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Federal Agency of Health Protection and Social Development Stavropol State Medical Academy Biology with Ecology Department Mackarenko E.N., Boldyreva G.I., Parshintseva N.N. Hereditary diseases of a man Stavropol 2007 ФЕДЕРАЛЬНОЕ АГЕНСТВО ПО ЗДРАВООХРАНЕНИЮ И СОЦИАЛЬНОМУ РАЗВИТИЮ МИНЕСТЕРСТВА ЗДРАВООХРАНЕНИЯ РФ Ставропольская государственная медицинская академия Кафедра биологии с экологией Federal Agency of Health Protection and Social Development Stavropol State Medical Academy Biology with Ecology Department Э.Н. Макаренко, Г.И. Болдырева, Н.Н. Паршинцева Mackarenko E.N., Boldyreva G.I., Parshintseva N.N. НАСЛЕДСТВЕННЫЕ ЗАБОЛЕВАНИЯ ЧЕЛОВЕКА Учебное пособие для студентов англоязычного отделения Hereditary diseases of a man Ставрополь 2007 Stavropol 2007 УДК 535.317.68 (07.07) ББК 54-1,4 М 15 НАСЛЕДСТВЕННЫЕ ЗАБОЛЕВАНИЯ ЧЕЛОВЕКА. Учебное пособие для студентов англоязычного отделения (на английском языке). – Ставрополь: Изд-во СтГМА. – 2007. – 48с. Hereditary diseases of a man. – Stavropol. – Publisher: Stavropol State Medical Academy. – 2007. – 48 p. Авторы: Макаренко Элина Николаевна, кандидат медицинских наук, старший преподаватель кафедры биологии с экологией; Болдырева Галина Ивановна, старший преподаватель кафедры биологии с экологией; Паршинцева Наталья Николаевна, старший преподаватель кафедры иностранных языков с курсом латинского языка. Authors: Senior Lecturers of Department of Biology with Ecology Mackarenko E.N., Boldyreva G.I. and Teacher of Latin and Foreign Languages Department of Stavropol State Medical Academy Parshintseva N.N. Учебное пособие включает в себя основные темы курса «Генетика человека» для студентов англоязычного отделения. Оно состоит из следующих разделов: «Мутации», «Болезни человека», «Хромосомные синдромы» и «Молекулярные болезни». Presented methodological manual includes the basic themes of course “Genetics of a man” for the students of the English-speaking Medium. It consists of following chapters: “Mutations”, “Human diseases”, “Chromosomal syndromes”, “Molecular diseases”. Рецензенты: Ходжаян Анна Борисовна, доктор медицинских наук, профессор, зав. кафедрой биологии с экологией СтГМА; Знаменская Стояна Васильевна, кандидат педагогических наук, доцент кафедры иностранных языков с курсом латинского языка СтГМА, декан англоязычного отделения деканата иностранных студентов. Reviewers: Hodzhayan Anna Boriusoivna, Professor, Doctor of Medicine, Head of Department of Biology with Ecology of Stavropol State Medical Academy, Znamenskaya Stoyana Vasilievna, Dean of the English-speaking Medium. УДК 535.317.68 (07.07) ББК 54-1,4 М 15 Рекомендовано к изданию Цикловой методической комиссией Ставропольской государственной медицинской академии по англоязычному обучению иностранных студентов. © Stavropol State Medical Academy. 2007 INTRODUCTION Методическое пособие по биологии на английском языке предназначено для студентов англоязычного отделения. Оно включает основные темы из курса «Генетика человека». Цель методического пособия – это знакомство студентов первого курса с наследственными заболеваниями. Причинами наследственных заболеваний являются мутации, в начале изложения темы дается определение понятия «мутации», приводятся современные классификации мутаций, структура генных, геномных мутаций и хромосомных аберраций. Следующие разделы – это хромосомные синдромы и молекулярные болезни, наиболее часто встречающиеся в практической деятельности врача. Эти разделы изложены по плану: синонимы синдрома, которые можно встретить в литературе; популяционная частота; минимальные диагностические признаки; клинические проявления и диагностика наследственного заболевания. «Генетика человека» вызывает затруднения у первокурсников. Поэтому в методическом пособии кратко и в доступной форме изложены теоретические аспекты данной темы. Кроме того, представлен обширный наглядный материал в виде таблиц, кариограмм, фотографий больных. В конце методической разработки приводится словарь медицинской терминологии, которая используется при описании клинических проявлений наследственных заболеваний. The methodical manual in biology in English is for students of English-speaking medium. It includes the basic themes from a course « Genetics of a man ». The purpose of the methodical manual is an acquaintance of the first year students with hereditary diseases. The reasons of hereditary diseases are mutations. Concepts of «mutation» are defined at the beginning of a theme statement. Modern classifications of mutations, the structure of gene, genome mutations and chromosomal aberrations are given. The following chapters are chromosomal syndromes and the molecular illnesses most frequently meeting in practical activities of the doctor. These chapters are stated under the plan: synonyms of a syndrome, which can be met in the literature; population frequency; the minimal diagnostic attributes; clinical displays and diagnostics of hereditary disease. « The genetics of a man» causes difficulties in the first-year students. Therefore in the methodical manual it is brief and in the accessible form theoretical aspects of the given theme are stated. Besides the extensive evident material as tables, karyograms, and photos of patients is submitted. At the end of methodical manual the dictionary of medical terminology that is used at the description of clinical displays of hereditary diseases is resulted. Mutations Mutations in a broad sense include all those heritable changes, which alter phenotype of an individual. Hugo de Vries used the term “mutation” to describe phenotypic changes, which were heritable. He is, therefore, credited to have differentiated between heritable and environmental variations. However, the term mutation is now used in a rather strict sense to cover only those changes, which alter the chemical structure of the gene at the molecular level. These are commonly called gene mutations or point mutations. In practice, sometimes it is rather difficult to distinguish between gene mutations and structural changes in the chromosomes, because certain structural changes may have the same phenotypic effects as the gene mutations. Small deficiencies cannot be discovered by cytological observations. Although on Drosophila small deficiencies can also be detected in the giant salivary gland chromosomes, in other organisms the only test for a deficiency is that it will not revert back to the wild type character. However, gene mutations would be able to give reverse mutations. The distinction between point mutations and the chromosomal aberrations is thus a rather superficial one. If chromosomes are not studied under the microscope, in certain cases we may not be in a position to say with certainty whether a particular phenotypic character is due to point mutation or due to a structural change. Many mutations, described by de Vries in Oenothera lamarckiana, are now known to be due to certain numerical and structural changes in the chromosomes. For instance, “giant» mutant in Oenothera lamarckiana was later found to be due to polyploidy. Brief History The earliest record of point mutations dates back to 1791 when Seth Wright noticed a lamb with unusually short legs in his flock of sheep. Wright thought that it would be worthwhile having a whole flock of these shortlegged sheep, which could not get over the low stone fence and damage the crop in the adjacent fields. In the successive generations, this trait was transferred and a line was developed where all sheep had short legs. This character resulted from a recessive mutation and the short-legged individuals were homozygous recessive. Once this mutation occurred in a particular cell, this will be carried in all the cells descending from this parent cell. This point mutation was discovered at a time when the science of genetics did not even have its birth. The short-legged breed of sheep was known as Ancon breed. The scientific study of mutations started in 1910, when Morgan started his work on fruit fly, Drosophila melanogaster, and reported white-eyed male individuals among red-eyed male individuals. Later it was found that gene responsible for this character is located on sex chromosome (Xchromosome) and expresses itself in a male individual (male individuals have one X- chromosome and one Y- chromosome; the female has two Xchromosomes). When these rare white-eyed males were crossed to their sisters, red-eyed females; white-eyed females could also be obtained in some cases proving that the females involved were heterozygous. Modern Classifications of Mutations Mutations are the spontaneous, resistant, indirect, spasmodic changes of a genotype. Mutations are: 1) Spontaneous (natural) mutations and induced (artificial) mutations. Spontaneous mutations happen in the nature without intervention of the person. The person receives artificial mutations purposefully. 2) Dominant mutations and recessive mutations. Dominant mutation is phenotypically shown in that organism in which it has arisen. Recessive mutation will be shown only through some generations. For phenotypical expression it should be distributed in a population. In the nature dominant mutations occur less often, than recessive mutations. 3) Somatic mutations and generative mutations. Somatic mutations take place in cells of a body (somatic cell). These are expressed phenotypically at that organism at which have arisen and transferred only at asexual reproduction. Frequently a man uses them in selection of plants. Generative mutations occur in sexual cells (gametes); therefore these are expressed phenotypically in the following generation only. They are handed down only at sexual reproduction. 4) Nuclear mutations and cytoplasmic mutations. Nuclear mutations are connected to changes of DNA included in chromosomes. Cytoplasmic mutations are caused by changes extranuclear DNA (1 %). It is located in mitochondrion, plastid, in the cell center. 5) Morphological, physiological and biochemical mutations. Morphological mutations result in change of structure, physiological – reorganization of functions. Biochemical mutations change a metabolism. These are connected with infringement of protein synthesizing, which catalyze the certain type of chemical reactions in an organism. 