V.G. Vakharlovsky - medical geneticist, pediatric neuropathologist of the highest category, candidate of medical sciences. Doctor of the Genetic Laboratory for Prenatal Diagnostics of Hereditary and Congenital Diseases of the I.A. BEFORE. Otta - for more than 30 years he has been engaged in medical and genetic counseling on the prognosis of the health of children, the study, diagnosis and treatment of children suffering from hereditary and congenital diseases of the nervous system. Author of over 150 publications.
Each of us, thinking about a child, dreams of having only a healthy and ultimately happy son or daughter. Sometimes our dreams fail, and a child is born seriously ill, but this does not mean at all that this own, dear, blood (scientifically: biological) child in the overwhelming majority of cases will be less loved and less dear. Of course, when a sick child is born, there are immeasurably more worries, material costs, physical and moral stress than when a healthy one is born. Some condemn the mother and / or father for abandoning a sick child. But, as the Gospel tells us: "Do not judge and you will not be judged." They refuse a child for a variety of reasons, both on the part of the mother and / or father (social, material, age-related, etc.), and the child (the severity of the disease, the possibility and prospects of treatment, etc.). The so-called abandoned children can be both sick and practically healthy people, regardless of age: both newborns and infants, as well as older ones.
For various reasons, the spouses decide to take a child from an orphanage or immediately from a maternity hospital to the family. Less often this, from our point of view, a humane and bold civil act, is done by single women. It happens that disabled children also leave the orphanage, their named parents deliberately take a child with an illness or with cerebral palsy, etc. into the family.
The task of this work is to highlight the clinical and genetic characteristics of the most common hereditary diseases that manifest themselves in a child immediately after birth and at the same time, based on the clinical picture of the disease, a diagnosis can be made, or during subsequent years of a child's life, when pathology is diagnosed depending on the time the appearance of the first symptoms specific to this disease. Some diseases can be detected in a child even before the onset of clinical symptoms using a number of laboratory biochemical, cytogenetic and molecular genetic studies.
The probability of having a child with a congenital or hereditary pathology, the so-called population or general statistical risk, equal to 3-5%, haunts every pregnant woman. In some cases, it is possible to predict the birth of a child with a particular disease and diagnose pathology already in the intrauterine period. Some congenital malformations and diseases are established in the fetus using laboratory biochemical, cytogenetic and molecular genetic techniques, more precisely, a set of methods for prenatal (prenatal) diagnostics.
We are convinced that all children proposed for adoption / adoption should be examined in detail by all medical specialists in order to exclude the corresponding profile pathology, including examined and examined by a geneticist. In this case, all known data about the child and his parents must be taken into account.
Chromosomal mutations
In the nucleus of every cell of the human body there are 46 chromosomes, i.e. 23 pairs, which contain all hereditary information. A person receives 23 chromosomes from a mother with an egg and 23 from a father with a sperm. When these two germ cells merge, we get the result that we see in the mirror and around us. A cytogenetic specialist is engaged in the study of chromosomes. For this purpose, blood cells called lymphocytes are used, which are specially processed. A set of chromosomes distributed by a specialist in pairs and in sequence number - the first pair, etc., is called a karyotype. We repeat, the nucleus of each cell contains 46 chromosomes or 23 pairs. The last pair of chromosomes is responsible for a person's gender. In girls, these are XX chromosomes, one of them is received from the mother, the other from the father. Boys have XY sex chromosomes. The first was received from the mother and the second from the father. Half of the sperm contains the X chromosome and the other half of the Y chromosome.
There is a group of diseases caused by a change in the set of chromosomes. The most common of these is Down's disease (one in 700 newborns). The diagnosis of this disease in a child should be made by a neonatologist in the first 5-7 days of a newborn's stay in a maternity hospital and confirmed by examining the child's karyotype. In Down's disease, the karyotype is 47 chromosomes, the third chromosome is found in the 21st pair. Girls and boys suffer from this chromosomal abnormality in the same way.
Only girls can have Shereshevsky-Turner disease. The first signs of pathology are most often noticeable at the age of 10-12, when the girl has a small stature, low-set hair on the back of her head, at 13-14 years old there is no hint of menstruation. There is a slight lag in mental development. The leading symptom in adult patients with Shereshevsky-Turner disease is infertility. The karyotype of such a patient is 45 chromosomes. One X chromosome is missing. The incidence of the disease is 1 in 3,000 girls and among girls with a height of 130-145 cm - 73 per 1000.
Only males have Kleinfelter's disease, which is most often diagnosed at 16-18 years of age. The patient has a high growth (190 cm and above), often a slight lag in mental development, disproportionate to the growth of long arms, covering the chest with its girth. When studying the karyotype, 47 chromosomes are observed - 47, XXY. In adult patients with Kleinfelter's disease, infertility is the leading symptom. The prevalence of the disease is 1: 18,000 healthy men, 1: 95 boys with mental retardation and one among 9 men who are infertile.
Above, we have described the most common chromosomal diseases. More than 5,000 diseases of a hereditary nature are classified as monogenic, in which there is a change, a mutation, in any of the 30,000 genes found in the nucleus of a human cell. The work of certain genes contributes to the synthesis (formation) of the protein or proteins corresponding to this gene, which are responsible for the functioning of cells, organs and systems of the body. A disruption (mutation) of a gene leads to a violation of protein synthesis and further disruption of the physiological function of cells, organs and systems of the body, in the activity of which this protein is involved. Let's look at the most common of these diseases.
According to data provided by the World Health Organization, about 6% of children are born with various developmental disabilities caused by genetics. This indicator also takes into account those pathologies that do not appear immediately, but as babies grow up. In the modern world, the percentage of hereditary diseases is increasing every year, which attracts attention and greatly worries specialists around the world.
Given the role of genetic factors, hereditary human diseases can be divided into the following three groups:
1. Diseases, the development of which is due only to the presence of a mutated gene
Such pathologies are transmitted from generation to generation. These include six-fingered, myopia, muscular dystrophy.
2. Diseases with a genetic predisposition
Their development requires the influence of additional external factors. For example, a certain natural component in the composition of the product can cause a serious allergic reaction, and head injury can lead to epilepsy.
3. Diseases caused by the influence of infectious agents or trauma, but not having an established connection with genetic mutations
In this case, heredity still plays a role. For example, in some families, children very often suffer from colds, while in others, even with close contact with infectious patients, they remain healthy. Researchers believe that the hereditary characteristics of the organism also determine the variety of types and forms of the course of various diseases.
Causes of hereditary diseases
The main cause of any hereditary disease is mutation, that is, a persistent change in the genotype. Mutations of human hereditary material are different, they are divided into several types:
— Gene mutations are structural changes in DNA sections - a macromolecule that provides storage, transmission and implementation of the genetic program for the development of the human body. Such changes become dangerous when they lead to the formation of proteins with unusual characteristics. As you know, proteins are the basis of all tissues and organs of the human body. Many genetic diseases develop as a result of mutations. For example, cystic fibrosis, hypothyroidism, hemophilia and others.
— Genomic and chromosomal mutations- these are qualitative and quantitative changes in chromosomes - structural elements of cell nuclei, ensuring the transmission of hereditary information from generation to generation. If transformations take place only in their structure, then violations of the basic functions of the body and human behavior may not be so pronounced. When the changes also affect the number of chromosomes, very serious diseases develop.
— Sexual or somatic mutations(not participating in sexual reproduction) cells... In the first case, the fetus already at the stage of fertilization acquires genetically determined developmental deviations, and in the second, only some parts of the body tissues remain healthy.
Experts identify a number of factors that can provoke mutations in the hereditary material, and in the future - the birth of a child with genetic abnormalities. These include the following:
— The relationship between the father and mother of the unborn baby
In this case, the risk that the parents will be carriers of genes with identical damages increases. Such circumstances will exclude the baby's chances of acquiring a healthy phenotype.
— Age of future parents
Over time, an increasing amount of genetic damage, albeit very insignificant, appears in the germ cells. As a result, the risk of having a child with a hereditary abnormality increases.
— Father or mother belonging to a particular ethnic group
For example, Ashkenazi Jews often have Gaucher disease, and Mediterranean peoples and Armenians have Wilson's disease.
— Exposure of one of the parents to radiation, a potent poisonous substance or drug.
— Unhealthy Lifestyle
The structure of chromosomes is influenced by external factors throughout a person's life. Bad habits, poor nutrition, severe stress and many other reasons can lead to gene breakdowns.
If, when planning a pregnancy, you want to exclude the genetic diseases of the unborn baby, be sure to undergo an examination. By doing this as early as possible, parents have an additional chance to present their child with good health.
Diagnosis of genetic disorders
Modern medicine is able to detect the presence of a hereditary disease at the stage of fetal development and, with a high probability, predict possible genetic disorders during pregnancy planning. There are several diagnostic methods:
1. Biochemical analysis of peripheral blood and other biological fluids in the mother's body
It allows you to identify a group of genetically determined diseases associated with metabolic disorders.
2. Cytogenetic analysis
This method is based on the analysis of the internal structure and mutual arrangement of chromosomes inside the cell. Its more perfect analogue is molecular cytogenetic analysis, which allows detecting the slightest changes in the structure of the most important elements of the cell nucleus.
3. Syndromological analysis
It involves the selection of a number of signs from the whole variety, inherent in a particular genetic disease. This is done by carefully examining the patient and using special computerized programs.
4. Fetal ultrasound
Detects some chromosomal diseases.
5. Molecular genetic analysis
Determines even the smallest changes in the structure of DNA. Allows you to diagnose monogenic diseases and mutations.
It is important to timely determine the presence or likelihood of hereditary diseases in the unborn baby. This will allow you to take action in the early stages of fetal development and anticipate opportunities to minimize adverse effects in advance.
Methods for the treatment of hereditary diseases
Until recently, genetic diseases were practically not treated due to the fact that it was considered hopeless. Their irreversible development and the absence of a positive result were assumed in the course of medical and surgical intervention. However, experts have made significant progress in the search for new effective methods of treating hereditary pathologies.
Today, there are three main methods:
1. Symptomatic method
It is aimed at eliminating painful symptoms and slowing down the progress of the disease. This technique includes the use of analgesics for pain, the use of nootropic drugs for dementia, and the like.
2. Pathogenetic therapy
It involves the elimination of defects caused by a mutated gene. For example, if it does not produce a certain protein, then this component is artificially introduced into the body.
3. Etiological method
It is based on gene correction: isolation of the damaged DNA region, its cloning and further use for medicinal purposes.
Modern medicine successfully treats dozens of hereditary diseases, but it is still impossible to talk about achieving absolute results. Experts recommend timely diagnostics and, if necessary, take measures to reduce possible genetic disorders of your unborn child.
Each healthy person has 6-8 damaged genes, but they do not disrupt cell function and do not lead to disease, since they are recessive (non-manifest). If a person inherits two similar abnormal genes from his mother and father, he becomes ill. The probability of such a coincidence is extremely small, but it increases sharply if the parents are relatives (that is, they have a similar genotype). For this reason, the incidence of genetic abnormalities is high in closed populations.
Each gene in the human body is responsible for the production of a specific protein. Due to the manifestation of the damaged gene, the synthesis of an abnormal protein begins, which leads to dysfunctions of cells and developmental defects.
The doctor can establish the risk of a possible genetic abnormality by asking you about the diseases of relatives "up to the third generation", both on your part and on the part of your husband.
There are a great many genetic diseases, and some of them are very rare.
List of rare hereditary diseases
Here are the characteristics of some genetic diseases.
Down syndrome (or trisomy 21)- a chromosomal disease characterized by mental retardation and impaired physical development. The disease occurs due to the presence of the third chromosome in the 21st pair (in total, a person has 23 pairs of chromosomes). It is the most common genetic disorder, affecting about one in 700 newborns. The frequency of Down syndrome increases in children born to women over 35 years of age. Patients with this disease have a special appearance and suffer from mental and physical retardation.
Turner syndrome- a disease that affects girls is characterized by the partial or complete absence of one or two X chromosomes. The disease affects one in 3000 girls. Girls with this condition are usually very short and have no ovarian function.
X-trisomy syndrome- a disease in which a girl is born with three X chromosomes. This disease occurs on average in one out of 1000 girls. The X-trisomy syndrome is characterized by slight mental retardation and, in some cases, infertility.
Klinefelter's syndrome- a disease in which a boy has one extra chromosome. The disease occurs in one boy out of 700. Patients with Klinefelter's syndrome, as a rule, are tall, there are no noticeable external anomalies of development (after puberty, the growth of facial hair is difficult and the mammary glands are slightly enlarged). Intelligence in patients is usually normal, but speech disorders are common. Men with Klinefelter syndrome are usually infertile.
Cystic fibrosis- a genetic disease in which the functions of many glands are impaired. Cystic fibrosis affects only Caucasians. Approximately one in 20 white people has one gene that can cause cystic fibrosis if present. The disease occurs when a person receives two of these genes (from the father and from the mother). In Russia, cystic fibrosis, according to various sources, occurs in one newborn out of 3500-5400, in the USA - in one in 2500. In this disease, the gene responsible for the production of protein is damaged, which regulates the movement of sodium and chlorine through the cell membranes. There is dehydration and an increase in the viscosity of the secretions of the glands. As a result, a thick secret blocks their activity. In patients with cystic fibrosis, protein and fat are poorly absorbed, as a result, growth and weight gain are greatly slowed down. Modern methods of treatment (taking enzymes, vitamins and a special diet) allow half of patients with cystic fibrosis to live more than 28 years.
Hemophilia- a genetic disease characterized by increased bleeding due to a deficiency of one of the blood coagulation factors. The disease is inherited in the female line, while affecting the vast majority of boys (on average, one in 8500). Hemophilia occurs when genes that are responsible for the activity of blood clotting factors are damaged. With hemophilia, there are frequent hemorrhages in the joints and muscles, which can ultimately lead to their significant deformation (that is, to a person's disability). People with hemophilia should avoid bleeding situations. People with hemophilia should not take drugs that reduce blood clotting (for example, aspirin, heparin, and some pain relievers). To prevent or stop bleeding, the patient is injected with a plasma concentrate containing a large amount of the missing coagulation factor.
Tay Sachs disease- a genetic disease characterized by the accumulation of phytanic acid (a product of the breakdown of fats) in the tissues. The disease occurs mainly among Ashkenazi Jews and French Canadians (one in 3600 newborns). Children with Tay-Sachs disease from an early age lag behind in development, then they become paralyzed and blind. As a rule, patients live up to 3-4 years. There is no cure for this disease.
The article reflects modern data on the prevalence, clinic, diagnosis, including prenatal and neonatal, more common hereditary diseases, the timing of studies for prenatal diagnosis and interpretation of the data obtained. Data on the principles of therapy for hereditary diseases are also presented.
Hereditary diseases- diseases, the occurrence and development of which is associated with changes (mutations) of the genetic material. Depending on the nature of the mutations, monogenic hereditary, chromosomal, mitochondrial and multifactorial diseases are distinguished. (E.K. Ginter, 2003). Congenital diseases should be distinguished from hereditary diseases, which are caused by intrauterine damage caused, for example, by infection (syphilis or toxoplasmosis) or the effect of other damaging factors on the fetus during pregnancy.
According to the WHO, 5-7% of newborns have various hereditary pathologies, in which monogenic forms make up 3-5%. The number of registered hereditary diseases (HD) is constantly growing. Many genetically determined diseases do not appear immediately after birth, but after some, sometimes very long, time. Not a single medical specialty can do without knowledge of the basics of medical genetics, since hereditary diseases affect all organs and systems of human organs. The key point of medical genetics is the development of methods for the diagnosis, treatment and prevention of hereditary human diseases.
Hereditary diseases have their own characteristics:
1. NBs are often family in nature. At the same time, the presence of the disease in only one of the members of the pedigree does not exclude the hereditary nature of this disease (new mutation, the appearance of a recessive homozygote).
2. With NB, several organs and systems are involved in the process at once.
3. NB is characterized by a progressive chronic course.
4. In NB, there are rare specific symptoms or their combinations: blue sclera speak of osteogenesis imperfecta, darkening of urine on diapers - about alkaptonuria, mouse smell - about phenylketonuria, etc.
Etiology of hereditary diseases. Etiological factors of hereditary diseases are mutations (changes) of hereditary material. Mutations affecting the entire chromosome set or individual chromosomes in it (polyploidy and aneuploidy), as well as sections of chromosomes (structural rearrangements - deletions, inversions, translocations, duplications, etc.) lead to the development of chromosomal diseases. In chromosomal diseases, the balance of the set of genes is disturbed, which can lead to intrauterine death of embryos and fetuses, congenital malformations and other clinical manifestations. The more chromosomal material is involved in the mutation, the earlier the disease manifests itself and the more significant the disturbances in the physical and mental development of the individual. There are about 1000 types of chromosomal abnormalities detected in humans. Chromosomal diseases are rarely transmitted from parent to child, mainly a new mutation that has arisen by chance. But about 5% of people are carriers of balanced changes in chromosomes, therefore, in case of infertility, stillbirth, recurrent miscarriage or the presence of a child with a chromosomal pathology in the family, it is necessary to examine the chromosomes of each of the spouses. Gene diseases are diseases caused by changes in the structure of the DNA molecule (gene mutations).
Monogenic diseases (actually hereditary diseases) - phenotypically gene mutations - can manifest themselves at the molecular, cellular, tissue, organ and organism levels.
Polygenic diseases (multifactorial) - diseases with a hereditary predisposition, caused by the interaction of several (or many) genes and environmental factors.
The contribution of hereditary and congenital diseases to infant and child mortality in developed countries (according to WHO materials) is great. Among the main causes of death before the age of 1 year, the share of perinatal factors is 28%, congenital and hereditary diseases -25%, sudden child death syndrome - 22%, infections -9%, others - 6%. The main causes of death at the age from 1 to 4 years are accidents (31%), congenital and hereditary diseases (23%), tumors (16%), infections (11%), others (6%).
The significant role of hereditary predisposition in the occurrence of widespread diseases (stomach and duodenal disease, essential hypertension, ischemic heart disease, ulcerative psoriasis, bronchial asthma, etc.) has been proven. Therefore, for the prevention and treatment of these diseases, it is necessary to know the mechanisms of interaction of environmental and hereditary factors in their occurrence and development.
Hereditary diseases did not respond to treatment for a long time, and the only method of prevention was the recommendation to refrain from childbearing. Those days are over. Modern medical genetics has armed clinicians with methods of early, pre-symptomatic (preclinical) and even prenatal diagnosis of hereditary diseases. Methods of preimplantation (before embryo implantation) diagnostics are being intensively developed and in some centers are already being used.
Now a harmonious system for the prevention of hereditary diseases has developed: medical and genetic counseling, pre-conceptual prevention, prenatal diagnostics, mass diagnostics in newborns of hereditary metabolic diseases amenable to dietary and drug correction, medical examination of patients and their families. The introduction of this system ensures a 60-70% reduction in the frequency of birth of children with congenital malformations and hereditary diseases.
Monogenic diseases (MB) or gene (as they are called abroad) diseases. MBs are based on single gene or point mutations. MB make up a significant proportion of hereditary pathology and today there are more than 4500 diseases. According to the literature, in different countries they are detected in 30-65 children per 1000 newborns, which is 3.0-6.5%, and in the structure of the total mortality of children under 5 years old, they account for 10-14%. Diseases are numerous and characterized by pronounced clinical polymorphism. Gene diseases are most often manifested by hereditary metabolic defects - fermentopathies. The same gene disease can be caused by different mutations. For example, over 200 such mutations are described in the cystic fibrosis gene, and 30 in the phenylketonuria gene. In some cases, mutations in different parts of the same gene can lead to various diseases (for example, mutations in the RET oncogene).
Pathological mutations can be realized at different periods of ontogenesis. Most of them are manifested in utero (up to 25% of all hereditary pathology) and at pre-pubertal age (45%). About 25% of pathological mutations appear in puberty and adolescence, and only 10% of monogenic diseases develop over the age of 20.
Substances that accumulate as a result of the absence or decrease in the activity of enzymes, either themselves have a toxic effect, or are included in the chain of secondary metabolic processes, as a result of which toxic products are formed. The overall frequency of gene diseases in human populations is 2-4%.
Gene diseases are classified: according to the types of inheritance (autosomal dominant, autosomal recessive, X-linked dominant, etc.); by the nature of the metabolic defect - hereditary metabolic diseases - NBO (diseases associated with a violation of amino acid, carbohydrate, lipid, mineral metabolism, nucleic acid metabolism, etc.); depending on the system or organ most involved in the pathological process (nervous, ocular, skin, endocrine, etc.).
Among the NBO, there are:
- diseases of amino acid metabolism (PKU, tyrosinosis, alkaptonuria, leucinosis, etc.);
- diseases of carbohydrate metabolism (galactosemia, glycogenosis, mucopolysaccharidosis);
- diseases of porphyrin and bilirubin metabolism (Gilbert, Crigler-Nayyard syndromes, porphyria, etc.);
- diseases of the biosynthesis of corticosteroids (adrenogenital syndrome, hypoaldosteronism, etc.);
- diseases of purine and pyramidine metabolism (orotic aciduria, gout, etc.);
- diseases of lipid metabolism (essential familial lipidosis, gangliosidosis, sphingolipidosis, cerebrosidosis, etc.);
- erythron disease (Fanconi anemia, hemolytic anemias, glucose-6-phosphate dehydrogenase deficiency, etc.);
- Metabolic diseases (Wilson-Konovalov, Menkes disease, familial periodic paralysis, etc.);
diseases of the transport of the kidney systems (de Toni-Debre-Fanconi disease, tubulopathy, vitamin D-resistant rickets, etc.).
Chromosomal diseases (chromosomal syndromes) 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 the development of an organism. 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 embryonic development during the cleavage of the zygote, the karyotype of the fetus will be mosaic. Mosaic organisms can contain several (2, 3, 4 or more) cell clones with different karyotypes. This phenomenon can 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 (chromosomal aberrations) and some genomic mutations (changes in the number of chromosomes). In humans, there are only 3 types of genomic mutations: tetraploidy, triploidy and aneuploidy. Of all the variants of aneuploidy, only trisomies by autosomes, polysomies by sex chromosomes (tri-, tetra- and pentasomies) are found, and from monosomies, only monosomy X.
All types of chromosomal mutations are found in humans: deletions, duplications, inversions and translocations. Deletion (lack of a site) in one of the homologous chromosomes means partial monosomy for this site, and duplication (duplication of a site) means partial trisomy.
Chromosomal diseases in newborns occur with a frequency of about 2.4 cases per 1000 births. Most chromosomal abnormalities (polyploidy, haploidy, trisomy for large chromosomes, monosomy) are incompatible with life - embryos and fetuses are eliminated from the mother's body, mainly in the early stages of pregnancy.
Chromosomal abnormalities also occur in somatic cells with a frequency of about 2%. Normally, such cells are eliminated by the immune system if they manifest themselves as foreign. However, in some cases (activation of oncogenes) chromosomal abnormalities can be the cause of malignant growth. For example, a translocation between chromosome 9 and 22 causes chronic myeloid leukemia.
Common to all forms of chromosomal disease is the multiplicity of damage. These are craniofacial lesions, congenital malformations of organ systems, delayed intrauterine and postnatal growth and development, mental retardation, dysfunctions of the nervous, immune and endocrine systems.
The phenotypic manifestations of chromosomal mutations depend on the following main factors: the characteristics of the chromosome involved in the abnormality (specific set of genes), the type of anomaly (trisomy, monosomy, complete, partial), the size of the missing (with partial monosomy) or excess (with partial trisomy) genetic material, the degree of mosaicity of the organism for aberrant cells, the genotype of the organism, environmental conditions. It has now become clear that with chromosomal mutations, the manifestations most specific for a particular syndrome are due to changes in small sections of chromosomes. So, specific symptoms of Down's disease are found with trisomy of a small segment of the long arm of chromosome 21 (21q22.1), cat cry syndrome - with deletion of the middle part of the short arm of chromosome 5 (5p15), Edwards syndrome - with trisomy of a segment of the long arm of chromosome
The final diagnosis of chromosomal diseases is established by cytogenetic methods.
Trisomies. The most common trisomies in humans are on the 21st, 13th and 18th pair of chromosomes.
Down syndrome (disease) (DM) - trisomy 21 syndrome is the most common form of chromosomal pathology in humans (1: 750). Cytogenetically, Down's syndrome is represented by simple trisomy (94% of cases), translocation form (4%) or mosaicism (2% of cases). In boys and girls, pathology occurs equally often.
It has been reliably established that children with Down syndrome are more likely to be born to older parents. The possibility of a second case of the disease in a family with trisomy 21 of chromosome 21 is 1-2% (with the age of the mother, the risk increases). Three quarters of all translocations in Down's disease are due to a de novo mutation. 25% of cases of translocation are familial, while the recurrent risk is much higher (up to 15%) and largely depends on which parent carries a symmetric translocation and which chromosome is involved.
Patients are characterized by: a rounded head with a flattened nape, narrow forehead, wide, flat face, typical epicanthus, hypertelorism, sunken nasal dorsum, oblique (Mongoloid) incision of the eye slits, Brushfield spots (light spots on the iris), thick lips, thickened tongue with deep grooves, protruding from the mouth, small, rounded, low set auricles with a hanging curl, underdeveloped upper jaw, high palate, abnormal growth of teeth, short neck.
Of the defects of internal organs, the most typical are heart defects (defects of the interventricular or interatrial septa, fibroelastosis, etc.) and digestive organs (duodenal atresia, Hirschsprung's disease, etc.). Among patients with Down syndrome with a higher frequency than in the population, there are cases of leukemia and hypothyroidism. Muscle hypotonia is pronounced in young children, and cataracts are often found in older children. From an early age, there is a lag in mental development. The average IQ is 50, but moderate mental retardation is more common. The average life expectancy in Down syndrome is significantly lower (36 years) than in the population.
Patau syndrome (SP) - trisomy 13 syndrome - occurs with a frequency of 1: 7000 (taking into account stillbirths). There are two cytogenetic variants of Patau syndrome: simple trisomy and Robertsonian translocation. 75% of cases of trisomy of chromosome 13 are due to the appearance of an additional chromosome 13. There is a relationship between the incidence of Patau syndrome and the age of the mother, although it is less strict than in the case of Down's disease. 25% of cases of SP are a consequence of translocation involving chromosomes of the 13th pair, including de novo mutation in three out of four such cases. In a quarter of cases, translocation involving chromosomes of the 13th pair is hereditary with a recurrent risk of 14%.
With SP, severe congenital defects are observed. Children with Patau syndrome are born with a body weight below normal (2500 g). They have: moderate microcephaly, impaired development of various parts of the central nervous system, low sloping forehead, narrowed eye slits, the distance between which is reduced, microphthalmia and coloboma, corneal opacity, - sunken nose bridge, wide base of the nose, deformed auricles, cleft of the upper lip and palate , polydactyly, flexor position of the hands, short neck.
In 80% of newborns, cardiac malformations are found: defects of the interventricular and interatrial septa, vascular transposition, etc. Fibrocystic changes in the pancreas, accessory spleens, and embryonic umbilical hernia are observed. The kidneys are enlarged, have increased lobulation and cysts in the cortical layer, malformations of the genital organs are revealed. For SP is characterized by mental retardation.
The majority of patients with Patau syndrome (98%) die before the age of one year, the survivors suffer from profound idiocy.
Edwards syndrome (SE) - trisomy 18 syndrome - occurs with a frequency of approximately 1 in 7000 (including stillbirths). Children with trisomy 18 are more often born to older mothers, the relationship with the mother's age is less pronounced than in cases of trisomy 21 and 13. For women over 45, the risk of having a sick child is 0.7%. Cytogenetically, Edwards syndrome is represented by simple trisomy 18 (90%), mosaicism is observed in 10% of cases. It occurs in girls much more often than in boys, which is possibly due to the greater vitality of the female body.
Children with trisomy 18 are born with a low birth weight (average 2177 g), although the gestational age is normal or even exceeding the norm.
The phenotypic manifestations of Edwards syndrome are diverse: anomalies of the cerebral and facial skull are often noted, the cerebral skull is dolichocephalic, the lower jaw and mouth opening are small, the palpebral fissures are narrow and short, the auricles are deformed and in the overwhelming majority of cases are located low, somewhat elongated in the horizontal plane, the lobe , and often the tragus is absent; the external auditory canal is narrowed, sometimes absent, the sternum is short, due to which the intercostal spaces are reduced and the rib cage is wider and shorter than normal, abnormal development of the foot: the heel protrudes sharply, the arch sags (rocking foot), the big toe is thickened and shortened; defects of the heart and large vessels are noted: a defect of the interventricular septum, aplasia of one cusp of the valves of the aorta and pulmonary artery, hypoplasia of the cerebellum and corpus callosum, changes in olive structures, severe mental retardation, decreased muscle tone, turning into an increase with spasticity.
The life expectancy of children with Edwards syndrome is short: 60% of children die before the age of 3 months, only one child in ten survives to one year; the survivors are deeply oligophrenic.
Trisomy X syndrome. The frequency of occurrence is 1: 1000. Karyotype 47, XXX. Currently, there are descriptions of tetra- and pentosomies X. Trisomy on the X-chromosome occurs as a result of nondisjunction of sex chromosomes in meiosis or during the first division of the zygote.
Polysomy X syndrome has significant polymorphism. The female body with a masculine physique. Primary and secondary sexual characteristics may be underdeveloped. In 75% of cases, patients have a moderate degree of mental retardation. Some of them have impaired ovarian function (secondary amenorrhea, dysmenorrhea, early menopause). Sometimes such women can have children. The risk of schizophrenia is increased. With an increase in the number of additional X chromosomes, the degree of deviation from the norm increases.
Shereshevsky-Turner syndrome (monosomy X). The frequency of occurrence is 1: 1000.
Karyotype 45, X. 55% of girls with this syndrome have a 45, X karyotype, 25% have a change in the structure of one of the X chromosomes. In 15% of cases, mosaicity is detected in the form of two or more cell lines, one of which has a karyotype 45, X, and the other is represented by karyotypes 46, XX or 46, XY. The third cell line is most often represented by the karyotype 45, X, 46 ^ XX, 47, XXX. The risk of inheriting the syndrome is 1 in 5000 newborns. The phenotype is female.
In newborns and infants, there are signs of dysplasia (short neck with excess skin and pterygoid folds, lymphatic edema of the feet, legs, hands and forearms, hallux valgus, multiple age spots, short stature. 135-145 cm) and in the development of secondary sexual characteristics.For adults, it is characteristic: low location of the auricles, underdevelopment of primary and secondary sexual characteristics, gonadal dysgenesis, accompanied by primary amenorrhea, 20% of patients have heart defects (coarctation of the aorta, aortic stenosis, malformations development of the mitral valve), in 40% - kidney defects (doubling of the urinary tract, horseshoe kidney).
Patients with a Y-chromosome cell line may develop gonadoblastoma, and autoimmune thyroiditis is often observed. Intelligence rarely suffers. Ovarian underdevelopment leads to infertility. To confirm the diagnosis, along with the study of peripheral blood cells, a skin biopsy and a study of fibroblasts are performed. In some cases, genetic testing reveals Noonan syndrome, which has similar phenotypic manifestations, but is not etiologically associated with Shereshevsky-Turner syndrome. Unlike the latter, with Noonan syndrome, both boys and girls are susceptible to the disease, and mental retardation dominates in the clinical picture, the Turner phenotype is characteristic with a normal male or female karyotype. Most patients with Noonan syndrome have normal sexual development and fertility. In most cases, the disease does not affect the life expectancy of patients.
Klinefelter's syndrome. The frequency of occurrence is 1: 1000 boys. Karyotype 47, XXY. In 80% of boys with Klinefelter's syndrome, mosaicism is found in 20% of cases, in which one of the cell lines has a 47, XXY karyotype. The recurrent risk for Klinefelter syndrome does not exceed the general population indicators and is 1 case in 2000 live births. The phenotype is male.
The clinic is distinguished by a wide variety and non-specificity of manifestations. In boys with this syndrome, the height exceeds the average indicators typical for this family, they have long limbs, a female body type, gynecomastia. Poorly developed hairline, reduced intelligence. Due to the underdevelopment of the testes, primary and secondary sexual characteristics are poorly expressed, the course of spermatogenesis is impaired. Sexual reflexes are preserved. Early treatment with male sex hormones is sometimes effective. The more X chromosomes there are in the set, the more significantly reduced intelligence. Infantilism and behavioral problems in Klinefelter's syndrome create difficulties in social adaptation.
Sometimes there are cases of an increase in the number of Y-chromosomes: XYY, XXYY, etc. In this case, patients have signs of Klinefelter's syndrome, high growth (on average 186 cm) and aggressive behavior. There may be anomalies of the teeth and skeletal system. The sex glands are developed normally. The more Y-chromosomes in the set, the more significant the decrease in intelligence is the aggressive behavior.
In addition to complete trisomy and monosomy, syndromes are known associated with partial trisomy and monosomy on almost any chromosome. However, these syndromes are less common than one case per 100,000 births.
Diagnostics of NB. In clinical genetics, for the diagnosis of various forms of hereditary pathology, the following are used: the clinical and genealogical method, special and additional (laboratory, instrumental) research methods.
Medical genetic counseling. The main goal of medical genetic counseling is to inform interested persons about the likelihood of the risk of occurrence in the offspring of patients. The promotion of genetic knowledge among the population also belongs to medico-genetic activities, since this contributes to a more responsible approach to childbirth. Medical genetic counseling refrains from coercive or rewarding measures in matters of childbirth or marriage, assuming only the function of information.
Medical genetic counseling (MGC) is a specialized assistance to the population to prevent the appearance of patients with hereditary pathology in the family, to identify, consult patients with NB, inform the population about NB, as well as ways to prevent and treat it.
The main tasks of the MGK:
- establishing an accurate diagnosis of a hereditary disease and determining the type of inheritance of the disease in a given family;
- making a prognosis for the birth of a child with a hereditary disease, calculating the risk of recurrence of the disease in the family;
- determining the most effective way of prevention, helping the family in making the right decision;
- propaganda of medico-genetic knowledge among doctors, the population.
Indications for MGK:
- delayed physical development; dwarf growth (no more than 140 cm for adults), congenital deformity of the upper and / or lower extremities, fingers, spine, chest, skull, deformity of the face, change in the number of fingers and toes, syndactyly, combinations of congenital deformities, congenital fragility of bones;
- delayed sexual development, undetermined gender; underdevelopment of NGOs and secondary sexual characteristics;
- mental retardation, mental retardation, congenital deafness or deaf-dumbness;
- increased number of stigmas of dysembryogenesis;
- multiple malformations or a combination of isolated malformations and small developmental anomalies;
- muscle atrophy, muscle hypertrophy, spastic muscle twitching, violent movements, paralysis, non-traumatic lameness, gait disturbance, immobility or stiffness in the joints;
- blindness, microphthalmos, congenital cataract, congenital glaucoma, colobomas, aniridia, nystagmus, ptosis, progressive deterioration of twilight vision;
- dryness or increased keratinization of the skin of the palms and soles, other parts of the body, brown spots and multiple tumors on the skin, spontaneous or induced blistering, absence of nails, alopecia, dentition;
- chronic progressive diseases of unknown origin;
- a sharp deterioration in the condition after a short period of normal development of the child. The asymptomatic interval can range from several hours to weeks and depends on the nature of the defect, diet and other factors;
- lethargy or, conversely, increased tone and convulsions in a newborn, incessant vomiting in a newborn, progressive neurological disorders;
- unusual body and / or urine odor ("sweet", "mouse", "boiled cabbage", "sweaty feet"), etc .;
- the presence in the family of hereditary pathology, developmental defects, similar cases of the disease in the family, cases of sudden death of a child at an early age;
- infertility, recurrent miscarriage, stillbirth;
- consanguineous marriage
Even before planning childbirth, as well as at the birth of a sick child (retrospectively), each married couple should undergo medical genetic counseling.
Stages of the IGC:
1. Verification of the clinical diagnosis of hereditary (or presumably
hereditary).
2. Establishing the nature of the inheritance of the disease in the consulted family.
3. Assessment of the genetic risk of recurrence of the disease (genetic prognosis).
4. Determination of methods of prevention.
5. Explaining to the applicants the meaning of the collected and analyzed medical and genetic information.
Methods for prenatal diagnosis of hereditary diseases. Prenatal diagnostics is associated with solving a number of biological and ethical problems before the birth of a child, since this is not about curing the disease, but about preventing the birth of a child with a pathology that cannot be treated (usually by terminating pregnancy with the woman's consent and holding a perinatal consultation). At the current level of development of prenatal diagnostics, it is possible to establish a diagnosis of all chromosomal diseases, most congenital malformations, enzymopathies, in which a biochemical defect is known. Some of them can be established at almost any stage of pregnancy (chromosomal diseases), some - after 11-12 weeks (reduction defects of the limbs, atresia, anencephaly), some - only in the second half of pregnancy (heart, kidney, central nervous system).
Table 1
Scheme of examination of a pregnant woman to assess the state of intrauterine development of the fetus (according to the order of the Ministry of Health of the Russian Federation No. 457 of 12/28/2000)
| Study type | Purpose of the study |
| The first stage of the study (10-14 weeks of pregnancy) | |
| Ultrasound examination of all pregnant women in antenatal clinics Chorionic villus aspiration (according to indications): - the age of the pregnant woman is over 35 years old - family carriage of a chromosomal abnormality - family history of an identified monogenic disease - Ultrasound markers (extended TVP) | Establishment of the duration and nature of the course of pregnancy. Mandatory assessment of the thickness of the collar space, the state of the chorion. Formation of a risk group for chromosomal pathology and for some congenital malformations in the fetus. Cytogenetic diagnosis of chromosomal pathology, fetal sex determination. |
| The second stage of the study (20-24 weeks of pregnancy) | |
| Ultrasound examination Doppler study of uteroplacental blood flow. | A detailed assessment of the anatomy of the fetus in order to detect malformations, markers of chromosomal diseases, early forms of fetal growth retardation, pathologies of the placenta, abnormal amounts of water. Formation of a risk group for the development of preeclampsia, fetal growth retardation, placental insufficiency in the third trimester. Formation of a risk group for the birth of children with chromosomal diseases and some congenital malformations. Cytogenetic diagnosis of chromosomal diseases in the fetus. Diagnostics of a specific form of a monogenic disease by methods of biochemical or DNA diagnostics using fetal cells. |
| The third stage of the study (32-34 weeks of pregnancy) | |
| Ultrasound examination of all pregnant women in antenatal clinics | Assessment of fetal growth rates, detection of congenital malformations with late manifestation. Assessment of the state of development of the fetus. |
Indications for prenatal diagnosis:
- the presence in the family of a well-established hereditary disease;
- the mother's age is over 37 years old;
- carriage by the mother of the X-linked recessive disease gene;
- a history of spontaneous abortions in pregnant women in early pregnancy, stillbirths of unknown origin, children with multiple malformations and chromosomal abnormalities;
- the presence of structural rearrangements of chromosomes (especially translocations and inversions) in one of the parents;
- heterozygosity of both parents for one pair of alleles in pathology with an autosomal recessive type of inheritance;
- pregnant women from the zone of high radiation background.
Currently, indirect and direct methods of prenatal diagnosis are used.
With indirect methods, a pregnant woman is examined (obstetric and gynecological methods, blood serum for alpha-fetoprotein, hCG, n-estriol, PAPP-a protein); with straight lines - the fruit.
Direct non-invasive (without surgery) methods include ultrasonography; to direct invasive (with violation of tissue integrity) - chorion biopsy, amniocentesis, cordocentesis and fetoscopy.
Ultrasonography (echography) is the use of ultrasound to obtain an image of the fetus and its membranes, the state of the placenta. From the 5th week of pregnancy, you can get an image of the membranes of the embryo, and from the 7th week - and the embryo itself. By the end of the 6th week of pregnancy, the cardiac activity of the embryo can be recorded. In the first two months of pregnancy, ultrasound does not yet reveal fetal abnormalities, but it is possible to determine its viability. At 12-20 weeks of pregnancy, it is already possible to diagnose twin pregnancy, localization of the placenta, malformations of the central nervous system, gastrointestinal tract, MPS, osteoarticular system, congenital heart disease, etc.
The general opinion is that the method is safe, therefore, the duration of the study is not limited and, if necessary, it can be reused. In the physiological course of pregnancy, it is necessary to carry out a three-fold ultrasound scan, and in pregnancy with a high risk of complications, it is repeated at intervals of 2 weeks.
Ultrasound can detect developmental anomalies in the fetus in 85-90% of cases - anencephaly, hydrocephalus, polycystic or agenesis of the kidneys, dysplasia of the extremities, hypoplasia of the lungs, multiple congenital defects, heart defects, dropsy (edema) of the fetus and placenta, etc. data on the size of the fetus (length of the trunk, thigh, shoulder, biparietal diameter of the head), on the presence of dysmorphia, on the function of the myocardium, on the volume of amniotic fluid and the size of the placenta.
Doppler ultrasound scanning (as well as color Doppler imaging) reflects blood circulation in various tissues of the fetus.
Echography of the placenta allows you to establish its location, the presence of detachment of its individual areas, cysts, calcifications (a sign of "aging" of the placenta). Thinning or thickening of the placenta indicates the likelihood of fetoplacental insufficiency.
A triad of research methods has become widespread: the study of the level of alpha-fetoprotein, the content of chorionic gonadotropin (CG) and free estriol in the blood of women in the 2nd trimester of pregnancy. The content of alpha-fetoprotein is also determined in the amniotic fluid, and free estriol in the urine of pregnant women. Deviations in the plasma levels of alpha-fetoprotein, chorionic gonadotropin, free estriol in a pregnant woman serve as indicators of a high risk to the fetus. Threshold (indicating a high risk) are the levels of alpha-fetoprotein and hCG in the blood of a pregnant woman, exceeding 2 MoM, and for a reduced level of alpha-fetoprotein in Down's disease, the threshold value is less than 0.74 MoM. A decrease in the level of free estriol, corresponding to a value of 0.7 MoM and below, is also taken as a threshold, indicating placental insufficiency.
Alpha-fetoprotein is found in the amniotic fluid as early as the 6th week of pregnancy (1.5 μg / ml); its highest concentration is observed at 12-14 weeks (about 30 μg / ml); then it sharply decreases and at the 20th week it is only 10 μg / l. Good results are obtained by determining the level of alpha-fetoprotein in the mother's blood serum at a period of 16-20 weeks. pregnancy. Its increase is due to the intake of this protein from the serum of the fetus through the placenta with some malformations.
All pregnant women with altered levels of alpha-fetoprotein in the blood require additional examination. The content of alpha-fetoprotein in biological fluids is increased in case of multiple malformations, spinal hernia, hydrocephalus, anencephaly, malformations of the gastrointestinal tract and defects of the anterior abdominal wall, hydronephrosis and agenesis of the kidneys, as well as in fetoplacental insufficiency, fetal retention, multiple fetuses , preeclampsia, Rh-conflict and viral hepatitis B.
In cases of chromosomal diseases in the fetus (for example, Down's disease) or the presence of type I diabetes mellitus in a pregnant woman, on the contrary, the concentration of alpha-fetoprotein in the blood of pregnant women is reduced.
An increase in the level of hCG and its free beta-subunits of more than 2 MoM indicates a delay in intrauterine development of the fetus, a high risk of antenatal fetal death, placental abruption, or other types of placental insufficiency
Currently, the study of serum markers is carried out in the 1st trimester of pregnancy by simultaneously determining the specific for pregnant protein A. (PAPP-a) and hCG.This makes it possible to diagnose Down's disease and some other chromosomal abnormalities in the fetus already at 10-13 weeks of gestation.
Invasive diagnostic methods:
Chorion biopsy - taking the epithelium of the chorionic villi for examination is carried out transabdominally under the control of ultrasonography between the 9th and 14th weeks of gestation.
Placentopuncture is performed from 15 to 20 weeks. pregnancy.
The resulting tissue is used for cytogenetic and biochemical studies and DNA analysis. This method can detect all types of mutations (gene, chromosomal and genomic). If any abnormalities in the development of the fetus are detected, the parents decide to terminate the pregnancy, then terminate the pregnancy until the 12th week.
Amniocentesis is the collection of amniotic fluid and fetal cells for further analysis. This study became possible after the development of the technology of transabdominal amniocentesis, carried out under the guidance of ultrasound. Obtaining the test material (cells and fluid) is possible at the 16th week of pregnancy. The amniotic fluid is used for biochemical studies (gene mutations are detected), and cells are used for DNA analysis (gene mutations are detected), cytogenetic analysis and the detection of X and Y chromatin (genomic and chromosomal mutations are diagnosed). Simple biochemical studies of amniotic fluid can provide valuable diagnostic information - studies of the content of bilirubin, estriol, creatinine, cortisol, 17-hydroxyprogesterone, the ratio of lecithin and sphingomyelin. Diagnosis of adrenogenital syndrome in the embryo (21-hydroxylase deficiency) is possible already at the 8th week of gestation, when an increased content of 17-hydroxyprogesterone is found in the amniotic fluid.
The study of the spectrum of amino acids of the amniotic fluid makes it possible to identify some hereditary metabolic diseases in the fetus (arginine-succinic aciduria, citrullinuria, etc.), and the determination of the spectrum of organic acids is used to diagnose organic aciduria (propionic, methylmalonic, isovaleric aciduria, etc.).
To recognize the severity of hemolytic disease in the fetus with Rh sensitization of a pregnant woman, a direct spectrophotometric study of the amniotic fluid is performed.
Cordocentesis - taking blood from the umbilical cord of the fetus, the cells and serum of which are used for cytogenetic, molecular genetic and biochemical studies. This procedure is performed from the 21st to the 24th week of pregnancy under ultrasound control. Cordocentesis can also be performed during embryopetoscopy. For example, the determination of virus-specific DNA or RNA (by reverse transcription) in fetal blood is crucial for the diagnosis of intrauterine infections - HIV, rubella, cytomegaly, parvovirus B19.
Fetoscopy - examination of the fetus with a fiberoptic endoscope inserted into the amniotic cavity through the anterior wall of the uterus. The method allows you to examine the fetus, umbilical cord, placenta and make a biopsy. Fetoscopy is accompanied by a high risk of termination of pregnancy and is technically difficult, therefore, has limited application.
Modern technologies allow biopsy of the skin, muscles, and fetal liver for the diagnosis of genodermatosis, muscular dystrophy, glycogenosis and other severe hereditary diseases.
The risk of termination of pregnancy when using invasive methods of prenatal diagnosis is 1-2%.
Vesicocentesis, or puncture of the fetal bladder, is used to obtain urine for examination in cases of serious diseases and malformations of the organs of the urinary system.
Pre-implantation diagnosis of serious hereditary diseases has become possible in the last decade thanks to the development of in vitro fertilization technology and the use of polymerase chain reaction to obtain multiple copies of embryonic DNA. At the stage of cleavage of a fertilized egg (blastocyst), when the embryo consists of 6-8 individual cells, one of them is separated by micromanipulation methods for DNA extraction, its multiplication and subsequent analysis using DNA probes (primer polymerase chain reaction, Sauthern-blot, research polymorphism of restriction DNA fragments, etc.). This technology is used to detect hereditary diseases - Tay-Sachs, hemophilia, Duchenne muscular dystrophy, fragile X-chromosome and a number of others. However, it is available to few large centers and has a very high research cost.
Methods are being developed for isolating fetal cells (erythroblasts, trophoblasts, etc.) circulating in the blood of a pregnant woman for carrying out cytogenetic, molecular genetic and immunological analyzes for diagnostic purposes. So far, such a diagnosis is possible only in cases where the blood cells (erythroblasts) of the pregnant woman have chromosomes or fetal genes, for example, the Y chromosome, the Rh factor gene in a Rh negative woman, and HLA antigens inherited from the father.
Further development and dissemination of methods for prenatal diagnosis of hereditary diseases will significantly reduce the incidence of hereditary pathology in newborns.
Neonatal screening. Within the framework of the ongoing Priority National Project "Health", the expansion of neonatal screening is envisaged, and now screening for phenylketonuria, congenital hypothyroidism, adrenogenital syndrome, galactosemia, cystic fibrosis is being carried out. Mass screening of newborns (neonatal screening) for NBO is the basis for the prevention of hereditary diseases in populations. Neonatal diagnostics of hereditary diseases makes it possible to determine the prevalence of the disease in a specific territory, in a specific constituent entity of the Russian Federation and in the country as a whole, to ensure early detection of children suffering from hereditary diseases and to begin treatment in a timely manner, prevent disability and the development of severe clinical consequences, and reduce child mortality from hereditary diseases. , to identify families in need of genetic counseling in order to prevent the birth of children with these hereditary diseases.
In the medical genetic consultation of the Perinatal Presidential Center of the Ministry of Health of the Czech Republic, neonatal screening is carried out, registration of all born and identified patients with hereditary pathology. The Republican register of hereditary diseases has been created, which makes it possible to predict the dynamics of the genetic load in the population and develop the necessary medical and social measures
The structure of chromosomal abnormalities for 1991-2008
| No. p \ p | Nosology | Qty. | Percentage of all pathology |
| 1 | S. Down | 217 | 35,57 |
| 2 | S. Shereshevsky - Turner | 114 | 18,68 |
| 3 | S. Klinefelter | 76 | 12,45 |
| 4 | S. Edwards | 6 | 0,9 |
| 5 | S. Patau | 4 | 0,65 |
| 6 | Polysomy for Y-chromosome | 4 | 0,65 |
| 7 | Polysomy on the X chromosome | 6 | 0,9 |
| 8 | Sex chromosome abnormalities | 18 | 2,95 |
| 9 | Minor chromosome abnormalities | 66 | 10,82 |
| 10 | Chromosomal aberrations | 88 | 14,42 |
| 11 | HML | 12 | 1,96 |
| TOTAL | 610 | 100 |
Analysis by years in recent years has not revealed a significant increase in the frequency of birth of children with hereditary pathology in the republic, but the frequency of birth of children with congenital defects is growing from year to year, especially congenital heart disease.
The results of newborn screening for hereditary metabolic diseases in the Chuvash Republic for the period from 1999-2008.
| Hereditary metabolic disease | Newborns examined | Revealed | The incidence of the disease in the Chuvash Republic | The incidence of the disease in the Russian Federation (Novikov P.V., 2008) |
| phenylketonuria | 117 559 | 18 | 1: 6531 | 1: 7 697 |
| congenital hypothyroidism | 115 878 | 56 | 1: 2069 | 1: 4 132 |
| cystic fibrosis | 43187 | 3 | 1: 14395 | 1: 11 585 |
| adrenogenital syndrome | 43187 | 2 | 1: 21593 | 1: 8 662 |
| galactosemia | 39849 | 1 | 1: 39849 | 1: 32 692 |
Treatment of hereditary diseases. Despite the great success in improving cytogenetic, biochemical and molecular methods for studying the etiology and pathogenesis of NZ, symptomatic treatment remains the main one, which differs little from the treatment of any other chronic diseases. And yet, at the present time in the arsenal of geneticists there are many means of pathogenetic treatment; first of all, it concerns hereditary metabolic diseases (NBO). Clinical manifestations in NBO are the result of disturbances in the chain of transformations (metabolism) of products (substrates) in the human body; gene mutation leads to defective enzymes and coenzymes. Pathogenetic therapy has been developed for approximately 30 NBOs. There are several directions of NBO therapy:
1. Diet therapy. Restriction or complete cessation of the intake of products into the body, the metabolism of which is impaired as a result of an enzymatic block. This technique is used in cases where excessive accumulation of the substrate has a toxic effect on the body. Sometimes (especially when the substrate is not vital and can be synthesized in sufficient quantity by roundabout ways) such diet therapy has a very good effect. A typical example is galactosemia. The situation is somewhat more complicated with phenylketonuria. Phenylalanine is an essential amino acid, therefore it cannot be completely excluded from food, but the physiologically necessary dose of phenylalanine must be individually selected for the patient. Also, diet therapy has been developed for tyrosinemia, leucinosis, hereditary fructose intolerance, homocystinuria, etc.
2. Replenishment of coenzymes. In a number of NBOs, it is not the amount of the required enzyme that changes, but its structure, as a result of which the binding with the coenzyme is disrupted, and a metabolic block occurs. Most often we are talking about vitamins. Additional administration to the patient of co-ferments (more often certain doses of vitamins) gives a positive effect. Pyridoxine, cobalamin, thiamine, carnitine preparations, folates, biotin, riboflavin, etc. are used as such "helpers".
3. Enhanced excretion of toxic products that accumulate in case of blocking their further metabolism. Such products include, for example, copper for Wilson-Konovalov disease (D-penicillamine is administered to the patient to neutralize copper), iron for hemoglobinopathies (desferal is prescribed to prevent hemosiderosis of parenchymal organs.
4. Artificial introduction into the patient's body of the product of the blocked reaction. For example, taking cytidylic acid for orthoaciduria (a disease in which the synthesis of pyrimidines suffers) eliminates the phenomena of megaloblastic anemia.
5. Impact on "spoiled" molecules. This method is used to treat sickle cell anemia and is aimed at reducing the likelihood of hemoglobin 3 crystals forming. Acetylsalicylic acid enhances the acetylation of HbS and thus reduces its hydrophobicity, which causes the aggregation of this protein.
6. Replacement of the missing enzyme. This method is successfully used in the treatment of adrenogenital syndrome (administration of steroid hormones with gluco- and mineralocorticoid activity), pituitary dwarfism (administration of growth hormone), hemophilia (antihemophilic globulin). However, for effective treatment, it is necessary to know all the subtleties of the pathogenesis of the disease, its biochemical mechanisms. New advances on this path are associated with the achievements of physicochemical biology, genetic engineering and biotechnology.
7. Blocking the pathological activity of enzymes using specific inhibitors or competitive inhibition by analogs of the substrates of this enzyme. This method of treatment is used for excessive activation of blood coagulation systems, fibrinolysis, as well as for the release of lysosomal enzymes from destroyed cells.
Transplantation of cells, organs and tissues is increasingly used in the treatment of ND. Thus, normal genetic information is introduced into the patient's body together with the organ or tissue, which ensures the correct synthesis and work of enzymes and protects the body from the consequences of the mutation that has occurred. Allotransplantation is used to treat: Di Giorgi syndromes (hypoplasia of the thymus and parathyroid glands) and Nezelof - thymus transplantation; recessive osteopetrosis, mucopolysaccharidosis, Gaucher disease, Fanconi anemia - bone marrow transplant; primary cardiomyopathies - heart transplant; Fabry disease, amyloidosis, Alport syndrome, hereditary polycystic kidney disease - kidney transplant, etc.
The latest new direction in the treatment of hereditary diseases is gene therapy. This direction is based on the transfer of genetic material into the human body, and the following conditions must be met: decoding of the gene that causes the disease, knowledge of biochemical processes in the body controlled by this gene, successful delivery of the gene to target cells (through vector systems using viruses, chemical and physical methods) and long-term effective work of the transplanted gene in the body.
M.V. Krasnov, A.G. Kirillov, V.M. Krasnov, E.N. S. Avaskin, A.V. Abrukova
Chuvash State University named after I. N. Ulyanova
Presidential Perinatal Center of the Ministry of Health of the SR CR
Krasnov Mikhail Vasilievich - Doctor of Medical Sciences, Professor, Head of the Department of Childhood Diseases
Literature:
1. Ginter E.K. Ginter EK, Zinchenko R.A. Hereditary diseases in Russian populations. VOGiS Bulletin 2006; vol. 10: 1: 106-125.
2. Ginter E.K. Medical genetics: textbook. M. 2003.448s.
3. Vakharlovsky V.G., Romanenko OP, Gorbunova V.N. Genetics in Pediatric Practice: A Guide for Physicians. SPb. 2009.288s.
4. Valivach M.N., Bugembaeva M.D. A Quick Guide to Diagnostic Criteria for Physicians, ICD-10, 2003
5. Zinchenko R.A., Elchinova G.I., Kozlova SI. and other Epidemiology of hereditary diseases in the Republic of Chuvashia. Medical Genetics 2002; vol. 1: 1: 24-33
6. Zinchenko R.A., Kozlova S.I., Galkina V.A., Ginter E.K. The occurrence of isolated brachydactyly B in Chuvashia. Medical Genetics 2004; vol. 3: 11: 533-
7. Zinchenko R.A., Mordovtseva V.V., Petrov A.N., Ginter E.K. Hereditary recessive hypotrichosis in the republics of Mari El and Chuvashia. Medical Genetics 2003: vol. 2: 6: 267-272.
