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Genetic Disorders

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Title: Genetic Disorders


1
Genetic Disorders
2
INTRODUCTIONDEFINITION OF TERMS
  • CHROMOSOMES- cellular structures where genes are
    located
  • GENES- basic units of heredity carry  information
     necessary  to  determine specific biologic
    structures functions
  • ex. ABO Ag in RBC membrane coded by chromosome 9
  • LOCUS-  position in the chr where particular
     gene  is located all gene loci occur in pairs
    except X Y genes

3
INTRODUCTIONDEFINITION OF TERMS
  • ALLELES- alternative genes in a single locus
  • ex. Kell blood group system
  • alleles K k
  • KK- homozygous Kk- heterozygous
  • HOMOZYGOUS GENES- gene pair that are alike
  • HETEROZYGOUS GENES- gene pair that are not alike
  • GENOTYPE- actual gene composition that make the
    trait
  • PHENOTYPE- manifestation of the structure/ form
     produced  by the genes

4
INTRODUCTIONDEFINITION OF TERMS
  • DOMINANT  GENES-  genes  that are  always
     expressed  in  the phenotype whether homozygous
    or heterozygous
  • RECESSIVE  (AMORPH) GENES- genes that are masked
     if  paired w/  a  dominant gene, thereby only
    expressed when  paired  w/ another recessive gene

5
INTRODUCTIONDEFINITION OF TERMS
  • EUPLOIDY- multiples of the haploid that is
    considered normal
  • HAPLOID (N) 23- OCCURS IN MEIOSIS
  • DIPLOID (2N) 46- OCCURS IN MITOSIS
  • ANEUPLOID- not exact multiples of the haploid
    only 1 pair of chr involved, therefore, germ
    cells have 2 copies of the same chr or lack the
    affected chr entirely
  • HYPODIPLOID 2N- 1, -2, ETC. (MONOSOMY)
  • HYPERDIPLOID 2N 1, 2, ETC. (TRISOMY)

6
INTRODUCTIONDEFINITION OF TERMS
  • POLYPLOID-  multiples of haploid entire  set
     of chrs fail to divide all the chrs are
    segregated in a single daughter cell
  • TRIPLOID (3N) 69
  • TETRAPLOID (4N) 92

7
Congenital Disorders
  • Non Genetic
  • Developmental defects Malformations
  • Genetic Disorders
  • Chromosomal
  • Gene - Mendelian
  • Multifactorial

8
Mutations
  • Genome whole set Polyploidy 4n, 8n etc.
  • Chromosomal change in chromosome
  • Number Trisomy, monosomy
  • Structure Deletion, Translocation etc.
  • Gene Submicroscopic
  • Point mutation single base sequence
  • Deletions
  • Insertions

9
Cytogenetic Abnormalities
  • Abnormal of chrs
  • Non-disjunction - Downs Syndrome
  • Anaphase lag - Turners xxx
  • Abnormal Structure (normal )
  • Deletion - 5q- Cri - du - chat syndrome
  • Inversion -
  • Translocation - Ph Chromosome - t(922) CML,

10
GENETIC PATHOLOGY
  • DEFINITION  Abnormalities or disease states that
    may or may  not be congenital, transmitted by
    genes or chromosomal aberrations, that  may be
    heritable (familial) or mutational
  • If  mutational, may give the following outcomes
  • Heritable
  • Disappear
  • Lethal
  • Sterility
  • Malignancy

11
CATEGORIES
  • CHROMOSOMAL ABNORMALITIES/ MUTATIONS
  • GENE ABNORMALITIES/ MUTATIONS
  • POLYGENIC/ MULTIFACTORIAL ABNORMALITIES

12
I. CHROMOSOMAL ABNORMALITIES/ MUTATIONS
GENERAL CONCEPTS
  • Children born to older women show more
    chromosomal aberrations than children born to
    younger women
  • Most major chromosomal abnormalities are
    incompatible w/ life
  • Detectable by karyotyping (chromosomal analysis)
    w/  or w/o banding techniques (use of stains)

13
I. CHROMOSOMAL ABNORMALITIES/ MUTATIONS TYPES
  • NONDISJUNCTION (Chromosomal numerical
    aberration)- failure of chrs to sort themselves
    in equal s into daughter cells
  • SUBTYPES
  • POLYPLOIDY- see previous definition
  • ANEUPLOIDY- see previous definition
  • MOSSAICISM/ MYXOPLOIDY

14
Non-disjunction
15
I. ANEUPLOIDY TRISOMY
  • TRISOMY- presence of 3 homologous chromosome in
    a cell
  • AUTOSOMAL TRISOMY- viable throughout pregnancy,
    even live born but die soon after birth except
     Down's syndrome
  • TRISOMY 21- DOWN'S SYNDROME
  • TRISOMY 18- EDWARD'S SYNDROME
  • TRISOMY 13- PATAU'S SYNDROME