6) Useful, neutral and harmful (lethal and semilethal) mutations. Useful mutations raise viability of an organism. Neutral mutations change the sign of an organism, but do not influence viability. Lethal mutations are the harmful mutations sharply lowering viability and resulting in destruction of an organism. Semilethal mutations are harmful too lowering viability of an organism and resulting in development of hereditary diseases. 7) Gene (point) mutations, chromosomal mutations (chromosomal aberrations), genome mutations. Gene mutations are the changes of a genotype connected to changes of DNA. They do not result in seen changes of a hereditary material; therefore refer as point mutations. Chromosomal aberrations are structural changes of chromosomes. Genome mutations are numerical changes of chromosomes. Gene Mutations Mutations at the molecular level should mean permanent alterations in the sequences of nucleotides (bases) in the nucleic acids, which form the genetic material. These alterations in base sequences may be of the following types: 1) deletion of bases, 2) insertion of bases, 3) inversion of a sequence, 4) replacement of a base pair. The deletion, insertion and inversion include those changes in base sequence, which involve breakage and reunion of DNA segments. However, replacement of a base pair may take place during replication of DNA without any breakage of DNA. The base pair replacement can be of two types: transitions and transversions. Transitions These are those base pair replacements, where a purine is replaced by another purine and a pyrimidine is replaced by another pyrimidine. It means that AT is replaced by GC and vice versa. Transversions These are those base replacements, where a purine is replaced by a pyrimidine and vice versa. It means that CG can be replaced by GC and vice versa and similarly AT can be replaced by TA and vice versa. Similar changes can also take place between TA and GC as well as between AT and CG in booth directions. A T G C (a) transitions A T C G T A G C ( b) transversions The base pair changes involved in transitions and transversions are diagrammatically represented. The changes involving base replacements take place due to mistakes in the incorporation of nucleic acid precursots or due to mistakes committed during replication. However, it is realized that among two types of base replacements, transitions are more frequent than transversions. For a study of details of molecular mechanisms involved in each event of transition or transversion following mutagenic treatments or during spontaneous mutations, the readers are advised to consult the author’s advanced book on Genetics “A Text Book of Genetics”. The base pair changes lead to changes in protein synthesized on the DNA template. For example, the disease sickle-cell anaemia is caused due to base pair replacement leading to replacement of an amino acid of β chain of haemoglobin. Structural Changes in Chromosomes Variations in the structure and number of chromosomes have been observed in natural populations and could also be produced artificially in a variety of organisms. These variations have been extensively studied and can be due to either 1) structural changes or 2) numerical changes. Structural changes can be of the following types: 1) deficiency, which involves loss of a part of a chromosome, 2) duplication, which involves addition of a part of chromosome, 3) translocation, which involves exchange of segments between nonhomologous chromosomes, 4) inversion, which involves a reverse order of the genes in a part of chromosome. These structural changes are diagrammatically represented in table №1, where two non- homologous chromosomes from the complete set are shown. Structural abnormalities may be found in both homologous chromosomes of a pair, or in only one of them. When both homologous chromosomes are involved, these are called structural homozygotes e.g. deficiency homozygote, duplication homozygote, etc. If only one chromosome is involved, this will be called a structural heterozygote. The constitution of a translocation heterozygote and that of a translocation homozygote are shown in table №1. Table № 1 two non-homologous chromosomes deletion 1 2 3 4 5 6 7 8 9 10 11 12 1 2 7 8 9 10 11 12 4 5 6 deletion duplication 1 2 3 3 4 5 6 7 8 9 10 11 12 addition translocation inversion 7 8 3 4 5 6 1 4 3 2 5 6 1 2 9 10 11 12 7 8 9 10 11 12 123456 7 8 9 10 11 12 123456 7 8 9 10 11 12 7 8 3 4 5 6 1 2 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 7 8 3 4 5 6 1 2 9 10 11 12 7 8 3 4 5 6 1 2 9 10 11 12 two pairs of chromosomes translocation heterozygote translocation homozygote Numerical Changes in Chromosomes Numerical changes in chromosomes or variation in the chromosome number (genome mutation), can be mainly of two types, namely (1) aneuploidy and (2) euploidy. Aneuploidy means the presence of chromosome number, which is different than a multiple of the basic chromosome number. Euploidy, on the other hand, means that the organism should possess one or more full sets of chromosomes. Let us imagine that 7 is the basic chromosome number (x) in a particular class of individuals where the diploid number (2n) is 14. In this case, the chromosome numbers 2n=15 and 2n=13 would be aneuploids, while those having 2n=7, 21, 28, 35 or 42 would be euploids. A classification of different kinds of numerical changes in chromosomes is presented below. Aneuploidy can be either due to the loss of one or more chromosomes (hypoploidy) or due to addition of one or more chromosomes to the complete chromosome complement (hyperploidy). Hypoploidy is mainly due to the loss of a single chromosome, monosomy (2n-1) or due to the loss of one pair of chromosomes, nullisomy (2n-2), Similarly, hyperploidy, may involve addition of either a single chromosome, trisomy (2n+1) or a pair of chromosomes, tetrasomy (2n+2). Numerical changes in chromosomes euploidy aneuploidy hypoploidy monoploidy diploidy (x) (2x) hyperploidy polyploidy (3x, 4x, 5x, 6x etc.) monosomy nullisomy (2n-1) (2n-2) trisomy (2n+1) tetrasomy (2n+2) Monosomy: since monosomics lack one complete chromosome, such aberrations create major imbalance and cannot be tolerated in diploids. These could be easily produced in polyploids. The polyploids have several chromosomes of same type and, therefore, this loss can be easily tolerated. The number of possible monosomics in an organism will be equal to the haploid chromosome number. Nullisomy: nullisomics are those individuals, which lack a single pair of homologous chromosomes, so that the chromosome formula would be 2n-2, and not 2n-1-1, which would mean a double monosomic. E.R.Sears had isolated all the 21 nullisomics in wheat. Trisomy: trisomics are those organisms, which have an extra chromosome (2n+1). Since the extra chromosomes may belong to any one of the different chromosomes of a haploid complement, the number of possible trisomics will be equal to the haploid chromosome number. Tetrasomy: tetrasomics have a particular chromosome represented in four doses. Therefore, the general chromosome formula for tetrasomics is 2n+2 rather than 2n+1+1, the later being a double trisomic. All the 21 possible tetrasomics are available in wheat. Besides these tetrasomics, E.R. Sears was also able to synthesize a complete set of compensating nullisomic tetrasomics (2n-2+2), where the addition of a pair of homologous chromosomes would compensate for the loss of another pair of homologous. Such non- homologous chromosomes, which are able to compensate for each other, are considered to be genetically related and are called homoeologous chromosomes. Euploidy: Euploids can be monoploids, diploids or polyploids. A brief account of the two types of aberrations in this class namely monoploidy and polyploidy will be presented below. Since the diploids are normal individuals, these will not be discussed. Cytology of haploids: Since in a haploid set, the chromosomes are nonhomologous and have no homologous to pair with, they are found as univalents at metaphase I of meiosis. Consequently, these univalents distribute at random during anaphase I. For instance, a haploid in maize (2n=20) will have 10 chromosomes and the number of chromosomes in a gamete can range from 0-10. Consequently, considerable sterility will be found. Moreover, since the univalents are scattered all over the cell, they may constitute a restitution nucleus including all the chromosomes and may thus give rise to gametes having a complete haploid set of chromosomes. Haploids (polyhaploids; n=3x=21) were used by E.R. Sears for the production of monosomics by pollinating the haploid by pollen from a diploid individual (hexaploid; 2n=6x=42). If the egg has a chromosome number less that the complete set, this will result into an aneuploid. Polyploidy: There are mainly three different kinds of polyploids, namely 1) autopolyploids, 2) allopolyploids. Let us imagine that A, B1, B2, and C are four different haploid sets of chromosomes and that genomes B1 and B2 are related. Different kinds of polyploids using these genomes are derived. Autopolyploids: Autopolyploids are those polyploids, which have the same basic set of chromosomes multiplied. For instance, if a diploid species has two similar sets of chromosomes or genomes (AA), an autotriploid will have three similar genomes (AAA), and an autotetraploid will have four such genomes (AAAA). Allopolyploids: Polyploidy may also result from the doubling of chromosome number in a F1 hybrid which is derived from two distinctly different species. This will bring two different sets of chromosomes in F 1 hybrid. The number of chromosomes in each of these two sets may differ. Let A represent a set of chromosomes (genome) in species X, and let B represent another genome in a species Y. The F1 will then have one A genome and another B genome. The doubling of chromosomes in this F1 hybrid (AB) will give rise to a tetraploid with two A and two B genomes. Such a polyploid is called an allopolyploid or amphidiploid. Hereditary diseases On the basis of the importance of hereditary and environmental factors all human diseases are divided on 3 groups: ● ● ● hereditary pathology; diseases with hereditary predisposition (DHP); nonhereditary illnesses. The reason of hereditary diseases is mutations. Environmental factors can change the expression of clinical symptoms and current character of the illness, therefore they influence only on gene’s expressivity*. hereditary diseases = genome environmental factors on expressivity Molecular diseases and chromosomal syndromes are hereditary pathology. 