metabolites are converted into soluble harmless compounds and excreted.

Multifactorial diseases differ from monogenic diseases in that the relationship between genetic characteristics and the likelihood of developing pathology is much more complex for them. In different populations, the disease can be caused by a unique combination of genetic and environmental factors. The role of genetic factors largely depends on environmental conditions and a person’s lifestyle.

The concept of diseases with unconventional inheritance (mitochondrial, imprinting diseases, trinucleotide repeat expansion diseases). Examples. General approaches to the treatment of hereditary diseases.

Among them are: imprinting diseases, mitochondrial diseases, trinucleotide repeat expansion diseases with the phenomenon of anticipation, etc.

Imprinting diseases. Features of inheritance and phenotypic manifestation in imprinting diseases are determined by the phenomenon genomic imprinting(GI).

The phenomenon of genomic imprinting is associated with specific changes in chromosomes or their regions during the formation of male and female gametes. This explains the differential marking of paternal and maternal chromosomes in offspring.

The exact mechanisms of differential marking of chromosomes or their regions in spermatogenesis or oogenesis have not yet been fully elucidated. However, an important role probably belongs to the processes of specific methylation of cytosine DNA bases, which turn off gene transcription.

The phenomenon of GI explains, for example, the selective inactivation of the paternal X chromosome in the cells of provisional organs in mammals. In the cells of the embryo itself, there is an equally probable inactivation of the paternal and maternal X chromosomes.

Mitochondrial diseases. Depending on the type of mutation, mitochondrial diseases are divided into 4 groups:

A)diseases caused by point mutations leading to the replacement of conservative amino acids in the mitochondria's own proteins. These include retinitis pigmentosa and Leber neuroophthalmopathy, which causes bilateral vision loss.

b)diseases caused by mutations in tRNA genes, leading to numerous degenerative diseases with varying degrees of severity clinical manifestations, which correlates with the amount of mutant mtDNA;

V)diseases caused by divisions and duplications of sections of mitochondrial genes. A severe disease of young and middle age is described in a person - delayed cardiopathy, in which deletions of mtDNA of cardiocytes are detected. The disease is familial in nature. In some cases, X-linked inheritance is assumed, which suggests the existence of a nuclear gene.

G)diseases caused by a decrease in the number of mtDNA copies, which is a consequence of certain mutations. This group includes lethal infantile respiratory failure and lactic acidosis syndrome.

Changes in mitochondrial DNA are accompanied by disruption of their functions associated with cellular respiration. This determines the nature and severity of clinical manifestations of mitochondrial diseases.

Diseases of expansion of trinucleotide repeats with the phenomenon of anticipation. Genetic anticipation refers to the earlier manifestation and increasing severity of symptoms of a hereditary disease in subsequent generations of the pedigree. Anticipation actually manifests itself in certain types of monogenic neurological pathology, as well as in some multifactorial diseases.

The phenomenon of expansion in the number of trinucleotide repeats was first discovered in the study of Martin-Bell syndrome or fragile X syndrome, the main phenotypic manifestation of which is mental retardation. Fragile X syndrome is characterized by a fairly wide prevalence in the population (1:1000) and an unusual pattern of inheritance. Only 80% of male carriers of the mutant locus have clinical and cytogenetic signs of the disease. 20% of carriers are both clinically and cytogenetically normal, but after passing the mutation to all their daughters they may have affected grandchildren. The unexpressed mutant gene in this case becomes expressed in subsequent generations.

MONOGENIC DISEASES Monogenic diseases are diseases that are based on a single gene mutation, leading to a change in the order of DNA nucleotides, which in turn certainly affects the sequence of amino acids in the protein that is encoded by this gene.

The main properties of monogenic diseases 1) Mendelian nature of inheritance 2) Chronic Crogras 3) Genetic heterogeneity 4) Clinical polymorphism The main feature indicating the monogenic nature of the pathology is the Mendelian nature of the study.

Monogenic diseases can be divided according to the type of inheritance 1) Autosomal dominant 2) Autosomal recessive 3) X - Linked dominant 4) X - Linked recessive

No other groups of hereditary pathologies (chromosomal and multifactorial diseases) are inherited in this way. Another property of monogenic diseases, caused by the constant action of an etiological factor (gene mutation), is the chronic progradient nature of the course of the disease.

Genetic heterogeneity means that the development of a similar phenotype (i.e. clinical picture) may be caused by mutations of different genes. Genetic heterogeneity was noticed back in the 30s by the Soviet scientist S. N. Davidenkov, who discovered that for the same disease the type of inheritance can be different.

Genetic heterogeneity can be considered using the example of congenital hypothyroidism. Insufficient production of thyroid hormones in this disease in childhood leads to the development of cretinism. What causes hypothyroidism to develop?