16
I. ANEUPLOIDY TRISOMY
  • SEX CHR. TRISOMY- abnormal development but non
    lethal of X chr. is directly proportional to
    mental retardation while number of Y chr. is
    directly proportional to aggressive behavior
  • TRIPLE X

17
I. ANEUPLOIDY MONOSOMY
  • MONOSOMY-  absence of one of  a  pair  of
    homologous chr
  • AUTOSOMAL MONOSOMY- IUFD is the usual outcome
  • SEX CHR. MONOSOMY- compatible w/  life only if
    the conserved chr is an X, if not it will be
     less viable
  • TURNER'S SYNDROME- 45, XO

18
Hydrops Fetalis Monosomy X
19
I. ANEUPLOIDY MOSSAICISM/  MYXOPLOIDY
  • MOSSAICISM/  MYXOPLOIDY- nondisjunction at a
    later cell division resulting to population of
    normal trisomic or monosomic cells coexisting
    in an individual
  • AUTOSOMAL MOSSAICISM- rare lethal
  • SEX CHR. MOSSAICISM- common
  • GONADAL DYSGENESIS- TURNER'S SYNDROME 45, XO
  • KLINEFELTER'S SYNDROME 47 XXY

20
I. CHROMOSOMAL ABNORMALITIES/ MUTATIONS TYPES
I. MORPHOLOGIC/ STRUCTURAL SUBTYPES
  • DELETION- loss of chromosomal material following
    a break in the chr arm or partial monosomy
  • CRI DU CHAT- partial monosomy of p5
  • RETINOBLASTOMA- q13
  • WILM'S TUMOR ANIRIDIA SYNDROME- p11

21
I. MORPHOLOGIC/ STRUCTURAL SUBTYPES
  • TRANSLOCATION- transfer of segment of chromosomal
    material to another chromosome leading to
    imbalance of material in each daughter cell
    between non homologous chr
  • RECIPROCAL- acentric segments of chr exchanged
    for similar segment from a heterologous chr use
    banding techniques for detection
  • ROBERTSONIAN (CENTRIC FUSION)- 2 acrocentric chr
    broken near centromere, exchange 2 arms and form
    new large metacentric chr and a small fragment,
    devoid of centromere lost during subsequent
    division

22
I. MORPHOLOGIC/ STRUCTURAL SUBTYPES
  • TRANSLOCATION
  • BALANCED- transfer w/ no loss of genetic
    material individuals are normal except for
    infertility if fertile, have a high risk of
    having malformed offspring
  • UNBALANCED-  transmitted  in the haploid gamete
    paired w/ a new set of genes from the other
    parent
  • MALIGNANT LYMPHOMA- between 8 14
  • LEUKEMIAS- between 22 9
  • DOWN'S SYNDROME- chr 21

23
I. MORPHOLOGIC/ STRUCTURAL SUBTYPES
  • TRANSLOCATION
  • ISOCHROMOSOMAL- faulty division of centromere at
    the transverse plane of the long axis w/
    formation of a pair of isochromosome (one short
    arm one long arm)
  • TURNER'S SYNDROME

24
I. MORPHOLOGIC/ STRUCTURAL SUBTYPES
  • INVERSION- break of a chr at 2 points, followed
    by inversion of the intermediate segments
    reunion results in the formation of a chr w/
    rearranged distribution of genes
  • PERICENTRIC- rotation occurs around the
    centromere
  • PARACENTRIC- rotation occurs only on the acentric
    portion of the arm

25
I. MORPHOLOGIC/ STRUCTURAL SUBTYPES
  • RING CHROMOSOME- break in the telomeric ends of
    the chr followed by deletion of the broken
    acentric segments end to end fusion of the
    remaining portion

26
II. GENE ABNORMALITIES/ MUTATIONS GENERAL
CONCEPTS
  • Single gene defect detectable in the phenotype
  • Modified by penetrance, expressivity whether
    defect is dominant, intermediate, recessive or X
    linked
  • Dominant pattern of inheritance usually due to
    alteration of aa sequence in the gene
  • Recessive pattern of inheritance (inborn errors
    of metabolism) usually is due to manufacture of
    abnormal enzymes or enzyme deficiencies
  • Follows Mendelian patterns of inheritance

27
PATTERNS OF INHERITANCE AUTOSOMAL DOMINANT
  • Autosome- gene location
  • Gene expression- both homozygous heterozygous
    state
  • Transmission of traits in every generation unless
    Low penetrance or modified by gene mutations
  • Unaffected family members do not transmit trait
     to offspring affected family members usually
    heterozygous transmit trait to only half of the
    offspring
  • M F

