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  2. 1. Genotype. Phenotype. Karyotype. 2. Mutation, types of mutation, mutagens. 3. Genetic diseases. Classification of genetic diseases. 4. Chromosome diseases resulting from chromosome muta tion: cat cry syndrome. 5. chromosome diseases (resulting from genome mutation) : a) numeric anomalies of autosomes: down syndrome, pata u syndrome, edwards syndrome; b) numeric anomalies of sex chromosomes: Turner syndro me, Klinefelter syndrome, XYY syndrome (supermale), XX X syndrome (superfemale). 6. Gene genetic diseases. 7. Methods of genetic. 8. Phenocopy. Congenital diseases. 9. Diathesis. Types of diathesis.
  3. Deoxyribonucleic acid (DNA) is a nucleic acid th at contains the genetic instructions used in the dev elopment and functioning of all known living organi sms (with the exception of RNA viruses). The DNA segments that carry this genetic information are ca lled genes. Gene is the segment of DNA carried the informatio n about one polypeptide chain of protein. Chromosome - a threadlike linear strand of DNA and associated proteins in the nucleus of eukaryoti c cells that carries the genes and functions in the tr ansmission of hereditary information.
  4. Genotype is the complex of all genes in organism. Genotype is the sum of inheri ted characters received from parents. Phenotype is sum of external and inter nal signs resulting from interaction of ge notype with environment.
  5. Karyotype is complex of signs (number, size , form etc.) of full number of chromosomes in trinsic for biological species Haploid: A single set of each chromosome (23 in h umans). Only germ cells have a haploid number (n) of chromosomes. Diploid: A double set (2n) of each of the chromoso mes (46 in humans). Most somatic cells are diploid. In humans the normal chromosome count is 46 46,XX for women 46,XY for men
  6. MUTATION is sudden and spontaneous cha nges in DNA. Mutations are caused by mutag ens.
  7. Mutagens EXOMUTAGENES 1)Physical (ionizing and ultraviol et radiation, temperature etc.) 2)Chemical (formalin, salts of he avy metals, some drugs etc.) 3)Biological (viruses, bacterial to xins etc.) ENDOMUTAGENES The products of metabolism
  8. CLASSIFICATION OF MUTATI ONS 1) nuclear 2) cytoplasmic
  9. 1. Spontaneous 2. Induced - occurs under the influence of mutagens
  10. 1. Generative (occur in sex cell s) 2. Somatic (occur in somatic ce lls)
  11. 1. chromosome mutation 2. genomic mutation 3. gene mutation.
  12. Chromosome mutation is change of structure of chromo somes. TYPES:
  13. Genomic mutation is change of q uantity of chromosomes: - polyploid (is lethal mutation in hu mans) n(haploid)→2n(diploid-norma)→3n →4n… - aneuploid (loss or addition of chr omosomes): 2n+1 trisomy 2n-1 monosomy 2n+2 tetrasomy
  14. Nondisjunction is a failure of paired chro mosomes or chromatids to separate and mo ve to opposite poles of the spindle at anaph ase, during mitosis or meiosis. Numerical ch romosomal abnormalities arise primarily fro m nondisjunction. Nondisjunction leads t o aneuploidy if only one pair of chromosome s fails to separate. It results in polyploidy if t he entire set does not divide and all the chro mosomes are segregated into a single daug hter cell.
  16. Gene mutation (point mutation) results from the substitution of a single nucleotide base by a diffe rent base, resulting in the replac ement of one amino acid by ano ther in protein product.
  17. GENETIC DISEASES: 1.chromosome (resulting from chromosome and genome muta tions) 2. gene (resulting from gene mu tations)
  18. CHROMOSOME DISEASES resulting from chromosome mutation: cat cry syndrome partial deletion of the short arm of chromosome 5.