50 % from them are congenital diseases. Their other half can be expressed on different stages of postembryonic period of ontogenesis according to terms of gene’s expressivity: ● in childhood – mucoviscidosis, Duchenne's pseudohypertrophic muscular dystrophy, etc.; ● in mature – myotonic dystrophy, Huntington's hereditary chorea; ● in old age – Alzheimer's disease. Hereditary diseases (more than 2.000) molecular illnesses chromosomal syndromes ≈ 750 Illnesses with hereditary predisposition (DHP): their development is determined equally both genome and environmental factors. DHP = genome + environmental factors penetrance Such illnesses are phenotypically expressed after contact of a mutant gene with the certain environmental factors promoting penetrance* of abnormal genes. Therefore, they are called multifactor diseases (atherosclerosis, essential hypertension, tuberculosis, eczema, psoriasis, etc.) Multifactor diseases Monogenic character Polygenic character Multifactor diseases can be expressed both at children and at adults. The reason for nonhereditary illnesses is environmental factors. Burns, traumas, the infectious diseases, harmful habits form this group of diseases. Genetic factors can influence only on the current of pathological process (on recovery, regenerative processes, compensation of dysfunctions). nonhereditary illnesses = environmental factors genome influence on current of pathological process Sometimes nonhereditary illnesses can be shown at a birth. Then they are similar to hereditary diseases in phenotypical expression (phenocopy*). So, the congenital malformations arisen in result of teratogenesis effect of external factors (physical, chemical, biological genesis) during antenatal period. Congenital malformations caused by agents of syphilis, rubella have a lot of similarity with chromosomal syndromes. There is a genetic classification of hereditary illnesses (N.P. Bochkov, 2001). It includes 5 classes: Hereditary diseases: 1 Gene illnesses; 2 Chromosomal illnesses; 3 Illnesses with hereditary predisposition; * 4 Genetic illnesses of somatic cells; * 5 Illnesses with genetic incompatibility of mother and fetus * Genetic illnesses of somatic cells are allocated into separate groups recently. Occasion has served the detection in cells of the specific chromosomal reorganizations causing oncogenes activation of malignant tumors, for examples retinoblastoma, Wilms tumor. There are some evidences that sporadic cases of congenital anomalies are results of mutations in somatic cells during the critical ontogenesis periods. It is rather probable, that autoimmune processes and old age can be attributed from same category of a genetic pathology. * Illnesses with tissues incompatibility of mother and a fetus are a result of immune reactions of mother’s organism on fetus antigens. The most typical and well investigated disease from this group is congenital haemolytic icterus, for instance, Rhesus-factor incompatibility in pregnant female (Rhesus blood group – negative) and a fetus (Rhesus blood group – positive). Also immune conflicts arise at incompatible combinations of antigens and antibodies on ABO blood groups in mother and a fetus. Chromosomal illnesses The reasons: structural and numerical changes of chromosomes (chromosomal aberrations or genome mutations). Frequency of occurrence: 0, 7 % in human populations among newborns. 60 % are genome mutations: Aneuploidy among them is prevailing, because polyploidy or monoploidy in a man are incompatible with a life. It is counted up, that 10 % embryos at medical abortions and 25 % at spontaneous abortions – polyploid organisms. As a rule, aneuploidy has sporadic character. 40 % are chromosomal aberrations. Chromosomal aberrations intrachromosomal interchromosomal (translocations) balanced (transpositions, inversions) unbalanced (deletions, duplications) all gene’s loci are present in genome, but in the other order some gene’s loci are lost or doubled phenotypic deviations are insignificant the pathological phenotype is formed 50 % of structural reorganizations have family character. Clinical displays: 1) plural congenital anomalies of development; 2) retardation of growth and physical development; 3) backlog in mental development; 4) disorders of nervous system and endocrine glands; 5) high lethality (6 % among index of perinatal mortality, 95-98 % among the reasons of spontaneous abortions). The mechanism of development. Mutations can arise: ● in gametes of parents → disorders of chromosomal set in all cells → abnormal organisms → bright clinic expression ● in somatic cells on early stages of embryogenesis → abnormal chromosomal set in a part of cells (as well autosomes as sexual chromosomes) → mosaic organism (somatic mosaicism) → the erased clinic expression. Sometimes the abnormal cells number in organism is very little. Such individuals are normal in phenotypical expression. Feature: autosome disorders proceed more hardly, than anomalies of sexual chromosomes. Chromosomal anomalies meet on 25 % more in premature newborns, than in full-term newborns. Diagnostics: 1) research of a phenotype; 2) clinical observations; 3) genealogic method (it is especially used at chromosomal aberrations); 4) cytogenetical analysis (definition of sex chromatin, karyotype) – it is predominantly performed at genome mutations; 5) dermatogliphic research; 6) pathoanatomical descriptions. Chromosomal diseases 1. The chromosomal diseases caused by chromosomal aberrations: 1.1. "Cat-like cry syndrome” 1.2. Translocation form of Down’s syndrome 1.3. Syndrome of “Philadelphian chromosome” 1.4. Martin – Bell's syndrome 2. The chromosomal diseases caused by genome mutations in autosomes: 2.1. Patau syndrome 2.2. Edwards's syndrome 2.3. Down’s syndrome 3. The chromosomal diseases caused by genome mutations allosomes: in 3.1. Turner’s syndrome 3.2 Klinefelter’s syndrome 3.3 X– trisomy syndrome ( X – polysomy) 3.4 Y – trisomy syndrome ( Y – polysomy) 1.1 "Cat-like cry syndrome” Synonym: Chromosome 5p-syndrome. J. Lejeune described it in 1963. Reason: deletion of a short arm of the 5-th chromosome. Population frequency – 1 : 50 000 newborns. Minimal diagnostic attributes: unusual cry reminding cat's meowing; microcephaly*; antimongoloid set of the eyes*; mental retardation; deletion of a short arm of the 5-th chromosome (Fig. 1.). Clinical characteristic. The most typical attributes are specific crying (98 %), low birth weight (72 %), growth retardation (85 %), microcephaly* (98 %), intellectual backwardness (100 %), muscular hypotonia* (60-80 %), moon-like face (70 %), facial asymmetry (25 %), wide nose bridge (84 %), micrognathia* (75-85 %), malformed low-set auricles (85 %), abnormal occlusion (70-80 %), high palate (50-75 %), anomalies of larynx (55-65 %), hypertelorism* (90-95 %) or hypotelorism, epicanthus* (85-90 %), Fig. 1. • Moon-like face; • Epicanthus*; • Antimongoloid set of the eyes*; • Microcephaly* antimongoloid set* of the eyes (75-85 %) or mongoloid set* of the eyes, strabismus*, usually divergent strabismus (60-70 %), congenital heart diseases (15-30 %), short metacarpal and metatarsal bones (65-75 % in an adult), transversal palmar fold (80-90 %), distal axial triradius (80-90 %), flatfoot (65-75 %), clinodactyly*, partial syndactyly* (25-30 %), decreased wings of iliac bones or increased iliac angle (70-80 %), scoliosis* (55-65 %), inguinal [groin] hernia (25-30 %), divergence of direct abdominal muscles (30-35 %), short neck (45-55 %). Sometimes cryptorchism* and anomaly of kidneys are met. The patients are inclined to infectious diseases of upper respiratory tracts. It is necessary to note, that in most cases such attributes as the cat's meowing, a muscular hypotonia*, moon-like face completely disappear with age. Frequently simple deletion of a short arm of the 5-th chromosome is present. The typical phenotype, apparently, is caused by deletion of a site р14 – р15. Sometimes mosaicism or the 5-th ringchromosome is found. Approximately in 10-15 % of cases the syndrome is connected with translocation. Diagnostics: karyotype research and detection of morphologically changed 5-th chromosome. 1.2 Translocation form of Down’s syndrome Reason: translocation of the additional 21-st chromosome on the 15- th or either the 21-st. Karyotype of these patients contains 46 chromosomes. Therefore, two chromosomes from the 21-st pair are normal, one the 15-th is normal too, but another – “abnormal large chromosome”. It represents connection with the additional 21-st chromosome. Other translocation form can be connection among themselves two 21-st chromosomes from three, taking place in a chromosomal set. Clinical characteristic. As a rule, the clinical symptoms of genome variant and translocation form are practically indiscernible. If translocation form of Down’s syndrome takes place, one of parents of the sick child has balanced translocation one of chromosomes of the 21-st pair on the 15-th or another 21-st chromosome. During gametogenesis the part of gametes of such parent can receive both the normal 21-st chromosome and translocational chromosome. In a result, at fertilization of an abnormal gamete by normal, the zygote containing three 21 chromosomes develops. If Down’s syndrome (trisomy variant) is met, as a rule, in elderly mothers, translocation forms of Down’s syndrome are equally characteristic both for young and for mature age. The risk of birth of a sick child in parents, one of which carries balanced translocation of the 21-st chromosomes, is much above than at trisomy form. Diagnostics: is similar to trisomy variant. At the following pregnancy amniocentesis is obligatory, if young parents have the child with Down’s syndrome. 