8. Kozlova S.I., Demikova N.S. Hereditary syndromes and medical genetic counseling. M., 2007.448s.
9. Kozlova SI, Demikova NS Hereditary syndromes and medical genetic counseling: atlas-reference book 3rd ed., Revised. and add. Publisher: Partnership of Scientific Publications "KMK" Year of publication: 2007. 448 p.
10. Prenatal dianostika of hereditary and congenital diseases. Edited by Acad. RAMS, prof. E.K. Fylamazyan, Corresponding Member of RAMS, prof. V.S.Baranova. M. 2007.416s.
11. Petrovsky V.I. First aid. Popular Encyclopedia, M., 1994.
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Everything genetic diseases, of which several thousand are known today, are caused by abnormalities in human genetic material (DNA).
Genetic diseases can be associated with a mutation of one or more genes, with a violation of the location, the absence or duplication of whole chromosomes (chromosomal diseases), as well as with maternally transmitted mutations in the genetic material of mitochondria (mitochondrial diseases).
More than 4000 single gene disorders alone have been described.
A little about genetic diseases
Medicine has long known that different ethnic groups have a predisposition to certain genetic diseases. For example, people from the Mediterranean Sea region are more likely to suffer from thalassemias. We know that the age of the mother strongly affects the risk of a number of genetic diseases in the child.It is also known that some genetic diseases arose in us as an attempt by the body to resist the environment. Sickle cell anemia, according to modern data, originated in Africa, where for many thousands of years malaria was a real scourge of humanity. In sickle cell disease, humans have a red blood cell mutation that makes the host resistant to Plasmodium malaria.
Scientists today have developed tests for hundreds of genetic diseases. We can test for cystic fibrosis, Down's syndrome, fragile X syndrome, hereditary thrombophilia, Bloom's syndrome, Canavan's disease, Fanconi's anemia, familial dysautonomy, Gaucher's disease, Niemann-Pick disease, Klinefelter's syndrome, thalassemias and many other diseases.
Cystic fibrosis.
Cystic fibrosis, known in English literature as cystic fibrosis, is one of the most common genetic diseases, especially in Caucasian and Ashkenazi Jews. It is caused by a deficiency in protein, which controls the balance of chloride in cells. The result of a deficiency of this protein is the thickening and disruption of the properties of the secretion of the glands. Cystic fibrosis is manifested by impaired functions of the respiratory system, digestive tract, and reproductive system. Symptoms can range from mild to very severe. For the disease to occur, both parents must be carriers of the defective genes.Down Syndrome.
This is the most famous chromosomal disorder that occurs due to the presence of excess genetic material on chromosome 21. Down syndrome is recorded in 1 child per 800-1000 newborns. This disease is easy to detect with prenatal screening. The syndrome is characterized by anomalies in the structure of the face, decreased muscle tone, malformations of the cardiovascular and digestive systems, as well as developmental delay. Children with Down syndrome have different symptoms, ranging from mild to very severe developmental disabilities. This disease is equally dangerous for all ethnic groups. The most important risk factor is the mother's age.Fragile X syndrome.
Fragile X syndrome, or Martin-Bell syndrome, is associated with the most common type of congenital mental retardation. Developmental delays can be very mild or severe, and sometimes the syndrome is associated with autism. This syndrome is found in 1 in 1,500 men and 1 in 2,500 women. The disease is associated with the presence of abnormal repeating areas on the X chromosome - the more such areas, the more severe the disease progresses.Hereditary coagulation disorders.
Blood coagulation is one of the most complex biochemical processes occurring in the body, so there is a huge variety of clotting disorders at different stages. Clotting disorders can lead to bleeding tendencies or, conversely, the formation of blood clots.Known diseases include thrombophilia associated with a Leiden mutation (factor V Leiden). There are other genetic coagulation disorders, including prothrombin (factor II) deficiency, protein C deficiency, protein S deficiency, antithrombin III deficiency, etc.
Everyone has heard of hemophilia - a hereditary disorder of coagulation, in which there are dangerous hemorrhages in internal organs, muscles, joints, abnormal menstrual bleeding is observed, and any minor injury can lead to irreparable consequences due to the inability of the body to stop the bleeding. The most common is hemophilia A (coagulation factor VIII deficiency); also known hemophilia B (deficiency of factor IX) and hemophilia C (deficiency of factor XI).
There is also a very common von Willebrand disease, in which spontaneous bleeding occurs due to a low level of factor VIII. The disease was described in 1926 by the Finnish pediatrician von Willebrand. American researchers believe that 1% of the world's population suffers from it, but in most of them the genetic defect does not cause serious symptoms (for example, women can only have heavy periods). Clinically significant cases, in their opinion, are observed in 1 person in 10,000, that is, in 0.01%.
Familial hypercholesterolemia.
This is a group of hereditary metabolic disorders that are manifested by abnormally high levels of lipids and cholesterol in the blood. Familial hypercholesterolemia is associated with obesity, impaired glucose tolerance, diabetes, strokes and heart attacks. Treatment for the disease includes lifestyle changes and a strict diet.Huntington's disease.
Huntington's disease (sometimes Huntington's) is an inherited disorder that causes gradual degeneration of the central nervous system. Loss of function of nerve cells in the brain is accompanied by behavioral changes, unusual abrupt movements (chorea), uncontrolled muscle contractions, difficulty walking, memory loss, speech and swallowing disorders.Modern treatment is aimed at combating the symptoms of the disease. Huntington's disease usually begins to manifest itself at the age of 30-40, and before that a person may not know about his fate. Less often, the disease begins to progress already in childhood. This is an autosomal dominant disease - if one of the parents has a defective gene, then the child has a 50% chance of getting it.
Duchenne muscular dystrophy.
With Duchenne muscular dystrophy, symptoms usually appear before the age of 6 years. These include fatigue, muscle weakness (starting in the legs and going up), possible mental retardation, heart and respiratory problems, and deformities of the spine and chest. Progressive muscle weakness leads to disability; by the age of 12, many children are already confined to a wheelchair. Boys are sick.Becker's muscular dystrophy.
With Becker muscular dystrophy, symptoms resemble Duchenne dystrophy, but occur later and develop more slowly. Muscle weakness in the upper body is not as severe as in the previous type of dystrophy. Boys are sick. The onset of the disease occurs at 10-15 years, and by the age of 25-30, patients are usually confined to a wheelchair.Sickle cell anemia.
In this hereditary disease, the shape of red blood cells is disrupted, which become like a sickle - hence the name. Altered red blood cells cannot deliver enough oxygen to organs and tissues. The disease leads to severe crises that occur repeatedly or only a few times in the patient's entire life. In addition to pain in the chest, abdomen and bones, there is fatigue, shortness of breath, tachycardia, fever, etc.Treatment includes pain relievers, folic acid to support hematopoiesis, blood transfusions, dialysis, and hydroxyurea to reduce the frequency of episodes. Sickle cell anemia occurs predominantly in people with African and Mediterranean roots, as well as in South and Central America.
Thalassemias.
Thalassemias (beta-thalassemias and alpha-thalassemias) are a group of hereditary diseases in which the correct synthesis of hemoglobin is disrupted. As a result, anemia develops. Patients complain of fatigue, shortness of breath, bone pain, they have an enlarged spleen and brittle bones, poor appetite, dark urine, yellowness of the skin. Such people are prone to infectious diseases.Phenylketonuria.
Phenylketonuria is the result of a deficiency in a liver enzyme that is required to convert the amino acid phenylalanine to another amino acid, tyrosine. If the disease is not diagnosed in time, large amounts of phenylalanine accumulate in the child's body, causing mental retardation, damage to the nervous system and seizures. Treatment consists of a strict diet and the use of the cofactor tetrahydrobiopterin (BH4) to lower blood phenylalanine levels.Alpha-1-antitrypsin deficiency.
This disease occurs due to an insufficient amount of the enzyme alpha-1-antitropsin in the lungs and blood, which leads to consequences such as emphysema. Early symptoms of the disease include shortness of breath and wheezing. Other symptoms: weight loss, frequent respiratory infections, fatigue, tachycardia.In addition to those listed above, there are many other genetic diseases. Today, there are no radical cures for them, but gene therapy has enormous potential. Many diseases, especially when diagnosed early, can be successfully controlled and patients are able to live full, productive lives.
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