  19. Clinical signs of cat cry syndrom : developmental lag low-birth-weight infant muscular hypotonia hypoplasia or changing of larynx (stenosis or softn ess of cartilages, decreases of epiglottis) resulting in cry like cat cardiac malformation, musculoskeletal system an d internals malformation microcephaly ptosis, deformation of auricle, skin fold before ears epicanthus
  21. DOWN SYNDROME • hypotonia in newborns • upslanting palpebral fissures • neck webbing • dysplasia of ears • flat occiput • single palmar crease • epicantic folds (inner canthus) • congenital heart defects, defects of other organs
  22. • mental retardation • macroglossia • male hypogenitalism • denture defects • short, broad hands, brachydactyly • immune system defects • higher risk of tumour diseases (leukemia)
  23. PATAU SYNDROME 47,XX/Y,+13 • severe developmental retardation • congenital heart defects • microcephaly • malformed, low-set ears • microphtalmia, micrognathia • polydactyly • kidney anomalies • cleft palate, cleft lip
  24. EDWARDS SYNDROME 47,XX/Y,+18 • severe developmental retardation • heart defects • malformed, low-set ears • hypoplastic nails • digits overlapping • micrognathia • prominent occiput • pedes equinovares (clubfoot) • microcephaly
  25. TURNER SYNDROME 45,XO • short stature • gonadal dysgenesis, primary amenorrhoea • average intelligence • short webbed neck (pterygium colli) • low posterior hairline • broad/shield chest • palms and feet edema (newborns)
  26. KLINEFELTER SYNDROME 47,XXY • tall stature • average intelligence • male psychosexual orientation • poor beard growth • hypoplastic testes, cryptorchism • sterility - azoospermia • gynaecomastia
  27. XXX SYNDROME (SUPERFEMAL E), 47,XXX • 1 : 1000, no specific phenotype • average intelligence • normal sexual development • decreased fertility (spontaneous aborti ons), without risk of chromosomal aberr ations in offspring • no increased occurrence of congenital disorders over to population risk
  28. XYY SYNDROME (SUPERMALE) 47, XYY • „robust“ growth (proportional), especia lly height • average intelligence • normal sexual development • normal fertility, without risk of chromosomal aberrations in offspring • controversy - affected psychosocial development
  29. GENE GENETIC DISEASES: (resulting from gene mutations) autosomal recessive disorder autosomal dominant disorder autosomal codominant disorder X-linked recessive disorder Y-linked recessive disorder
  30. AUTOSOMAL DOMINANT DIS ORDERS 1. Both male and female are affected 2. Disease in the homozygous state is more sever e than in the heterozygous. 4. When an affected person marries an unaffected one, every child has one chance in two of having t he disease. 5. Some individuals inherit the mutant gene but are phenotypically normal (reduced penetrance)
  31. AUTOSOMAL DOMINANT DIS ORDERS: Marfan syndrome Familial hypercholesterolemia Hereditary spherocytosis Von Willebrand disease
  32. MARFAN SYNDROME is an autosomal dominant, inherited disorder of connective tissue characterized by a variety of abnormalities in many organs, including the heart, aorta, skeleton, eyes, and skin.
  33. People with Marfan syndrome are tall; the lower body segment (pubis-to-sole) is longer than the upper body segment; a slender habitus, which reflects a pauc ity of subcutaneous fat, long, thin extremities and fingers, which accounts for the term arachnodactyly (s pider fingers).
  34. Autosomal Recessive Disorders: - Sickle cell anemia - Thalassemia - Myeloperoxidase deficiency - Phenylketonuria - Glycogen storage disease Ia (von Gierke disease) - Alkaptonuria