1.3 Syndrome of “Philadelphian chromosome” For the first time Tooge described it in Philadelphia city (USA) in 1961. Fig.2. Blood smear and abnormal karyotype at chronic myeloleukemia Reason: the 21-st chromosome loses the half of a long arm. So was considered till 1970. For last 30 years character of an aberration was specified. So translocations of deletion fragment of a long arm of the 22 chromosomes on a long arm of the 9-th chromosome, and a small fragment of the 9-th on the 22-nd – t (9; 22) (q 34; q 11) take place. Thus the structures possessing oncogenesis properties are formed (Fig.2.). Clinical characteristic. Chronic myeloleukemia* is developed. It is expressed in impetuous duplication of granulocytes (one of leukocytes kinds). As a result, many immature forms of these leukocytes appear in peripheral blood. Diagnostics: detection of a corresponding aberration at karyotype research. 1.4 Martin -Bell's syndrome Synonym: X- chromosome fragile syndrome. C. Lubs described the syndrome in 1968. Reason: deletion of a short arm of the Х-chromosome in a segment q28. Population frequency – 0, 5 : 1 000. Type of inheritance – X – linked recessive. Minimal diagnostic attributes: moderate or deep mental retardation; burdock-like ears, jutting out forehead and a massive chin; macroorchism* (Fig. 3.). Clinical characteristic. At a birth the weight and length of a body are normal or exceed norm, the circumference of a head is increased. Ears are burdock-like. In adolescents the face is rectangular with a high jutting out forehead, thin long nose, hyperplasia* of mandible. Wide hands are characteristic. There are a high palate and submucous cleft of the palate or uvula. The middle otitis* is marked quite often. Intellectual and speech retardation is typical. Sometimes spasms, changes on cardiogram, muscular hypotonia*, autism* and hyperactivity are observed. Macroorchism* is expressed with age of puberty. There are adiposity, gynaecomastia*, hypospadias* and soft extensible skin. The weakness of the ligament apparatus of a knee and ankle-joints, prolapse of the mitral valve take place. Fragility of the Х-q28 is found out at cytogenetical research. Intelligence is probably decreased in females-carriers. In male-hemizygote – clinical symptoms can be absent. Correlations between expression of clinical spectrum and presence of cytogenetical markers are not revealed. Fig. 3. Rectangular face; thin long nose and hyperplasia* of mandible; macroorchism* Diagnostics: karyotype research and detection of morphologically changed X-chromosome. 2.1 Syndrome Patau Synonym: Chromosome 13 trisomy syndrome. K. Patau described the syndrome in 1960. Reason: trisomy of the 13-th chromosomes. Population frequency - 1 : 7 800. Minimal diagnostic attributes: microcephaly*; polydactyly*; cleft of the lip and palate (Fig.4.). Clinical characteristic. Microcephaly* (58,7 %), trigonocephaly*, narrow palpebral fissure, wide nose basis, sunken bridge of the nose, low placed and deformed auricles (80 %), micrognathia* (32,8 %), cleft of the lip and palate (68 %), epicanthus*, microphthalmia* (77 %), coloboma* (35,5 %), short neck, polydactyly* (50 %), flexor position of fingers (44,4 %), long convex nails, transversal palmar fold are marked at trisomy-13. The internal defects include: Fig.4. Microcephaly*; polydactyly*; cleft of the lip and palate. arrhinencephaly* (63,4 %), aplasia* of a calloused body (19,3 %), cerebellum hypoplasia* (18,6 %); congenital heart anomalies (80 %) – the defect of ventricular septum (49,3 %) or the defect of atrial septum (37,6 %); anomalies of kidneys (58,6 %) – cysts or double renal pelves, hydronephrosis* or ureter duplication; the defects of digestive tract development (50,6 %) – incomplete intestinal rotation, Mekkel’s diverticulum. There are cryptorchism*, hypoplasia* of external genitals, hypospadias*, two-horned uterus or reduplication of uterus and vagina. Syndrome Patau is met in several cytogenetical variants: simple trisomy of the 13-th chromosome, Robertson’s translocation D/13 and mosaicism. The last variant is less common. Diagnostics: ♦ karyotype research and detection of trisomy of the13-th chromosome; ♦ typical dermatogliphic signs: – transversal palmar fold; – atd -angle is approximately 108°. 2.2 Edwards's syndrome Synonym: Chromosome 18 trisomy syndrome. J. Edwards described the syndrome in 1960. Reason: trisomy of the 18-th chromosome. Population frequency – 0, 14 : 1 000. Sex ratio – М 1: F 3. Minimal diagnostic attributes: multiple defects of development; retardation of psychomotor development (Fig.5.). Fig.5. Malformed low-set ears; prominent back of the head; elongated back of micrognathia*; the head skull; short palpebral fissure; microstomia*; clenched fingers; the fifth finger overlapping on the fourth finger. Clinical characteristic. Weak activity of a fetus, a small placenta (50 %), the single umbilical artery (80 %), hydramnion* are typical. An average weight of the newborn is 2.340 gramme. There are retardation of psychomotor development (100 %), a skeletal musculature hypoplasia* and hypoplasia* of a hypodermic adipose tissue (50 %), cryptorchism* (100 %), congenital heart diseases (90 %) – defect in the ventricular septum and open arterial Botallo’s duct, malformed low-set ears (80 %), prominent back of the head, elongated skull (80 %), high palate (80 %), micrognathia* (80 %), short palpebral fissure (50%), microstomia* (50%), flexor fingers deformations (80 %), clenched fingers (50 %), the fifth finger overlapping on the fourth , the second finger – on the third (50 %); nail hypoplasia* especially on V-finger and V-toe (50 %), short I-toe (50-80 %), short sternum (80 %), papilla hypoplasia* and papilla hypertelorism* (50 %), small pelvis (80 %), restriction of a thigh abduction (80 %), hypotonia* changing by hypertension (50-80 %), short neck (50-80 %), inguinal or umbilical hernia, prolapse of the rectum (50-80 %), distal triradius (50-80 %), abnormal development of kidneys [more often horseshoe-shaped kidney, hydronephrosis* and hydroureter (50-80 %)], very straightened I -finger (4060 %), additional skin fold on neck (40-60 %), foot with calcaneum-valgus deformation (40-60 %), Mekkel’s diverticulum (40-60 %), high localization of a diaphragm (10-50 %), ptosis* (10-50 %), short labrum (10-50 %), pathology of cerebrum or spinal cord (10-50 %), pylorostenosis* (10-50 %), partial syndactyly* (10-50 %), ulnar or radial deviation of a hand (10-50 %), the single palmar fold (10-50 %), the single flexor fold on V-finger (10-50 %), incomplete intestinal rotation (10-20 %), meningomyelitis (10-20 %), cleft of the lip or palate (10-20 %), choana atresia (10 %), tracheoesophageal fistula (10 %). Sometimes macroclitoris, two-horned uterus, ovary hypoplasia*, anus atresia*, funnel-shaped anus, hip dislocation, phocomelia*, stenosis* of external acoustic duct with hearing loss, claw-shaped deformation of hand, haemangioma*, hypoplasia* of thymus, adrenal and thyroid glands, hemivertebrae, scoliosis*, rib anomaly, union of the vertebrae are marked. Diagnostics: karyotype research and detection of the 18-th chromosome trisomy. 2.3 Down’s syndrome Synonym: Chromosome 21 trisomy syndrome. J. Down described the syndrome in 1866. Reason: trisomy of the 21- st chromosomes. Population frequency – 1 : 700. Sex ratio – М 1: F 1. Minimal diagnostic attributes: mental retardation, muscular hypotonia*, flat face, mongoloid set* of the eyes (Fig.6.). Clinical characteristic. There are flat face (90 %), mongoloid set* of the eyes (80 %), epicanthus* (80 %), open mouth (65 %), short nose (40 %), flat nose bridge (52 %), strabismus* (29 %), pigmentary spots on the edge of the iris – Brushfeeld’s stains (19 %), brachycephaly* (81 %), flat back of the head (78 %), displastic ears (43 %), arcual palmar (58 %), teeth anomalies (65 %), striated tongue (50 %), cataract in the age of more than 8 years (66 %), short broad neck (45 %), dermal fold on the neck in newborns (81 %), short limbs (70 %), V-finger clinodactyly* (66 %), high mobility of joints (80 %), congenital heart diseases (40 %), transversal palmar fold (45 %). All patients are mentally retarded. Atresia* or stenosis* of a duodenum and leukemia are observed in 8 % of cases. Fig.6. Phenotype of siсk children with Down’s syndrome The length of human life is determined by presence of defects of the gastrointestinal tract and heart. The most common form of Down’s syndrome is the simple trisomy form of the syndrome (94 %). The translocational form is marked in 4 % of cases, the mosaic form – in 2 %. Diagnostics: ♦ karyotype research and detection of the 21-st chromosome trisomy; ♦ typical dermatogliphic signs: – transversal palmar fold; – atd -angle is more 80°. 3.1. Syndrome Shereshevskiy – Turner Synonym: Chromosome X monosomy syndrome; ХО – syndrome; Turner’s syndrome Reason: full or partial monosomy of the Х-chromosome. Population frequency – 2 : 10 000. Minimal diagnostic attributes: edema of hands and feet in newborns; hypotonia* of newborns; dermal folds on the neck; short height; congenital heart diseases; primary amenorrhea* (Fig.7.). Fig.7. Edema of hands and feet in newborns; dermal folds on the neck; broad chest Clinical characteristic. Typical attributes of Turner’s syndrome are low growth (98 %), wing-like dermal folds on the neck (56 %), broad chest (60 %), X-shaped curvature of genua (56 %), sexual infantilism (94 %), primary amenorrhea* (96 %), sterility (99 %). An average adult’s height is 140cm. In 40 % of cases peripheral lymphatic edema of hands and feet in newborns are observed. Short neck (71 %), epicanthus* (30 %), the low line of a hair growth on the back of the head (73 %), hypoplasia* or hypertrophy* of nail plates (73 %), short metacarpal bones (especially IV) or metatarsal bones (44 %), high pigmentation of skin (60 %), high palate (39 %), decreased acuity of vision (22 %), hearing impairment (52 %), micrognathia* (40 %), funnelshaped chest (38 %), anomaly of urinary system (38 %) are marked. From defects of cardiovascular system (15 %) coarctation* of aorta and ventricular septum defect, arterial hypertension (27 %) are most frequently met. In 16 % of cases intellectual development is reduced. Less frequent and less important diagnostic signs are – ptosis*, nipples hypoplasia*, hypertelorism*, anomaly of ribs and long tubular bones, osteoporosis*. The changes of dermatoglyphics include the distal displacement of triradius, transversal palmar fold and other features. The risk of thyroiditis, probably, autoimmune genesis and diabetes is high. Diagnostics: ♦ karyotype research and detection of full or partial monosomy of the Х-chromosome, therefore, karyotype- 45, ХО; ♦ research of Barr body; at Shereshevskiy – Turner syndrome Barr bodies are not found out. 3.2 Klinefelter’s syndrome Synonym: Chromosome XXY syndrome H. Klinefelter described it in 1942. Reason: trisomy or tetrasomy on the Х-chromosome in a male organism. Population frequency - 1: 1 000 boys. Minimal diagnostic attributes: hypogonadism*, hypogenitalism*, karyotype 47, XXY (Fig.8.). Fig.8. Phenotype and karyotype at Klinefelter’s syndrome Clinical characteristic. The patients are tall with disproportionate long limbs. In the childhood they differ by a fragile constitution. Adiposity develops in the adults. Distinctive attributes of the syndrome are testicles and penis hypoplasia*. The secondary sexual attributes are poorly developed. Mature female pattern of hair distribution and gynaecomastia* (50 %) can be observed. At histological research of testicles hyalinosis*, fibrosis of seminiferous tubules and secondary hyperplasia* of Leidig’s cells are found out. Reduction of a sexual inclination, impotence and sterility are typical. The small deformations of helix, low line of a hair growth on the back of the head, brachycephaly*, V-finger clinodactyly*, transversal palmar fold, ulna-radial synostosis, scoliosis, neurological symptoms – spasms, ataxy*, tremor are possible. At 15-20 % of patients the coefficient of intelligence is lower than 80. Diagnostics: ♦ karyotype research and detection of superfluous number of the X-chromosomes in male organism, therefore, karyotype may be 47, ХХУ or 48, ХХХУ; ♦ research of Barr body; in male organism Barr bodies are found out at Klinefelter’s syndrome; ♦ typical dermatogliphic signs: – transversal palmar fold; – atd -angle is 40 – 42 °. 3.3 Syndrome of trisomy (polysomy) on the X-chromosome For the first time the syndrome was described by Jecobs in 1959 (England). Reason: superfluous number of the X-chromosomes in female karyotype. Trisomy (47, XXX) takes place more often, tetrasomy (48, XXXX) takes place less often and pentasomy (49, XXXXX) is absolutely rare. Population frequency – 1 or 1,4 on 1 000 born girls. Clinical characteristic. At trisomy (47, XXX) female phenotype can be normal. However, the definite degree of intellectual retardation is marked. Besides, presence of the additional X-chromosomes increases risk of development of psychical diseases (especially schizophrenia or psychoses) in 2 times. At a part of patients typical hysterical features of a behavior take place. Occasionally ovary dysfunction, amenorrhea (absence of menses) and sterility are observed at trisomy. Similar attributes and a various degree of mental retardation – from moderate backwardness up to heavy moronity – are more often met at tetra- and pentasomy for the Х-chromosome. Diagnostics: ♦ karyotype research and detection of superfluous number of the X-chromosomes in the female organism; ♦ search of the sex X-chromatin (presence of additional Barr bodies in somatic cells). 3.4 Syndrome of the additional Y-chromosomes Reason: the additional У-chromosome in male karyotype. Population frequency – 1 : 1000 newborn boys. Clinical characteristic. High growth of males is characteristic (average growth approximately 186 cm). Sometimes acromegaly* traits as a large nose, the big lips, increased bottom of jaw, etc. are marked. The intelligence may be normal or insignificantly reduced. Individuals with corresponding karyotype are inclined to asocial acts, because these males are very aggressive. Therefore, they are frequently found in prison. Them reproductive function basically does not suffer. However, there is increased infancy death rate among children, in which fathers are with additional Y-chromosome. Their offsprings usually have the normal karyotype, but sometimes sons are born with karyotype XYY. Diagnostics: ♦ detection of the Y-chromatin by a fluorescent method; ♦ at karyotype research – one (47, XYY) or more number of the additional Y – chromosomes (48, XYYY) are determined. MOLECULAR (gene) DISEASES Suppose a mutation destroys a crucial part of the genetic code for a protein essential to life. An organism that fails to produce an active form of that protein will die prematurely, and the responsible allele is called a lethal allele. Dominant lethal alleles are possible, but most are rapidly eliminated. Exceptions are those not usually expressed until after the individual has passed reproductive age, in which case the allele is passed on to half of the offspring, on average. (An example is Huntington’s disease in humans, not usually expressed until age 35 or later.) Recessive lethal alleles, on the other hand, are eliminated by selection only when they occur in homozygotes. These alleles usually occur heterozygously, masked by a dominant allele that permits the individual to survive and pass on the recessive lethal allele to future generations. A lethal allele may even become quite common if it is closely linked to an advantageous allele of another gene or if the heterozygous condition has some advantage, as in the case of sickle haemoglobin, discussed shortly. It has been calculated that the average human is heterozygous for perhaps three to five lethal recessive alleles. This is part of the reason that marriages between close relatives produce a disproportionate frequency of offspring with lethal inherited traits. Sometimes just one copy of a normal allele does not make enough of its protein to produce the normal phenotype. In this case the normal allele shows incomplete dominance to the lethal allele, and the heterozygote has a different phenotype from either homozygote. An example in humans there is the lethal allele that causes the middle bone in the fingers of heterozygotes to be unusually short, a condition called brachydactyly (brachy = short; dactyl = finger or toe). This makes the fingers appear to have only two bones instead of three. In homozygotes, this allele results in abnormal development of the skeleton. Homozygous babies lack fingers and have other skeletal defects that cause death in infancy. In a marriage between two brachydactylic people, each child has a onefourth chance of being homozygous for the lethal allele and dying as an infant; a one-half chance of being a brachydactylic heterozygote; and a onefourth chance of not inheriting an allele for brachydactyly. This 1:2:1 offspring ration is typical of a monohybrid cross involving incomplete dominance. Some lethal alleles are mutations of genes that code for proteins essential to embryonic development. Embryos that die early miscarry or, in the case of pregnancies with more than one offspring, may be resorbed back into the uterus. A 2:1 ration is observed among offspring that develop to term (normal birth age): two-thirds heterozygotes to one-third homozygous normal offspring. In mice, for example, the short-tail allele (T’) causes early embryonic death in the homozygote. The embryo is then resorbed. If such embryos are taken from the uterus early in pregnancy, before they can be resorbed, they are seen to have no backbone and none of the mesoderm tissue normally destined to form the muscles, kidneys, and many other important organs. Heterozygotes (TT’) have shorter tails than wild-type mice (TT). Manx cats are heterozygous for a similar lethal allele. The backbone is so short that the cat has no tail. The last vertebrae of the back and the last part of the digestive tract may be abnormal, and in this case the cat may have problems that prevent it from living out a full nine lives. Characteristics of Molecular Diseases The reasons: abnormalities in structure of DNA molecule (gene mutations). Frequency of occurrence: 1-2 % in human populations. The following monogenic diseases on the data of McKusick (1988, USA) are known: ● 2106 autosomal dominant; ● 1321 autosomal recessive; ● 276 Х-linked. There are many polygenic illnesses (diabetes, atherosclerosis, essential hypertension, schizophrenia, etc.). Their clinical spectrum depends from a genotype and environment factors (a feed, stresses, the infections, harmful habits), therefore they are also named as multifactor disease. Criteria of occurrence frequency: ● high frequency – 1 patient on 10 thousand newborns; ● average frequency – 1: 10 – 40 thousand newborns; ● low frequency – 1: 40 thousand and more. Classification: it is submitted on the diagram. Clinical spectrum has a number of features: 1) molecular diseases arise during the different ontogenesis periods (right after birth, in the early childhood, in pubertal period, but up to reproductive age). 2) they are characterized by variety of clinical symptoms – polymorphism (disorders in physical and mental development are observed). 3) they have different degree of pathological current. It is caused by influence of genes - modifiers and environment factors. As result, at a similar genotype pathological attributes have various expressivity and penetrance even among close relatives. 4) they result in the adverse forecast (partial or full invalidity; reduction of life expectancy); Diagnostics: biochemical researches (neonatal screening program): ● On Ist stage: there are qualitative reactions (screening-test). ● On IInd stage: ▪ the biochemical analysis (blood, urine, amniotic fluid, etc.); ▪ microbiological methods; ▪ electrophoresis ; ▪ chromatography; ▪ the radio-immunological analysis. Treatment: efficiency of treatment depends on terms of disease diagnosing (if earlier, then better). Treatment has symptomatic character. MOLECULAR DISEASES Pathology of structural proteins Pathology of fermentative proteins Pathology of transport proteins ENZYMOPATHY 1. EHLERS – DANLOS SYNDROME IMBALANCE of aminoacid exchange– TYROSINOSES: 1. Phenylketonuria; 2. Alcaptonuria; 3. Albinism IMBALANCE of IMBALANCE of carbohydrate exchange lipid exchange 1. Galac tosaemia; 2. Fructosuria Tay – Sachs disease IMBALANCE of mineral exchange Hereditary form of rickets (hypo- phosphataemic rickets) POLYGENIC– INHERITED DISEASES : 1. pancreatic [insular] diabetes; 2. atherosclerosis; 3. schizophrenia and other. HAEMOGLO– BINOPATHY: ∙ SICKLE CELL AENEMIA; ∙ THALASSAEMIA. 2. WILSON’S DISEASE Inborn Errors of Metabolism in Man Many genes code for proteins that are enzymes for a step in one of the body’s metabolic pathways. When such a gene mutates, the new code may produce a defective enzyme unable to carry out its metabolic reaction at a normal rate. The resulting genetic abnormality is an inborn error of metabolism. The metabolic disorder of Tay-Sachs disease is lethal, but others are less severe, and some do little or no apparent harm to affected individuals. The earliest cases of biochemical mutations were described in man by A.E. Garrod in 1909 in his book “Inborn Errors of Metabolism”. There are three important diseases associated with the metabolic breakdown of phenylalanine. 1) Phenylketonuria is due to accumulation of phenylpyruvic acid and causes mental disorders. The children suffering with this disease are known as phenylpyruvic idiots and are unable to break down phenylpyruvic acid into hydroxyphenylpyruvic acid. 2) Alcaptonuria is due to lack of ability to break down homogentisic acid into acetoacetic acid. Due to accumulation of homogentisic acid, the urine of the patients suffering with this disease turns black as soon as it comes in contact with air. 3) Albinism is due to the absence of melanin pigment and the individuals suffering with this disease are incapable of converting dihydroxyphenylalanine into melanin. Another disease tyrosinosis is also associated with the same metabolic pathway. Phenylketonuria and albinism are two human hereditary disorders resulting from defective alleles for enzymes that happen to be on the same metabolic pathway. Phenylketonuria This disease was described by Phelling in 1934. Synonyms: PKU or Phelling’s disease. Type of inheritance: autosomal recessive. The reason: lack the enzyme phenylalanine – 4 – hydrolase. Population frequency – 1 – 4 sick children : 10 000 newborns. PKU-affected individuals are homozygous recessives who lack the enzyme that normally converts the amino acid phenylalanine to another amino acid, tyrosine. Without this enzyme, phenylalanine builds up, perhaps to 50 times its normal level. Minor metabolic pathways convert some of this phenylalanine to various other products, such as phenylpyruvic acid, which is excreted in the urine, giving it a characteristic odor. High concentrations of phenylalanine and its products inhibit the activity of many metabolic enzymes. This damages various organs, especially the brain, and without treatment children with PKU become mentally retarded. PKU can now be controlled by a special diet low in phenylalanine during childhood. This prevents most brain damage, but some patients may still have learning disabilities. Since this treatment must begin within a few weeks of birth, may state now require that newborns receive a blood test for PKU (and for several other metabolic disorders). When brain development is complete, PKU patients can adopt a normal diet. If a woman homozygous for PKU becomes pregnant, the high phenylalanine level in her blood is transferred to the fetus through the placenta. This puts the fetus at risk of mental retardation or microcephaly (small head). Some such women have returned to a low– phenylalanine diet during pregnancy, but it is not yet clear whether this eliminates the risks to the fetus. Since the mother is homozygous for PKU, her children must inherit one copy of the recessive allele from her. Hence, they will all be PKU carriers (or homozygotes if they also receive a PKU allele from their father). Albinism Type of inheritance: autosomal recessive. The reason: insufficiency of enzyme-tyrosinase what normally converts tyrosine to melanin. Population frequency – 1 sick child : 25. 000 newborns. Albinism is a condition characterized by absence of melanin, the dark pigment that makes eyes, hair, and skin brown or black. True albinos have white hair and very light skin and eyes. There are two common types of albinism in humans. In one form, people homozygous for a recessive allele lack an enzyme that normally converts tyrosine to melanin. People with the other common kind of albinism are homozygous recessive for an abnormal allele of a different gene; these people do make the tyrosine-tomelanin enzyme, but for unknown reasons this enzyme produces almost no melanin pigment in their bodies. Some marriages between two albino people have produced normally pigmented children, indicating that one spouse was homozygous recessive for the first allele, and the other spouse was homozygous recessive for the second. If both spouses are homozygous recessive for the same allele, their children are all albino. You may wonder whether victims of PKU are also albino, since they cannot make the tyrosine that is eventually converted to melanin. There is no answer, because tyrosine can be obtained in the diet as well as from conversion of phenylalanine. However, people homozygous for PKU usually have light coloring because phenylalanine products inhibit the pigment-forming enzymes. Of course, a person could be homozygous recessive for both PKU and albinism. Alcaptonuria This disease was described by Harrods in 1902 (England). Synonyms: black urine disease or ochronosis. Type of inheritance: autosomal recessive. The reason: defect in the enzyme homogentisic acid oxidase. Population frequency – 2 – 5 sick children: 10. 000. 000 newborns. Alcaptonuria is a rare inherited genetic disorder of tyrosine metabolism. This is an autosomal recessive trait that is caused by a defect in the enzyme homogentisic acid oxidase. The enzyme normally breaks down a toxic tyrosine byproduct, homogentisic acid (also called alkapton), which is harmful to bones and cartilage and is excreted in urine. Symptoms: A distinctive characteristic of alkaptonuria is that urine or earwax exposed to air turns reddish or inky black, depending on what one has eaten, after several hours because of the build-up of homogentisic acid. Similarly, urine exposed to air can become dark; this is most obvious in young children still in diapers. In adulthood, but usually not before age forty, persons suffering from alkaptonuria develop progressive arthritis (especially of the spine), due to the long-term buildup of homogentisate in bones and cartilage. Diagnosis: Presumptive diagnosis can be made by adding sodium or potassium hydroxide to urine and observing the formation of a dark brown to black pigment on the surface layer of urine within 30 minutes to l hour. Diagnosis can be confirmed by demonstrating the presence of homogentisic acid in the urine. This may be done by paper chromatography and thin-layer chromatography. (Seegmiller, 1998). Treatment: Prevention is not possible and the treatment is aimed at ameliorating symptoms. Reducing intake of the amino acids phenylalanine and tyrosine to the minimum required to sustain health (phenylalanine is an essential amino acid) can help slow the progression of the disease. Galactosemia For the first time this disease was described by Royse in 1908. Type of inheritance: autosomal recessive. The reason: deficiency or absence of an enzyme Gal-l-PUT . Population frequency – 1 sick child : 70. 000 newborns. Galactosemia literally means ‘galactose in the blood’. Galactose is a sugar, which mainly comes from lactose, the sugar found in milks. Lactose is normally broken down into the two simple sugars, galactose and glucose. The galactose is then broken down further and used in many parts of the body including the brain. In galactosemia it cannon be broken down completely and used because of deficiency or absence of an enzyme, galactose-l-phosphate uridyl transferase or Gal-l-PUT. Galactose, galactose-l-phosphate and other harmful chemicals build up and lead to the serious illness that occurs in the first few weeks of life once the baby is fed on milk containing lactose. It is a lifelong condition. The enzyme is deficient or absent because of a mistake or mutation in the genetic code, the DNA. Our chromosomes are made of DNA and carry a coded message rather like a computer program and make us what we are, for example giving us a particular hair colour. We have two copies of all our chromosomes (except the sex chromosomes) and we inherit one copy from our mother and one from our father. In galactosemia the child inherits a mistake in the area that codes for the missing enzyme from both parents. The parents are perfectly healthy because they have one normal gene, which allows them to make enough of the enzyme to keep them healthy. There is way of knowing that a parent may carry this disorder until they have an affected child. In each and every pregnancy there is a 1:4 chance of having another affected baby. We can look for the genetic mistake (or mutation) in the DNA and when we do this we find that in quite a high proportion of children there is the same mutation. We are trying to study whether the mutation is related in any way to the sorts of problems that children with galactosemia have, but at the moment there only seems to be a loose association between the mutation and outcome of affected children. Galactosemia is rare. In the UK, about l child in 45.000 is born with this condition so between 12 and 18 children are born each year with it. Someone with galactosemia is unable to break down and use galactose. The main dietary source of galactose is lactose, which is found in milks. This is why the baby becomes unwell, usually in the first week, having appeared completely normal at birth. Galactose and galactose-l-phosphate levels