28
PATTERNS OF INHERITANCE AUTOSOMAL DOMINANT
  • Pp x pp
  • Pp Pp pp pp
  • DIABETIS INSIPIDUS
  • MUSCULAR DYSTROPHY
  • POLYDACTYLISM
  • MARFAN'S SYNDROME
  • ACHONDROPLASTIC DWARFISM
  • HUNTINGTON'S CHOREA
  • GARDNER'S SYNDROME
  • GOUT
  • HEMOCHROMATOSIS

29
PATTERNS OF INHERITANCE AUTOSOMAL RECESSIVE
  • Autosome- gene location
  • Gene expression only in the homozygous state
  • Both parents usually heterozygous for the  trait
      clinically unaffected
  • Symptoms appear in 25 of offspring
  • 50 of all siblings will be heterozygous for the
    trait thus assymptomatic
  • M F

30
PATTERNS OF INHERITANCE AUTOSOMAL RECESSIVE
  • Nn x Nn
  • NN Nn Nn nn
  • ANDROGENITAL SYNDROME
  • ALBINISM
  • ALKAPTONURIA
  • DEAF MUTISM
  • GALACTOSEMIA
  • PHENYLKETONURIA
  • FAMILIAL GOITROUS CRETINISM
  • CYSTIC FIBROSIS
  • GLYCOGEN STORAGE DISEASES
  • MUCOPOLYSACCHARIDOSIS
  • LIPID STORAGE DISEASE
  • WILSON'S DISEASE
  • TYROSINOSIS
  • BILIRUBIN METABOLIC ABNORMALITIES

31
PATTERNS OF INHERITANCE X LINKED RECESSIVE
  • X chromosome - Gene location
  • Expression of traits
  • 100 heterozygous male
  • Rare homozygous female
  • Partial heterozygous female if X Chromosome
    inactivation occurs
  • Transmission via asymptomatic female
  • Each son of heterozygous female carrier has 1 in
    2 chances of having the disease
  • Affected males do not transmit trait to their
     sons, only to their daughters Unaffected males
    do not transmit the gene

32
PATTERNS OF INHERITANCE X LINKED RECESSIVE
  • FEMALE X MALE (HEMOPHILIAC)
  • XX x Xh Y
  • XXh XY XXh XY
  • FEMALE (CARRIER) x MALE (NORMAL)
  • Xh X x XY
  • Xh X Xh Y XX XY
  • HEMOPHILIC
  • COLOR BLINDNESS
  • G6 PD DEFICIENCY
  • MUSCULAR DYSTROPHY- DUCHENNE TYPE

33
PATTERNS OF INHERITANCE X LINKED DOMINANT
  • Rare
  • Affected heterozygous female transmit to 50 sons
    50 daughters
  • Affected males transmit to 100 daughters none
    to their sons
  • VIT. D RESISTANT RICKETS

34
PATTERNS OF INHERITANCE Y LINKED
  • Not clinically significant
  • Hairy ears

35
III. POLYGENIC/ MULTIFACTORIAL ABNORMALITIES
GENERAL CONCEPTS
  • Environmentally influenced interactions of a
    number of different gene pairs
  • HYPERTENSION
  • DIABETIS MELLITUS
  • PEPTIC ULCER
  • OTHER CONGENITAL HEART DISEASES

36
CHROMOSOMAL DISEASESSEX CHROMOSOMAL
ABNORMALITIES
  • X DEFICIENCY
  • TURNER'S SYNDROME 45, XO
  • Short stature female w/ webbed neck, cubitus
    valgus, immature genitalia w/ small fibrotic
    (streak) ovaries, coarctation  of aorta mostly
    abort no Barr Bodies almost 50 are mossaics w/
    less stigmata
  • ULLRICH NOONAN SYNDROME (46, XX or XY 46,
    X(Xq)
  • Turner like phenotype often w/ pulmonary
    stenosis giant Barr Bodies

37
CHROMOSOMAL DISEASESSEX CHROMOSOMAL
ABNORMALITIES
  • KLINEFELTER'S SYNDROME 47, XXY
  • Most common of X chromosomal abnormality
  • Tall eunuchoid male w/ gynecomastia, small testis
     w/o spermatogenesis (infertile)
  • Mossaics occur

38
CHROMOSOMAL DISEASESSEX CHROMOSOMAL
ABNORMALITIES
  • MISCELLANEOUS SYNDROMES
  • TRIPLE X (47 XXX)- mildly retarded normal female
    phenotype
  • 47 XYY- tall, aggressive, mildly retarded male
    increased incidence among criminal