  35. Phenylketonuria
  36. Phenylketonuria PKU patients have light pigmentation and are physically and mentally retarded.
  37. A. Phenylketonuria. Persons with genotype pp fail to produce enzyme phenylalanine hydroxylase (pa rahydroxylase) with the result that phenylalanine fa ils to convert into tyrosine and consequently, the c oncentration of phenylalanine rises in the blood pla sma, cerebrospinal fluid and urine. The urine of ph enylketonuric (PKUJ patient contains (in addition t o phenylalanine) elevated amounts of phenylpyruvi c acid, phenyl lactic acid and other derivatives of p henylalanine. PKU patients have light pigmentation and are physically and mentally retarded. The feeb
  38. C. Alkaptonuria. The persons with genotype hh f ail to produce the enzyme homogentisic acid oxida se which catalyzes the oxidation of homogentisic a cid. Therefore, in them, normal oxidation of homog entisic acid into water and carbon dioxide does not occur and large amounts of homogentisic acid are excreted in the urine, which turn black upon expos ure to the air. Moreover, the homogentisic acid acc umulate in the body and become attached to the c ollagen of cartilage and other connective tissues, d ue to which, the ear and sclerae are stained black. Persons with such phenotypic abnormalities are sa id to have alkaptonuria disease.
  39. B. Tyrosinosis. The recessive gene, t i n its homozygous condition, blocks the conversion of p-hydroxyphenylpyruvate into 2, S-dihydroxyphenyl pyruvate. Thi s leads to the accumulation of tyrosine, excesses of which are excreted via the urine. This condition is called tyrosinosi s. It is reported in only one human and cause no harmful effect.
  40. E. Albinism. The persons with rece ssive aa genotype lack in the tyrosi nase enzyme system which is requi red for the conversion of 3, 4-dihydr oxyphenyl alanine (DOPA) into mel anin pigment inside the melanocyte s. In an albino patient melanocytes are present in normal numbers in th eir skin, hairs, iris, etc., but lack in melanin pigment.
  41. X-linked recessive disorders ● A male child of a woman who is a carrier h as a 50% risk of inheriting the disorder. ● A female child of a woman who is a carrier has a 50% risk of inheriting the gene mutatio n and thus being a carrier herself. ● An affected male - if able to reproduce - wi ll pass on the gene mutation to all daughters , who are therefore obligate carriers. The aff ected male never passes the disease on to a son.
  42. X-linked recessive disorders Hemophilia A In general symptoms are internal or external bleeding episodes. Y-linked recessive disorders hypertrichosis of ears
  43. METHODS: 1.cytogenetic analysis 2.clinico-genealogical method of dermatoglyphics 4.Twin Studies 5.biochemical method 6.immunogenotypic analysis 7.population genetic and statistical methods 8.prenatal diagnostics 9.modelling
  44. Twin Studies The scientific reasoning behind twin studies is bett er than in family studies because monozygotic twin s (identical twins) have exactly the same genes, an d therefore their mental characteristics should be a lmost identical. Identical twins can be studied wher e atleast one is suffering from a mental illness and the concordance rate (percentage of times both twi ns are found to have the same illness) examined. Higher concordance rates than that of fraternal twi ns provides a strong argument for an hereditary eff ect on that illness.
  45. Phenocopy a phenotypic trait or condition that is i nduced by environmental factors but closely resem bles a phenotype usually produced by a specific g enotype. The trait is neither inherited nor transmitt ed to offspring. Such conditions as deafness, creti nism, mental retardation, and congenital cataracts are caused by mutant genes but can also result fro m a number of different agents, such as the rubella virus in the case of congenital cataracts. Because phenocopies may present problems in genetic scre ening and genetic counseling, all exogenous factor s must be ruled out before any congenital trait or d efect is labeled hereditary.
  46. Sensitivity of specific organs to teratogenic agents at critical stages of human embryogenesis
  47. Diathesis is a hereditary predisposition of the body to a disease, a group o f diseases, an allergy, or anothe r disorder.
  48. TYPES OF DIATHESIS: 1. arthritism, gouty diathesis 2. lymphohypoplastic diathesis 3. exudative diathesis 4. asthenic diathesis
  49. ARTHRITISM, GOUTY DIATHE SIS increased excitability obesity predisposition to joint disease, s kin disease, gout, rheumatism
  50. LYMPHOHYPOPLASTIC DIAT HESIS muscular hypotrophy pharyngitis, lymphocytosis, splenomegaly, predisposition to autoimmune di seases
  51. EXUDATIVE DIATHESIS predisposition to inflammation a nd allergy
  52. ASTHENIC DIATHESIS general adynamia vasomotor lability ptosis internal organs