rise in the baby’s blood and he or she becomes ill. Signs of liver disease including jaundice, lethargy, poor feeding and weight loss are very common. The severity of the liver disease varies a lot. Babies can also be prone to infection at this stage, although this does not continue to be a problem. Cataracts may also be present. These symptoms are not just seen in galactosemia and the pediatrician looking after your baby will do a range of tests to make the diagnosis. Once the galactose free diet has been started the liver disease will disappear and the baby will start to gain weight normally. Over time the cataracts will also disappear. Fructosuria Synonyms: fructose intolerance hereditary, fructosemia. Type of inheritance: autosomal recessive. The reason: insufficiency fructose -1- phosphate aldolase. The minimal diagnostic attributes: anorexia; vomiting; hepatomegaly; hypoglycemia. The clinical characteristic: the basic symptoms of fructosemia – disgust for the food containing fructose (100 %), vomiting (100 %), hepatomegaly (100 %), a jaundice (100 %) and the spasms caused by hypoglycemia (100 %). Disease is expressed in a suckling after addition in food of fruit juices or fruit mush and also at early artificial feeding. There is vomiting, persistent refusal of food. Attributes of hypoglycemia and hypotrophy are developed. Without treatment children perish on 2-6 month of a life owing to cachexia, dehydration and hepatic insufficiency. Diagnostics: Fructosuria, albuminuria, hyper aminoaciduria are found out at laboratory researches. Fructose loading causes sharp deterioration of a condition, which results in hyperfructosemia and expressed hypoglycemia. Fructose-1- phosphate aldolase deficiency in liver, kidneys, mucous of small intestine lays in a basis of disease. Treatment: The forecast is favorable at rational diet therapy. Tay - Sachs Disease For the first time this disease was described by Tay in 1881 and Sachs in 1887. Synonyms: amaurosis* idiocy. Type of inheritance: autosomal recessive. The reason: lacks the enzyme hexosaminidase, which metabolizes a lipid. Population frequency – 1: 250. 000 newborns, but in family of East European Jewish it is more. For instance, population frequency is 1: 5.000 among Jewish– Ashkenazi, what are born in Poland and Lithuania. The minimal diagnostic attributes: neuropathy and optic atrophy. Tay-Sachs disease, a metabolic disorder resulting in deterioration of the brain and death by about the age of four, is also the result of a lethal recessive allele. A homozygous recessive child lacks the enzyme hexosaminidase, which metabolizes a lipid in the brain’s nerve cells. Without this enzyme, the lipid accumulates and destroys the cells ability to function. So far, this condition is untreatable, but genetic tests that detect it very early in embryonic development are now widely used. The highest frequency of this allele occurs among people of East European Jewish extraction: one in 30 members of this group is a carrier (heterozygous) for this disorder. However, about one third of the TaySachs cases in the United States are among non-Jewish people. Vitamin D - resistant rickets Synonyms: family X – linked hypophosphataemia*; phosphate diabetes. Type of inheritance: X – linked dominant. The minimal diagnostic attributes: rickets signs, what are not giving in to treatment by vitamin D; hypophosphataemia*. The clinical characteristic: hypophosphataemia* is possible to reveal right after birth. Attributes of rickets appear at the end of the first or the beginning of the second year of a life when children start to go. Changes of lower limbs are most expressed as a curvature of long tubular bones. Low growth, restriction of mobility in large joints (knee, cubital and femoral articulations), dolichocephalous form of scull and nails dysplasia* are characteristic. Gait uncertain is typical, but in heavy cases patients cannot go at all. As against from rickets vitamin D – dependent the common condition of patients is not broken. Skeletal disorders are less expressed in females. Diagnostics: in blood the alkaline phosphatase concentration is increased, but calcium level is norm. Disease is caused by decrease of reabsorption phosphates in renal tubules. Ehlers – Danlos syndrome E. Ehlers in 1901 and H. Danlos in 1908 described it. Population frequency – 1 : 100 000. Type of inheritance: autosomal dominant. The minimal diagnostic attributes: the hyperelastic and fragile skin, the hypermobile joints, hemorrhagic diathesis. The clinical characteristic: The Ehlers – Danlos’s syndrome is pathology of the connective tissue affecting the skin and joints. It differs by types of inheritance, clinical features and by biochemical defects. Syndrome is characterized by generalized high mobility of joints and the expressed extensibility of skin. Vulnerability of skin is increased, therefore, formation of "cigarette tissue ", keloid scars are typical. There are hypodermic pseudo-tumors on elbows and knees, on a forward surface of shins – hypodermic nodules. Vein dilatations are observed. It is possible prematurity owing to early break of fetal membranes. Fragility of tissues creates difficulties at surgical intervention. Looseness of joints can lead to muscularskeletal deformations. Sickle-Cell Anaemia In humans, the allele responsible for sickle cell anaemia is often lethal in the homozygous condition. The gene involves codes for the beta (β) polypeptide chain of haemoglobin, the oxygen-carrying protein found in red blood cells and responsible for their red color. The sickle allele results from a point mutation: a change in just one nucleotide pair, which in this case substitutes valine for glutamic acid as the sixth amino acid in the haemoglobin beta chain. This seemingly small change has drastic consequences. Whet red blood cells containing sickle haemoglobin are exposed to low oxygen levels, the haemoglobin molecules aggregate and form rigid fibers. These fibers distort the cells into odd shapes, such as sickles. The sickle cells become stuck in the capillaries, the narrowest blood vessels, rather than bending and squeezing through in single file as normal red cells do. The stuck cells impede circulation to the areas supplied by the blocked capillaries. The sickle cells also break down easily, leaving the victim with fewer red blood cells than normal, a condition known as anemia. Poor circulation and anaemia deprive the tissues of needed oxygen, producing symptoms such as tiredness, headaches, muscle cramps, poor growth, and eventually perhaps failure of organs such as the heart and kidneys. An individual homozygous for a deleterious recessive allele is an affected individual, whereas a heterozygote is a carrier. People heterozygous for the sickle allele are sometimes referred to as “having sickle cell trait”. This phrase is unfortunate, since it suggests that the carrier is less fit than the normal homozygote, which is not usually the case. The sickle allele occurs most commonly (but not exclusively) in black people. In the United States, about l in 400 black newborns is homozygous for the sickle allele. The sickle and normal alleles are codominant: heterozygotes produce both normal and sickle beta chains. Their red blood cells sickle only when the oxygen level is extremely low. For instance, a study showed that black military recruits who were carriers of sickle cell trait were 28 times more apt to die from the strenuous exercise of basic training than were homozygous normal black recruits. Without special blood tests, heterozygotes such as there may be unaware that they are among the 8% of American black people who carry the sickle allele. People homozygous for the sickle allele are more severely affected because all of their beta chains are abnormal. About half of them die by the age of 20. Furthermore, women in this group have fewer babies than do heterozygous or homozygous normal women. We might expect natural selection to keep such a lethal allele quite rare, because many people homozygous for the sickle allele die without having children. Yet in large areas of tropical Africa, 20 to 40% of the people are heterozygous for the allele. This suggests that heterozygotes have some selective advantage compared with the normal as well as sickle homozygotes. In 1953 it was noted that these people lived in the areas with the highest rates of death from a virulent form of malaria, caused by Plasmodium falciparum, a parasite of red blood cells. Having a copy of the sickle allele lowers a person’s chances of developing malaria. Red blood cells containing sickle haemoglobin sickle more readily when they are infected with malaria parasites. When a cell sickles, the parasites inside it die. The body’s defenses may then be able to destroy the remaining parasites before malaria develops. In malaria infested regions, therefore, it is advantageous to be heterozygous for the sickle allele, which protects against a common deadly disease, even though the sickle allele is usually lethal in the homozygous state. Sickle-cell anaemia is a blood disease where the red blood cells become sickle shaped as compared with round shape in normal individuals. This results into various abnormalities and may ultimately result into death. This disease is caused by a single gene, which in heterozygous condition causes moderate sickling (sickle-cell anaemia). It was also found that the haemoglobin of normal individual and a patient have different mobilities in an electrophoretic field. Haemoglobin of sickle-cell anaemia moves in a direction opposite to that of normal haemoglobin. Such a difference was later discovered (by Ingram in 1957) to be due to the replacement of a single amino acid in β-chain of haemoglobin 1 2 3 4 5 6 normal haemoglobin A = val – his – leu – thr – pro – glu – glu sickle cell haemoglobin S = val – his – leu – thr – pro – val – glu In table are segments of β-chains of normal and abnormal haemoglobin showing amino acid replacement. Thalassemia The same explanation may account for the high frequency of thalassemia, a group of genetic conditions in which too little haemoglobin is produced, in