Monogenic diseases are common clinical features. Monogenic diseases Monogenic diseases are diseases in. Learning new material
Monogenic diseases (MS) are diseases whose etiology is based on a single gene mutation. MBs are inherited according to Mendel's laws. Currently, about 5,000 nosological units of MB have been described. They are detected in 3-6% of newborns, and in the structure of the total mortality of children under 5 years old, they account for 10-14%. MB, the genes of which are mapped on chromosomes, have up to 900 nosological units. For about 350 diseases, the nature of the gene mutation has been elucidated, and the nature of the biochemical defect has been established. For a number of MBs, specific mutant genes are physically mapped on chromosomes. The individual and population risk of developing MB differ significantly due to the uneven distribution of the genes that cause them. It is generally accepted that MB occurring with a frequency of 1:10,000 or more are common, and those with a frequency of less than 1:100,000 are rare diseases.
5.2. Classification of monogenic diseases
Monogenic diseases are extremely diverse in terms of phenotypic manifestations, therefore, their classification is possible according to certain criteria used by doctors of various specialties when working with monogenic diseases.
It is convenient for geneticists to base the classification of monogenic diseases on the type of inheritance, which, with an informative pedigree, allows narrowing the diagnostic search in catalogs and atlases of hereditary diseases by 2 times for autosomal or almost 10 times for sex-linked syndromes, calculate the amount of genetic risk, determine the genetic prognosis in family. The disadvantage is the high frequency of sporadic cases of hereditary diseases and the inability to determine the type of inheritance, as well as different types of inheritance (and, accordingly, different gene defects) with similar phenotypes.
Clinicians are comfortable with the so-called clinical classification, that is, according to the predominant lesion of any organ or system. The disadvantage is the polysystemic and polyorganic nature of most monogenic syndromes, as well as the predominant lesions of different organs within the same nosology.
For physicians, biochemists-genetics, the “biochemical” classification is convenient, which, first of all, divides all monogenic diseases into two unequal groups of diseases with identified and undiagnosed primary biochemical defects. Despite all the successes of modern biochemical genetics, there are many more diseases with an undiagnosed biochemical defect than diseases with a detected biochemical defect, which is a disadvantage of this classification.
The pathogenetic classification of monogenic diseases divides them into groups, depending on the main pathogenetic link: metabolic disorders, morphogenesis disorders, a combination of these components.
Hereditary metabolic diseases (HMDs) are one of the most numerous and well-studied groups of monogenic human diseases. The pathogenesis of this group of diseases is based on violations of certain biochemical processes with the accumulation of any metabolites, or with a lack of end reaction products. With all the diversity of NBOs, it is possible to distinguish common clinical signs that unite them into one group:
delayed psychomotor development in young children (mental retardation in children older than 3 years);
neurological disorders: convulsions, increased or decreased muscle tone, spastic paresis, microcephaly, ataxia, myopathy, etc.;
dyspeptic disorders, intolerance to certain foods and drugs, impaired intestinal absorption (malabsorption);
violation physical development- insufficient or overweight, abnormal growth, deformities of the bones of the trunk and limbs;
specific color and smell of urine (body);
cataracts, other visual and hearing impairments;
hepatosplenomegaly, prolonged neonatal jaundice, cirrhosis of the liver;
change in hair color and structure, skin manifestations;
sudden death syndrome.
Multiple congenital malformations (MCD) are understood as a complex of two or more malformations that are not induced by each other in different systems. We can talk about MVPR syndromes in the case of a stable combination of malformations in two or more patients.
MVPR syndromes can be based on chromosomal abnormalities (both numerical and structural), gene mutations, and the effect of adverse environmental factors (teratogens) on the fetus.
The term "non-chromosomal syndromes" is very often used, which is not entirely correct, but convenient to refer to MVPR syndromes that are not associated with chromosomal pathology.
The diagnosis of non-chromosomal CMDS is more difficult than the diagnosis of chromosomal CMDS. Accurate diagnosis of monogenic syndromes of MVPR is possible only with molecular genetic research methods. 20% of non-chromosomal CMDS are recessive-inherited forms with a high risk of recurrence in families. Taking into account all types of inheritance, the total risk of recurrence in families of non-chromosomal syndromes reaches 10%. This once again emphasizes the importance of diagnosing non-chromosomal syndromes.