39
CHROMOSOMAL DISEASESSEX CHROMOSOMAL
ABNORMALITIES
  • INTERSEX STATES- HERMAPHRODITISM
  • TRUE HERMAPHRODITE- XX or XY or both variable
    phenotype, both ovaries testis are present
  • PSEUDOHERMAPHRODITES (NORMAL GENECITY)
  • Male phenotypically female testicular
    feminization
  • Female phenotypically male virilizing ovarian or
    adrenal tumors

40
CHROMOSOMAL DISEASES AUTOSOMAL ABNORMALITIES
  • More severe effects than X chr anomalies
  • Monosomies more severe than trisomies
  • The larger chromosome involved, the more serious
    the phenotypic disorder

41
CHROMOSOMAL DISEASES AUTOSOMAL ABNORMALITIES
  • DOWN'S SYNDROME- TRISOMY 21, MONGOLISM 47 G21
  • Most common of the trisomies maternal risks
    increases w/ age incidence equal in both sexes
    usually due to maternal nondisjunction
  • Floppy infants w/ psychomotor retardation,
    mongoloid facies, epicanthic folds, flat nose,
    cardiovascular anomalies, simian palm creases,
    cryptorchidism, increased incidence of leukemia
  • Variant - Translocation type (heritable)- occurs
    at any maternal age 46 XY -D tDqGq

42
Downs Karyotype Trisomy-21
43
Downs Sy.Trisomy-21
44
Downs Syndrome - Trisomy-21
45
Downs Syndrome - Trisomy-21
Simian Crease
46
Downs Syndrome
  • Mental retardation
  • Neck folds
  • Epicanthic folds
  • Flat facial profile
  • Simian crease
  • Hypotonia
  • Umbilical hernia
  • Leukemia

47
CHROMOSOMAL DISEASES AUTOSOMAL ABNORMALITIES
  • EDWARD'S SYNDROME (16 - 18 TRISOMY, E TRISOMY)
    47, E18
  • Female predilection low set ears, epicanthic
    folds, micrognathia, CVS anomalies, overlapping
    2nd 5th finger, rocker bottom feet, renal
    anomalies, early death
  • PATAU'S SYNDROME (13 - 15 TRISOMY, D TRISOMY)
    47, D13
  • Least common, both sexes equally affected low
    set ears, micropthalmia, brain anomalies, cleft
    lip palate, overlapping 2nd 5th finger, CVS
    anomalies, rocker bottom feet

48
Cleft Lip - Trisomy 13
49
Polydactyly - Trisomy 13
50
CHROMOSOMAL DISEASES AUTOSOMAL ABNORMALITIES
  • CRI DU CHAT SYNDROME, 5p-
  • Rare, common in females, cat cry, moon faced,
    retarded, micrognathia, antimongoloid slant, CVS
    anomalies
  • D13p-, D13q-, E18q-, TRIPLOIDY
  • Severe anomalies, lethal
  • PHILADELPHIA CHROMOSOME, G22q-
  • Associated w/ CML good prognosis

51
Syndactyly - Triploidy
52
Philadelphia Chromosome (Ph)
  • Reciprocal translocation t(922)
  • Results in bcr/abl gene fusion
  • c-abl (Abelson) chr 9
  • bcr (break point cluster region) chr 22
  • Protein w/ tyrosine kinase activity - plays
    critical role in pathogenesis

53
CML - t(922) - (Ph chr)
54
(No Transcript)
55
DISEASES DUE TO GENE ABNORMALITIES AND
MUTATIONSAUTOSOMAL DOMINANT ABNORMALITIES
  • ACHONDROPLASIA
  • Defective endocndral ossification
  • Most common type of dwarfism
  • High incidence of early death
  • 80 sterility
  • HUNTINGTON'S CHOREA
  • Progressive neurologic disorder w/ choreic
    movements, seizures, dementia, death
  • Average  onset is 35 years of age so offspring is
    born before parent is affected
  • Reproduction not impaired

56
DISEASES DUE TO GENE ABNORMALITIES AND
MUTATIONSAUTOSOMAL DOMINANT ABNORMALITIES
  • MARFAN SYNDROME
  • Complex defective formation of collagen elastin
  • Tall, long extremities (arachnodactyly),
    subluxation of lens, cystic medial necrosis of
    aorta w/ dissecting aneurysm
  • Mechanism is single gene w/ multiple effects
    (pleiotropy), variable expression, forme fruste
    expression, may skip generations
  • GARDNER SYNDROME
  • Complex cyst of the skin, osteomas, lower
     intestinal polyps with development of colonic ca
  • Pleiotropy 

57
Cell Cycle
58
Mitosis
59
Meiosis
  • Reduction Division (4n-2n)
  • