4. Основные хромосомные болезни человека
Хромосомные болезни это большая группа клинически различных патологических состояний, у которых этиологическим фактором являются хромосомные или геномные мутации.
Классификация хромосомных болезней основана на типах мутаций (полиплоидии, анэуплоидии, транслокации, делеции, инверсии, дупликации) и вовлеченных хромосомах.
Хромосомная болезнь может возникать в результате мутаций в гаметах родителей или в результате мутаций в клетках эмбриона на ранних стадиях его развития. Мутации в гаметах приводят к развитию полных форм, а мутации, возникшие на ранних стадиях развития эмбриона (особенно на стадии дробления зиготы), приводят к образованию мозаичного организма (т.е. часть клеток имеет нормальный кариотип, а другая часть - аномальный)
У человека обнаружены все формы хромосомных и геномных мутаций. Полные формы тетраплоидиии и триплоидии обнаружены только при спонтанных абортах, что свидетельствует об их летальном эффекте на ранних стадиях развития. Летальный эффект других форм хромосомных и геномных мутаций зависит от типа вовлеченной хромосомы и характера нарушений.
У человека существует очень много видов хромосомных аномалий - только гаметического происхождения около 750, из них свыше 700 - структурные перестройки.
Патогенез хромосомных болезней. Характер и тяжесть проявления хромосомных болезней варьируете зависимости от вида аномалий и хромосомы. Общим для всех форм хромосомных болезней является множественность поражения:
черепно-лицевые дисморфии,
врожденные пороки развития внутренних и наружных органов,
замедленный рост и развитие,
задержка психического развития,
нарушения функций нервной и эндокринной системы.
При хромосомных болезнях наблюдается от 30 до 80 различных отклонений от нормы, касающихся физического и психического развития.
5. Профилактика наследственных болезней.
В настоящее время обосновано 4 подхода в борьбе с наследственными болезнями:
1. Массовое "просеивание" новорожденных на наследственные дефекты обмена веществ.
Пренатальная диагностика.
Медико-генетическое консультирование.
Контроль за мутагенной опасностью факторов окружающей среды.
1. Массовое "просеивание " новорожденных на наследственные болезни обмена веществ наряду с другими методами является основой профилактики наследственных болезней в популяциях.
"Просеивание" означает предположительное выявление недиагностированной ранее болезни с помощью тестов, обследований или других процедур, дающих быстрый ответ. "Просеивают" заболевания, для которых установлена связь между мутантным геном и поврежденной биохимической функцией. Современные программы массового просеивания предусматривают выявление фенилкетонурии, гипотиреоза, врожденной гипоплазии надпочечников, галактоземию, и др. В практике массового просеивания на наследственные болезни обмена веществ используется кровь (капиллярная, венозная) и сыворотка крови.2. Пренатальная диагностика осуществляется с помощью разных методов исследования в I и II триместрах беременности. В ней нуждается 10-15% семей, обращающихся в медико-генетическую консультацию. Показания к проведению пренатальной диагностики:
пожилой возраст родителей,
гетерозиготное носительство хромосомной аномалии,
предыдущее рождение ребенка с болезнью Дауна, врожденными пороками развития или умственной отсталостью,
наследственные дефекты метаболизма и др.
Пренатальная диагностика представляет собой комплексное исследование, основанное на использовании лабораторных и инструментальных методов:
3. Медико-генетическое консультирование включает:
- выявление наследственной формы патологии на основании осмотра больного, составления родословной, цитологических, биохимических и других методов диагностики наследственных болезней,
- определение степени риска появления потомства с наследственными дефектами развития у лиц из семей, отягощенных наследственной патологией, вступающих в брак и желающих иметь детей. В обоснованных случаях рекомендуется воздержаться от заключения брака, выявления нарушений в геноме, обменных процессов у плода с помощью методов пренатальной диагностики с возможным дальнейшим прерыванием беременности, если риск рождения больного ребенка достаточно высок. Однако, принятие окончательного решения о прерывании или сохранении беременности остается за супругами, искусственное осеменение от генетически здорового донора применимо в тех случаях, когда рождение здорового потомства невозможно из-за доминантного характера наследования патологии.
4. Контроль за мутагенной опасностью факторов окружающей среды осуществляют генетики, экологи, врачи гигиенического профиля, учитывая естественный фон радиации и его колебания, дрейф мутаций и т.п.
TOPIC №3. Hereditary illnesses and their PREVENTIVE MAINTENANCE.
1. A heredity and congenital illnesses.
2. Kinds of hereditary illnesses.
3. Etiology of the hereditary diseases
4. The basic chromosomal illnesses of the person
5. Preventive maintenance of hereditary illnesses.
1. A heredity and congenital illnesses.
Hereditary illnesses of the person are studied with medical genetics.