The group of monogenic syndromes of MVPR, which account for about 40% of all cases of syndromes of non-chromosomal etiology, is represented by the largest number of nosological forms, reaching several hundred. Numerically, the recessively and dominantly inherited forms are equal.
The number of known MVPR syndromes is very large and more and more new forms are constantly being identified. One can think of a new syndrome when an unusual complex of defects is found in several members of the same family and when an unusual complex of defects is found in several patients from different families.
Monogenic diseases result from damage to the genetic material (DNA) at the level of one gene. Violation of protein synthesis during mutation of the corresponding gene leads to a quantitative or qualitative change in the protein in the body. Gene mutations in humans are the causes of many forms of hereditary pathology. If a protein-enzyme that performs a catalytic function changes, then the complex chain of transformation of a substance in the body is disrupted: gene → enzyme → biochemical reaction → sign. In the biological literature, such changes are usually called biochemical mutations, in medical literature they are called hereditary metabolic defects or hereditary enzymopathies. Functional inferiority of the enzyme system leads to a sharp violation of a certain biochemical process or biochemical block. A metabolic block can be determined by the accumulation in the body of a substance that is formed at the stage preceding this block (Fig. 21).
The loss of a single metabolic link leads to serious secondary metabolic disorders and to multiple pathological changes in the body.
The degree of decrease in enzyme activity can be different both in various enzymopathies and in this enzymopathy. A decrease in enzyme activity or its absence may be due to various mutations occurring in different codons of the gene.
In addition, a decrease in enzyme activity may be associated with a mutational defect in one of the components of the enzyme system. Therefore, the same biochemical changes can be caused by allelic mutations or mutations in several non-allelic genes. Thus, the same enzymopathy can have several genetic forms. This phenomenon is called genetic heterogeneity.
The wide genetic heterogeneity of enzymopathy largely determines the variability of their clinical manifestations. However, only the features of the mutational gene cannot explain the unequal manifestation of the disease in different patients. To a large extent, the gene manifests itself in conjunction with other genes, regardless of whether they are transmitted in the family. These genes can enhance or inhibit the expression of the main gene. They can change the phenomenon of hereditary disease. The main gene, in turn, affects the manifestation of other genes, due to which the patient may have additional symptoms that are unusual for the underlying disease.
Thus, the effect of a mutant gene can be considered as a multi-stage process, the first stage of which is a primary biochemical defect, the second is the involvement of other enzyme systems in the process and the development of complex metabolic disorders, and the third is the formation of the clinical phenomenon of the disease.
Organizing time
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Lesson plan:
- Hereditary diseases:
- Classification of hereditary diseases
- Monogenic diseases
- Chromosomal diseases
- Polygenic diseases
- Risk factors for hereditary diseases
- Prevention and treatment of hereditary diseases
hereditary diseases
Hereditary diseases are associated with disorders in the genetic material (chromosomal and gene mutations that occur in parents or the organism itself), or certain combinations of genes in offspring. The consequences of inherited mutations, their phenotypic manifestation leads to certain symptoms of the disease. In single-gene disorders, the offending allele may be dominant over the normal allele or recessive. Such diseases are still untreatable, but the expression “hereditary means incurable” today no longer sounds like a fatal doom. The successes of modern medicine, of course, today cannot completely solve all the issues of treating this pathology in the problem of hereditary diseases. However, there is an opportunity to help the patient. In those cases where a hereditary disease does not lead to a gross developmental defect, timely treatment can to some extent reduce the suffering of the patient, alleviate his lot. To make possible his social and labor adaptation.
Hereditary diseases are human diseases caused by chromosomal and gene mutations.(Slide 3)
From hereditary diseases should be distinguished congenital diseases that are caused by intrauterine damage caused, for example, by infection (syphilis or toxoplasmosis) or exposure to other damaging factors on the fetus during pregnancy. Many genetically determined diseases do not appear immediately after birth, but after some, sometimes very long, time.
Classification of hereditary diseases
Among hereditary diseases that develop as a result of mutations, three subgroups are traditionally distinguished: monogenic hereditary diseases, polygenic hereditary diseases and chromosomal diseases (Slide 4).
Monogenic diseases
Inherited in accordance with the laws of classical Mendelian genetics. Accordingly, for them, genealogical research reveals one of three types of inheritance: autosomal dominant, autosomal recessive, and sex-linked inheritance. This is the broadest group of hereditary diseases. Currently, more than 4000 variants of monogenic hereditary diseases have been described. The vast majority of which are quite rare (for example, the incidence of sickle cell anemia is 1/6000).
(Slide 5)
- They are caused by mutations or the absence of individual genes and are inherited in full accordance with Mendel's laws (autosomal or X-linked inheritance, dominant or recessive).
- Mutations can capture either one or both alleles.
- Clinical manifestations arise as a result of the absence of certain genetic information or the implementation of a defective one.
- Although the prevalence of monogenic diseases is low, they do not completely disappear.
- For monogenic diseases, "silent" genes are characteristic, the action of which is manifested under the influence of the environment.
3.1. Autosomal dominant diseases (Slide 6)
- It is based on a violation of the synthesis of structural proteins or proteins that perform specific functions (for example, hemoglobin)
- The action of the mutant gene is almost always manifested
- Sick boys and girls are born with the same frequency.
- The probability of developing the disease in the offspring is 50%.
Examples of diseases: (Slide 7) Marfan's syndrome, Albright's disease, dysostoses, otosclerosis, paroxysmal myoplegia, thalassemia, etc.
Monogenic diseases are characterized by similar features - they are determined by one gene and are inherited according to Mendel's laws. Genes are divided into dominant and recessive and can be localized on autosomes or on sex chromosomes (almost always the X chromosome). According to the type of gene (dominant or recessive) and its localization (autosome or X-chromosome), there are different types inheritance:
Autosomal dominant type of inheritance, which is characterized by the "vertical" transmission of a pathological gene from one of the parents. The transmission probability is 50%. Sporadic cases (the only one affected in the family) of autosomal dominant diseases in the family are treated as a newly emerged "new mutation" with an extremely low risk of recurrence;
The autosomal recessive type of inheritance is characterized by the presence in the genome of both parents of the same recessive genes (heterozygous state). The transmission probability is 25%. The presence in the genome of the child of such parents of two identical genes (homozygous state) determines the development of the disease. The meeting of two spouses with the same autosomal recessive genes is a random event. However, if the future parents are relatives, then the probability of having the same recessive genes increases dramatically, so the relationship of the spouses if they have a child with a rare disease with a high probability indicates the autosomal recessive nature of this pathology.
Recessive, X-linked type of inheritance. With this type of inheritance, the recessive gene is located on the X chromosome and this does not manifest itself in any way in the phenotype of females with a set of 46, XX (two sex X chromosomes). However, in the presence of a 47,XY karyotype, i.e. in males, this gene will always show up as a trait or specific disease, such as hemophilia. Thus, healthy women are conductors (carriers) of a pathological gene and can pass this gene on to their daughters with a 50% probability and to their sons with the same 50% probability. However, in this case, the daughters will be healthy (conductors), and the sons will be sick.
Dominant, X-linked type of inheritance.
The dominant gene is located on the X chromosome and, therefore, can appear in both boys and girls. However, the presence of two sex chromosomes in the female causes a less pronounced manifestation of a trait or disease in girls and a significant manifestation of it in boys. Often the manifestation of an X-linked dominant gene is fatal for males (the lethal effect of the pathological gene). Mothers with a dominant X-linked gene have a 50% chance of passing this gene on to their daughters and sons. An affected father can only pass on the X-linked dominant gene to all of his daughters; the sons of such a father can never inherit this trait. Some examples of monogenic diseases with the frequencies of their occurrence in newborns are given in the table (Table 36-3).
Table 36-3. Monogenic diseases in newborns
More on the topic of monogenic diseases:
- Demylenizing diseases of the nervous system. Etiology, pathogenesis, clinical forms of diseases
- Terms of normalization of health after illness. Features of an individual approach to students with chronic diseases
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 get sick), for example - Marfan's 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 start preventive treatment and prevent the pathology from manifesting itself. For example, in phenylketonuria, mutations disrupt 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 the pair of genes is normal, the person remains healthy.