districts of Italy, Greece, and other areas where malaria was once common. So far there are no effective drugs to prevent disease in homozygous patients. Genetic engineering provides approaches that could help patients with sickle-cell anaemia or thalassemia. One way is to try to turn on the genes for gamma (γ) chains of haemoglobin, normally expressed only in the fetus. If these genes could stay turned on after birth, the gamma chains produced would combine with alpha (α) chains and form near-normal haemoglobin. Researchers recently isolated stem cells, which produce all the blood cells, from bone marrow. If a patient’s stem cells could be isolated, given transplants of normal beta chain alleles, cultured, and returned to the patient’s bone marrow, they would provide a lifelong cure. However, these homozygous patients would still pass on a copy of the sickle or thalassemia allele to each of their children. Wilson's disease For the first time this disease was described by Wilson in 1911 and N.Konovalov according to clinical disorders called it as hepatocerebral dystrophy. Synonyms: Wilson-Konovalov’s disease; hepatocerebral dystrophy, hepatolenticular degeneration. Type of inheritance: autosomal recessive. The reason: ceruloplasmin deficiency, providing copper transport in an organism. The minimal diagnostic attributes: the decrease of ceruloplasmin concentration in plasma; Kaiser-Flasher’s ring on the iris; the increase of the copper contents in a liver; hepatosplenomegaly; neurological symptoms. The clinical characteristic: Disease is expressed in the age from 6 till 50 years, but most frequently – in schoolchildren. The first symptoms can be hepatosplenomegaly, dysfunction of a liver, CNS, sometimes kidneys. Liver pathology is demonstrated as subacute hepatite with jaundice, vomiting and dyspepsia. At late stages the cirrhosis and a portal hypertension are developed. Neurological changes are as dysphagia*, unarticulated speech, salivation, increased muscular rigidity, hyperkinesias. Decrease in intelligence, change of behaviour is marked. A specific symptom is a pigmental green - brown ring on the iris (Kaiser-Flasher’s ring). On autopsy accumulation of copper in brain, liver, kidneys, spleen, cornea, iris and crystalline lens are found out. Diagnostics: the basic biochemical research is detection of ceruloplasmin deficiency, providing copper transport in an organism. As result the increase of copper concentration in blood is determined. There are a thrombopenia*, a leukopenia* and anaemia. Glossary • Acromegaly – growth of bones and soft tissues of face (enlargement of a nose, lips, a chin), the increase in sizes of internal organs and limbs. • Amaurosis – the full blindness. • Amenorrhea – absence of menses during fertile age. • Antimongoloid set of the eyes – dropped external angles of palpebral fissures. • Aplasia (agenesia) –congenital full absence of organ or its part. • Arrhinencephaly – aplasia of olfactory bulbs, furrows, tracts and laminae. • Ataxy – the loss of coordination in contractions of various muscles groups at any movements. • Atresia – the full absence of the ducts or natural foramens in organs. • Autism – isolation from people, from a life; absorption in the own world. • Brachycephaly – short-head person, increased transversal head size respecting decreased longitudinal size. • Cataract – eye disease in which basic symptom is turbidity of crystalline lens. • Clinodactyly– lateral or a medial curvature of a finger. • Coarctation – a stenosis (narrowing) of an artery. • Coloboma – eye absence or defect of any its structure. • Cryptorchism – the abnormal development of testes, in which testes don’t descend in scrotum as a result they are located in abdominal cavity or groin channel. • Dysphagia – disorder of swallowing. • Dysplasia - the abnormal embryonic laying and development of tissues or internal organs. • Epicanthus – the vertical skin fold near internal corner of an eye fissure. • Expressivity – the degree of phenotypical development of the trait (sign). • Gynaecomastia – excessive increase of mammary glands in male. • Haemangioma – a non-malignant growth of blood vessels. • Hyalinosis – a protein dystrophy kind at which homogeneous, translucent, dense protein substances are accumulated in tissues between cells. • Hydramnion – the superfluous accumulation of amniotic fluid in amniotic cavity. • Hydronephrosis – a progressing dilatation of renal canals and renal pelvis owing to disturbance of urine excretion with the subsequent necrosis of a kidney tissue. • Hyperplasia – increase of cells number. • Hypertelorism – increased distance between organs. • Hypertrophy – increased of cells volume. • Hypogenitalism – the abnormally small size of gonads, internal and external genitals. • Hypogonadism – decreased gonads. • Hypophosphataemia – the low concentration of phosphates in peripheral blood. • Hypoplasia – the insufficient development of tissues, organs, parts of a body or the whole organism. • Hypospadias – the inferior urethra cleft and displacement of urethra external orifice. • Hypotelorism – decreased distance between organs (usually about eyes). • Hypotonia – decreased tonus of tissues and organs. • Leukopenia – the low level of leukocytes in peripheral blood. • Macroclitoris – increased clitoris. • Macroorchism – enlargement of testes. • Meningomyelitis – an inflammation of spinal cord substances and its envelopes. • Microcephaly – the small sizes of a brain and a brain skull. • Micrognathia – decreased maxilla. • Microphthalmia – the small sizes of an eyeball. • Microstomia – a small oral slit. • Mongoloid set of the eyes – dropped internal angles of palpebral fissures. • Myeloleukemia – a kind of leukaemia at which number of immature leukocytes (promyelocytes and myelocytes) increases in peripheral blood. • Osteoporosis – imbalance of a bone tissue structure. • Otitis – inflammation of a middle ear. • Penetrance – quantitative index of phenotypical development of the trait (sign). • Phenocopy – phenotypical expressions similar to hereditary disease without changes in genotype. • Phocomelia – absence [significant lag] of limbs proximal parts. As a result, foots or hands seem attached directly to a body. • Polydactyly – increased number of fingers. • Ptosis – the lowering (usually palpebrae). • Pylorostenosis – the narrowing of the pylorus. • Scoliosis – a lateral bending of a backbone. • Stenosis – the narrowing of the internal organs ducts or orifices. • Strabismus – a squint [cross-eye]. • Syndactyly– full or partial concretion of the neighbour fingers or toes. • Synostosis – fused (merged) bones. • Trigonocephaly – a skull expansion in occipital and the narrowing in a frontal part. • Thrombopenia – the low level of thrombocytes in peripheral blood. BIBLIOGRAPHIC REGISTER: 1. 2. 3. 4. 5. 6. С.И.Козлова, Н.С.Демикова, Е.Семанова, О.Е.Блинникова «Наследственные синдромы и медико-генетическое консультирование». – Атлас-справочник. – Изд. 2-е дополн. – М.; Практика, 1996. – 416 стр., 392ил. A textbooik of cytology, genetics and evolution, ISBN 81-7133161-0, P.K. Gupta (a textbook for university students, published by Rakesh Kumar Rastogi for Rastogi publications, Shivaji Rood, Meerut- 250002. Biology, fourth edition, Karen Arms, Pamela S. Camp, 1995, Saunders college Publishing. Intermediate First Year, Zoology: Authors (English Telugu Versions): Smt. K.Srilatha Devi, Dr. L. Krishna Reddy, Revised Edition: 2000. Review Committee, Dr. K. Malla Reddy, Sri Y. Krishnanandam, Sri B.V.Gopalacharyulu, Sri G.Rama Joga Rao, Teludu Akademi. Биология/ А.А. Слюсарев, С.В.Жукова. – К.: Вища шк. Головное изд-во, 1987. – 415 с. CONTENTS: CHAPTER I: MUTATIONS Brief history………………………………………………………..…5 Modern classifications of mutations……………………………….…6 Gene mutations………………………………………………….……7 Structural changes in chromosomes……………………………….…8 Numerical changes in chromosomes…………………………..……10 CHAPTER II: HUMAN DISEASES Hereditary illnesses……………………………………………….…12 Illnesses with hereditary predisposition……………………………..13 Nonhereditary illnesses…………………………………………...…13 CHAPTER III: CHROMOSOMAL SYNDROMES Total characteristics of chromosomal illnesses……………………...14 Classification of chromosomal diseases………………..…………....16 “Cat-like cry syndrome”………………………………….……..…...16 Translocation form of Down’s syndrome…………………................17 Syndrome of “Philadelphian chromosome”……………………..…..18 Martin –Bell’s syndrome……………………………………….....…19 Syndrome Patau……………………………………………...……....20 Edwards’s syndrome………………………………………………....22 Down’s syndrome………………………………………...……….....23 Syndrome Shereshevskiy- Turner……………………....………........25 Klinefelter’s syndrome………………………………………...….….27 Syndrome of polysomy on the X - chromosome………...…………..28 Syndrome of the additional Y-chromosomes…...…………...…....….29 CHAPTER IY: MOLECULAR DISEASES Total characteristics of gene diseases…………………….…….……31 Classification of molecular diseases…………………………………32 Phenylketonuria ……………………...……………………………...33 Albinism ………………………………………………………..…...34 Alcaptonuria…………………………………………...…………….35 Galactosemia……………………………………………….………..36 Fructosuria……………………………………...……………………37 Tay-Sachs disease……………………………………………………38 Vitamin D-resistant rickets…………………………………..............38 Ehlers-Danlos syndrome…………………………….…………….....40 Sickle-cell anaemia……………………………..………………....…41 Thalassemia………………………………………………………..…42 Wilson’s disease…………………………………………...................43 GLOSSARY……………….………………………….......44 Hereditary diseases of a man Textbook for the students of the English-speaking Medium НАСЛЕДСТВЕННЫЕ ЗАБОЛЕВАНИЯ ЧЕЛОВЕКА Учебное пособие для студентов англоязычного отделения (на английском языке). Авторы: Макаренко Элина Николаевна, кандидат медицинских наук, старший преподаватель кафедры биологии с экологией; Болдырева Галина Ивановна, старший преподаватель кафедры биологии с экологией; Паршинцева Наталья Николаевна, старший преподаватель кафедры иностранных языков с курсом латинского языка. Authors: Senior Lecturers of Department of Biology with Ecology Mackarenko E.N., Boldyreva G.I. and Teacher of Latin and Foreign Languages Department of Stavropol State Medical Academy Parshintseva N.N.