The genetics is a science studying laws of a heredity and variability of organisms in general.
The medical genetics is a section of genetics of the person, studying is hereditary the caused morphological and functional infringements in ontogenesis of the person, law of its inheritance, of phenotypical realizations and distributions, and also diagnostics developing methods, preventive maintenance and treatment of these infringements.
The term " hereditary illnesses " sometimes identify " congenital illnesses " with the term. As congenital illnesses understand such conditions which exist already at a birth of the child. Congenital illnesses can be caused by hereditary and not hereditary factors. Congenital developmental anomalies of not hereditary nature which are phenocopies of the hereditary developmental anomalies concern to them. At the same time not all hereditary illnesses are congenital, very much many diseases are shown at considerably later age.
The phenocopy is not hereditary change of any attributes of an organism under influence of the environment, copying of the phenotypical display of the mutations absent in a genotype of the given individual. For example:
1. Congenital infections (toxoplasmosis, rubella, etc.) can induce a phenocopy of the pathological mutations at several sibsses (sibsses are children of one parental pair: brothers and sisters) and to cause thus suspicion on hereditary disease.
2. Phenocopies, caused by external factors of the chemical and physical nature, can to meet the certain frequency at sibsses if factors continue to operate and after a birth of the sick child.
The term " family illnesses " is not a synonym "hereditary". Family illnesses can be hereditary and not hereditary. This term testifies only that diseases meet among members of one family. Family disease can be caused by the identical harmful factor which operates in family: bad light exposure, a crude apartment, professional harm, etc.
Hereditary illnesses it is illnesses at which the etiological factor are mutations (genic, chromosomal or genomal). On the one hand, the majority of mutations increases polymorphism of human populations (groups of blood, color of hair, the form of a nose, etc.), and on the other hand mutations mention the vital functions and then illness develops.
In spite of the fact that there are no sharp transitions from the illnesses caused by external factors, to hereditary illnesses, from the genetic point of view depending on the relative importance hereditary and environmental factors in its development academician N.P.Bochkov (1978) divides all illnesses into 4 groups:
1. Hereditary illnesses. Display of pathogenic action of a mutation as etiological the factor practically does not depend on an environment. It can change only expressiveness of symptoms of illness. The determining role is played here with a heredity. All chromosomal and genic hereditary illnesses concern to diseases of this group with full display: illness of Down, a hemophilia, phenylketonuria, achondroplasia and ets.
2. Illnesses with hereditary predisposition. For these illnesses the heredity is the etiological factor, but for penetrance of the mutated genes the corresponding condition of an organism caused by harmful influence of environment (a gout, some forms of a diabetes - their display depends on a unlimited feed) is necessary. Such diseases are usually shown with the years at action of external factors: overfatigue, hyperalimentation, cooling, etc.
Similarly to illnesses 2-nd groups, they concern to illnesses with hereditary predisposition.
4. In an origin of illnesses of this group the heredity does not play any role. The etiological factors are only external (environmental) factors. The majority of traumas, infectious diseases, burns, etc. here concerns. Genetic factors can influence only current of pathological processes (recovery, regenerative processes, indemnification of the broken functions).
Such ranking of illnesses on groups is somewhat conditional, but it helps to estimate correlative value of a heredity and environment in development of illnesses of the person. Illnesses 2-nd and 3 groups can be incorporated into one group, these are illnesses with hereditary predisposition.It is known already more than 2000 illnesses and this list constantly replenishes with new forms. Its render significant influence on desease and death rate. 40 % of children's death rate in part or are completely caused by a hereditary pathology, not less than 40 % of spontaneous abortions is connected to chromosomal infringements. 10,5 % of the population suffer hereditary diseases or illnesses with hereditary predisposition. 5 % of newborns have those or other hereditary defects.
2. Kinds of hereditary illnesses.
Hereditary illnesses are classified from the clinical and genetic points of view. In a basis of clinical classification it is put the system and organismic principle as on etiology all hereditary illnesses are uniform (in their basis lays a mutation):
1. Illnesses of exchange (phenylketonuria, a gout, glycogenosis, homocystinuria, ets.).
Illnesses of connecting fabric (syndrome Marthan, achondroplasia, etc.).
Illnesses of blood (hemoglobinopathy, enzymolathy, etc.).
Mental diseases (schizophrenia, a manic - depressive psychosis, etc.).
Illnesses of gastroenteric path (Gee's disease, a peptized ulcer, etc.).
Illnesses of kidneys ( a hereditary greenstone, polycystosis of kidneys, etc.).
From the genetic point of view hereditary illnesses are classified as well as mutations as they are the etiological factor of illnesses.
Depending on a level of the organization (volume of damage) hereditary structures distinguish genic, chromosomal and genome mutations, and in this connection hereditary illnesses share on 2 big groups:
The genic diseases caused by genic mutations which are transferred from generation to generation.
The chromosomal diseases caused by chromosomal and genome mutations.
Depending on the genetic approach hereditary illnesses share on many groups:
1. By quantity of the involved loci hereditary illnesses can be:
a) Monogenic (mutated one gene) (phenylketonuria, a hemophilia, etc.);
b) Polygenic are illnesses with hereditary predisposition (hypertonic illness, an atherosclerosis, a diabetes, etc.). Polygenic diseases are allocated in separate group because of complex character of inheritance of illness and influence of environment on realization of predisposition.
2. Genic mutations can arise in structural and regulatorial genes. The great bulk of hereditary diseases is caused, obviously, mutations in structural genes.
Chromosomal illnesses subdivide depending on type of mutations on:
1. The syndromes caused by numerical anomalies (polyploidy, aneuploidy).
2. The syndromes caused by structural reorganizations (deletions, inversions, translocations, duplications).
Such division of chromosomal illnesses helps the doctor in an estimation of the forecast for the patient and in medicogenetic consultation. The majority of the chromosomal illnesses caused aneuploidies, at all is not transferred, and structural reorganizations (inversions, translocation) are transferred with additional overcombinations which parents have not.
There is one more group of the illnesses connected to a heredity are the illnesses arising at incompatibility of mother and a fruit on antigenes and developing on a basis of immunological reaction at mothers. The most typical and well investigated disease of this group is hemocatheretic illness of newborns. It arises in that case when the Rhesus factor - positive fruit develops in an organism of Rhesus factor - negative mother.
3. The etiology of the hereditary diseases
The reason of hereditary illnesses is mutations. The mutation is process of change of hereditary structures. Mutations in germinal cells conduct to development of a mutant organism. Its are characteristic for all cells and are transferred from generation to generation.
Somatic mutations grasp the certain site of a body depending on a stage of the ontogenesis on which there was a mutation. Its can be observed, for example, as leukodermaal spots on a leather, mosaic spots on iris at the person. Somatic mutations are not transferred the following generation through sexual cell. Distinguish spontaneous and induced mutagenesis. Such division in the certain degree is conditional.
Spontaneous mutagenesis is occurrence of a mutation at usual physiological conditions of an organism without additional influence by any external factors for an organism. It is determined by a number of the chemical substances formed during a metabolism, a natural background of radiation, mistakes of the replication, etc. Spontaneous mutational process depends on properties of the gene, system of a genotype, a physiological condition of an organism and fluctuations of factors of an environment.
Frequency chromosomal and genome mutations depends on age. At women after 35 years sharply (up to 10 times) the probability of a birth of children with chromosomal illnesses raises. The age of fathers has no value. The reason of it is unknown.
Induced mutagenesis is mediated damaging action of physical, chemical and biological factors (mutagens) on the genetic device of cells.
Radiation is the physical mutagen.
Chemical substances cause mutations on all 3 levels of the organization of hereditary structures (genes, a chromosome, a gene). They belong to different classes of chemical compounds: acids, spirits, salts, cyclic connections, heavy metals, etc. The mutagens contain in extremely wide set of foodstuff of daily demand, in medical products, air, water, etc. Besides many foodstuff, tobacco and various drinks contains substances, activated or inhibited of the mutagen activity of other connections. Chemical mutagens act in an organism with food, water, air, medical products.
In air arsenic, hydrogen sulphide, mercaptan, lead, organic oxidizers, cancerogenes an organic origin get. In water concentration of arsenic, chrome, fluorine, lead, pesticides, herbicides raises. The ground also is sated with pesticides, herbicides and other chemicals.
From industrial connections more than 20 have mutagen an effect. The strongest mutagen is a condensate of the cigarette smoke.
It is found out of the mutagenicity as condensate of the smoke formed at roasting of a of fish, beef, and extracts from superficial "crust" of fried pieces of sardines, a herring. The condensate of a smoke received at preparation of beefsteak on carbon, also is mutagen, but much to a lesser degree, than a condensate of a smoke from a fish.
Both chemical, and radiating mutagenesis are dangerous at involving in it of the big populations.
Antimetagens are the factors working in antagonism with mutagens. They are found in many vegetables: white cabbage, green pepper, apples, eggplants, leaves of mint, pineapples. Smaller antimutagen activity the garden radish, a grapes, a cauliflower, mushrooms possess.
Biological mutagens are less investigated, than physical and chemical though the facts of mutagenicity viruses are known for a long time. Ability to cause breaks of chromosomes viruses of a smallpox possess, reproach, a chicken pox, an epidemic parotitis, etc. In connection with mutagen activity of viruses the problem of vaccination began to be considered more widely, than earlier. Mutagen activity various toxins of the biological nature, and also various metabolites (for example, peroxides, free radicals, etc.) which name antimetagens..
Considerably modify frequency of occurrence of mutations at the person parasitizing organisms can.
4. The basic chromosomal illnesses of the person
Chromosomal illnesses it is the big group of clinically various pathological conditions at which the etiological factor are chromosomal or genome mutations.
Classification of chromosomal illnesses is based on types of mutations (polyploidy, aneuploidy, translocation, deletion, inversions, duplications) and the involved chromosomes.
Chromosomal illness can result from mutations in gametes of parents or as a result of mutations in cells of an embryo at early stages of his development. Mutations in gametes result in development of full forms, and the mutations which have arisen at early stages of development of an embryo (it is especial at a stage of crushing of a zygote), result in formation of a mosaic organism (i.e. the part of cells has normal karyotype, and other part has abnormal)
All forms of the chromosomal and genome mutations are found out in the person. Full forms of the tetraploid and triploid are found out only at spontaneous abortions that testifies to their lethal effect at early stages of development. The lethal effect of other forms chromosomal and genome mutations depends on type of the involved chromosome and character of infringements.
The person has many kinds of chromosomal anomalies (only gametic origins about 750, from them from above 700 - structural reorganizations).
Pathogeny of the chromosomal illnesses. Character and weight of display of chromosomal illnesses vary dependences on a kind of anomalies and chromosomes. The general for all forms of chromosomal illnesses is plurality of defeat:
Craniofacial dysmorphies,
Congenital developmental anomalies of internal and external bodies,
The slowed down growth and development,
Delay of mental development,
Infringements of functions nervous and endocrine systems.
At chromosomal illnesses it is observed from 30 up to 80 various rejections from the norm, concerning physical and mental development.
5. Preventive maintenance of hereditary illnesses.
Now 4 approaches in struggle against hereditary illnesses are proved:
1. Mass "sifting" of the newborns on hereditary defects of a metabolism.
The prenatal diagnostics.
The medicogenetic consultation.
The control over mutagen danger of factors of an environment.
1. Mass "sifting" of the newborns on hereditary illnesses of a metabolism alongside with other methods is a basis of preventive maintenance of hereditary illnesses in populations.
The "Sifting" means presumable revealing not diagnosed before illness with the help of tests, inspections or other procedures giving a prompt reply. "Sift" diseases for which communication between a mutant gene and the damaged biochemical function is established. Modern programs of mass sifting provide revealing of the phenylketonuria, hypothyroidism, congenital hypoplasia of the adrenal glands, galactosemia, etc. In practice of mass sifting on hereditary illnesses of a metabolism blood (capillary, venous) and whey of blood is used.
2. The prenatal diagnostics is carried out with the help of different methods of research in I and II trimesters of pregnancy. 10-15 % of the families addressing in medicogenetic the consultation require it. Indications to carrying out of the prenatal diagnostics diagnostics:
Advanced age of parents,
Heterozygotic carriage of chromosomal anomaly,
The previous birth of the child with illness of Down, congenital developmental anomalies or intellectual backwardness,
Hereditary defects of a metabolism, etc.
The prenatal diagnostics represents the complex research based on use of laboratory and tool methods:
3. The medicogenetic consultation includes:
- Revealing the hereditary form of a pathology on the basis of survey of the patient, drawing up of a family tree, cytologic, biochemical and other methods of diagnostics of hereditary illnesses,
- Definition of a risk degree of posterity occurrence with hereditary defects of development in persons from the families burdened by a hereditary pathology, marrying and wishing to have children. In the proved cases it is recommended to refrain from the conclusion of a marriage, revealing of infringements in genome, exchange processes at a fruit with the help of methods the prenatal diagnostics with possible further interruption of pregnancy if the risk of a birth of the sick child is high enough. However, acceptance of the final decision on interruption or preservation of pregnancy remains for spouses, artificial insemination from genetically healthy donor is applicable when the birth of healthy posterity is impossible because of prepotent character of inheritance of a pathology.
4. The control over mutagen danger of factors of an environment is carried out genetics, by ecologists, doctors of a hygienic structure, taking into account a natural background of radiation and its fluctuation, drift of mutations, etc.