Most of these mutations are passed down from generation to generation, remaining in the population. Each nation has its own range of characteristic mutations.
The same can be said about the autosomal recessive disease - Wilson-Konovalov's disease. Due to mutations in the gene associated with copper metabolism, copper accumulates in the body and, as a result of its toxic effect, the liver and brain are affected. The disease is latent 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 called multiple complexes. birth defects development 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, as well as gene mutations, can occur at different stages of an organism's development. If they arise in the gametes of the parents, then the anomaly will be observed in all cells of the developing organism (full mutant). If an anomaly occurs during embryonic development when crushing the zygote, the fetal karyotype 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.
Etiological factors of chromosomal pathology are all types of chromosomal mutations and some genomic mutations (changes in the number of chromosomes). There are only 3 types of genomic mutations found in humans: tetraploidy, triploidy, and aneuploidy. Of all the variants of aneuploidy, only trisomy for autosomes, polysomy for sex chromosomes (tri-, tetra- and pentasomy) are found, and from monosomy - only monosomy X.
All types of chromosomal mutations have been found in humans: deletions, duplications, inversions and translocations. A deletion (lack of a site) in one of the homologous chromosomes means a partial monosomy for this site, and a duplication (a doubling of the site) means a partial trisomy.
Multifactorial.
The diseases, the development of which depends on the interaction of many factors, both hereditary and environmental, include diabetes, ischemic disease heart, 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 the neutralization of 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 complicated for them. In different populations, the disease can be caused by a peculiar combination of genetic and environmental factors. The role of genetic factors largely depends on the environmental conditions and lifestyle of a person.
The concept of diseases with non-traditional inheritance (mitochondrial, imprinting diseases, trinucleotide repeat expansion diseases). Examples. General approaches to the treatment of hereditary diseases.
Among them are distinguished: imprinting diseases, mitochondrial diseases, diseases of the expansion of trinucleotide repeats with the phenomenon of anticipation, etc.
Diseases of imprinting. Features of inheritance and phenotypic manifestation in diseases of imprinting are due to 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 finally elucidated. However, an important role probably belongs to the processes of specific methylation of DNA cytosine bases, which switch off gene transcription.
The GI phenomenon 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, equiprobable inactivation of the paternal and maternal X chromosomes takes place.
Mitochondrial diseases. Depending on the type of mutations, mitochondrial diseases are divided into 4 groups:
but)diseases caused by point mutations leading to the replacement of conservative amino acids in the mitochondrial own proteins. These include retinitis pigmentosa and Leber's neuroophthalmopathy, in which bilateral vision loss occurs.
b)diseases caused by mutations in tRNA genes, leading to numerous degenerative diseases with varying degrees of severity of clinical manifestations, correlated with the amount of mutant mtDNA;
in)diseases caused by divisions and duplications of sections of mitochondrial genes. A severe disease of young and middle age - delayed cardiopathy, in which deletions of mtDNA of cardiocytes were detected, is described in a person. The disease wears family character. In some cases, X-linked inheritance is assumed, which makes it possible to think about the existence of a nuclear gene.
G)diseases caused by a decrease in the number of copies of mtDNA, which is the result of certain mutations. This group includes lethal infantile respiratory failure and lactic acidosis syndrome.
Changes in mitochondrial DNA are accompanied by a violation of their functions associated with cellular respiration. This determines the nature and severity of clinical manifestations of mitochondrial diseases.
Diseases of the expansion of trinucleotide repeats with the phenomenon of anticipation. Genetic anticipation refers to an earlier manifestation and an increase in the severity of symptoms of a hereditary disease in subsequent generations of a pedigree. Anticipation really manifests itself in certain types of monogenic neurological pathology, as well as in some multifactorial diseases.
The phenomenon of expansion of the number of trinucleotide repeats was first discovered in the study of Martin-Bell syndrome or fragile (fragile) X-chromosome 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 on to all their daughters, they may have affected grandchildren. The unexpressed mutant gene then becomes expressed in subsequent generations.