1. The intake of inorganic iodine into the body is reduced due to a lack of it in food and water, as a result of which the synthesis of thyroid hormones is disrupted and the clinical picture of hypothyroidism (endemic goiter) develops. 2. Inorganic iodine enters the body, but its conversion into organic is impaired. Thus, the synthesis of hormones in the thyroid gland is blocked, which leads to the same consequences.

3. Organic iodine is formed, but the biosynthesis of thyroid hormones in the gland tissue is impaired. The same clinical picture corresponds to this enzymatic defect. 4. The synthesis of hormones is not changed, but the mechanism of peripheral action of the hormone is disrupted due to deficiency of the enzyme that converts low-active thyroxine into biologically active triiodothyronine. This again leads to the development of a picture of hypothyroidism.

Consequently, as a result of all the reasons, three of which are caused by mutations of different genes, the same disease develops - hypothyroidism.

Determining genetic heterogeneity is of great practical importance: in this way the true pathogenesis of the disease is revealed, the correct diagnosis is made and adequate treatment is provided depending on the cause of its development.

Clinical polymorphism consists in differences in the clinical picture of the same disease. It manifests itself in monogenic diseases in the same way as in other forms of pathology: 1) Differences in the age of onset of the disease in different patients. 2) At the pace of its flow. 3) In the sequence of symptoms. 4) Their spectrum and degree of expression. The reasons causing clinical polymorphism can be divided into genetic and environmental.

Classification of monogenic diseases Clinical classification is based on organ and systemic principles. There are: 1) Hereditary diseases 2) Mental 3) Musculoskeletal 4) Neuromuscular 5) ENT organs 6) Dental system 7) Blood However, with most hereditary diseases, combined lesions of a number of organs and systems are observed

If we systematize monogenic diseases according to the etiological principle, we can distinguish diseases: 1) With an identified biochemical defect 2) With an unknown primary biochemical defect, which is understood as a violation of protein synthesis that is the cause of the disease.

Depending on the predominant damage to the type of metabolism, the following large groups of diseases can be distinguished: 1) Hereditary defects in carbohydrate metabolism 2) Lipid metabolism 3) Amino acid metabolism 4) Vitamin metabolism 5) Hormone metabolism 6) Purine metabolism 7) Perimidine metabolism 8) Defects of erythrocyte enzymes 9 ) Defects of circulating proteins (Hemoglobinopathies) 10) Defects of structural proteins (Collagen diseases)

Diseases of carbohydrate metabolism 1. Pompe disease 2. Gierke disease 3. McArdle disease These diseases are often called syndromic

Pompe disease is caused by a deficiency of the enzyme aglucosidase, which is responsible for breaking down excess glycogen, a complex sugar molecule, in lysosomes. Pompe disease is both a lysosomal storage disease and a metabolic muscle disease because glycogen accumulation affects muscle function.

Gierke's disease is glycogenosis (glycogen disease) caused by deficiency of glucose-6 phosphatase. With Gierke's disease, the ability to convert glucose into glycogen and deposit the latter in the tissues of various organs, mainly the liver, is retained.

McArdle disease is a glycogenosis associated with a defect in muscle phosphorylase. A disease caused by a violation of the catalytic function of this enzyme is accompanied by the deposition of a significant amount of glycogen in the muscles.

Vitamin deficiency is a pathological condition that develops due to the lack of a vitamin in the body and/or the inability to realize its effects. Causes of vitamin deficiency Lack of vitamin in food Impaired absorption of vitamins in the intestines Impaired transport of vitamins into tissues and organs

Hypovitaminosis is a pathological condition that occurs as a result of a decrease in the content and/or insufficiency of the effects of a vitamin in the body.

Thiamine deficiency Beriberi) (disease An adult needs at least 1.4 -2.4 mg of vitamin B 1 per day. There are dry and wet forms of beriberi disease. The dry form has symptoms: myalgia, muscle atrophy, myasthenia gravis, loss in weight. Areflexia, a sensitivity disorder occurs. In the wet form, acute heart failure develops and edema masks myocardial dystrophy, combined with dilatation of peripheral vessels and increased shunting of the blood, which leads to isotonic overload of the heart.

Vitamin D deficiency (Rickets) The daily requirement for the vitamin in children is higher than in adults and is 500 IU (12.5 mcg), while in pregnant women it is 400, and in adults it is 100 IU. Rickets is a disease caused by a deficiency of vitamin D. Vitamin D is produced by the skin under the influence of ultraviolet rays, and is also found in some products: fish oil, yolk, dairy products. Vitamin D actively promotes the absorption of calcium from the intestines and its proper distribution in the body, which is very important for the development of bone tissue and the functioning of the central nervous system. nervous system, other organs.

Scurvy The minimum requirement of an adult for vitamin C is estimated at 50 -100 mg/day. Scurvy (scorbut, the childhood form also appears under the eponym Möller-Bar. Low disease) is a disease caused by an acute deficiency of vitamin C ( ascorbic acid), which leads to disruption of collagen synthesis, and connective tissue loses its strength.

Pellagra is a disease, one of the hypovitaminosis diseases, which is a consequence of prolonged poor nutrition (lack of vitamin PP) and proteins. The classic name for pellagra is “the disease of the three Ds” - diarrhea, dermatitis, dementia.

A number of features of hereditary metabolic diseases can be noted. They appear early, often in childhood. Clinical symptoms are varied, as many organs and systems are affected. Most diseases in this group are progressive. (Progredient (lat. rgo-gredior - go further, move forward) development of the disease - the development of the disease with an increase in symptoms)

Pathogenesis comes down, on the one hand, to a deficiency in the formation of certain biological active substances or to their inactivation, and on the other hand - to the formation of abnormal metabolites, their accumulation in organs, tissues, cells, i.e. to thesaurismosis (metabolic diseases

A common feature hereditary diseases of amino acid metabolism are: skin disorders, decreased intelligence, convulsions, various neurological symptoms, cuts, paralysis, extrapyramidal disorders, ataxia. Hyperaminoaciduria (increased amino acid content in urine) is detected.

A group of hereditary mucopolysaccharides is characterized by damage to the musculoskeletal system, eyes, cardiovascular system and decreased intelligence. Joint contracture, flattened bridge of the nose, and dwarfism are noted.

Hereditary diseases of mineral metabolism include 2 main forms: Paroxysmal paralysis (This hereditary disease is based on a violation of calcium metabolism) and Hepatocerebral dystrophy (Hereditary disease of the subcortical nodes is characterized by the development of hyperkinesis, decreased intelligence, development of the Kayser ring. Fleischer on the iris of the eye. The disease is associated with copper metabolism disorder.

Hepatocerebral dystrophy Synonyms: hepatolenticular degeneration, Westphal disease. Wilson-Konovalov. GCD is a chronic progressive hereditary degenerative disease characterized by combined damage to the subcortical nodes of the central nervous system and liver.

Etiology and pathogenesis Hereditary disease with an autosomal recessive type of inheritance. The disease is genetically caused by a violation of the synthesis of the protein ceruloplasmin, which is part of alpha 2 globulins that transport copper.

Kayser-Fleischer rings are found in cases of chronic copper poisoning (for example, when feeding children milk heated in a copper container or drinking water with increased content copper).

Paroxysmal paralysis A group of neuromuscular diseases characterized by sudden attacks of muscle weakness and plegia. The pathogenesis is not clear.

1. Hypokalemic (Westphal disease). It is inherited in both an autosomal dominant and autosomal recessive manner. Appears between 6 and 15 years of age. Paroxysms are characterized by a sudden development of muscle weakness, immobility, decreased muscle tone, and tendon reflexes at night or in the morning.

2. Hyperkalemic (Gamstorp disease). Inherited in an autosomal dominant manner. Appears at the age of 1-5 years. Unlike hypokalemic, it usually develops during the day and is accompanied by severe paresthesia in the form of tingling, numbness, weakness of the facial muscles and articulation.

3. Normokalemic (periodic) paralysis. Inherited in an autosomal dominant manner. Proven up to 10 years of age. Its peculiarity is a relatively slowly paroxysmally increasing moderate weakness in the muscles of the trunk, limbs and masticatory muscles, as well as a slow regression of symptoms.

All forms of paroxysmal myoplegia have a slowly progressive course. Prognosis with a timely diagnosis, emergency measures and differentiated drug therapy favorable.

A large group of diseases are hereditary diseases with defects of the endocrine system. These include: 1) Adrero-genital syndrome - Anomalies in the development of the endocrine system and genital organs 2) Pituitary dwarfism 3) Dwarfism 4) Laurens - Moopa - Bardet - Biedl syndrome - Endocrine disorders with characteristic appearance

Selective screening 1. Delayed psychomotor development in young children (mental retardation in older children) 2. Neurological disorders (Seizures, decreased or increased muscle tone, spastic cuts) 3. Dyspeptic symptoms, intolerance to certain foods and medications, feeding disorders 4. Violation of the physical development of children (delayed weight gain, abnormal growth, deformation of bones, trunk and limbs 5. Other particular phenomena (cataracts, hearing impairment, vision impairment, specific color and smell of urine, skin manifestations and others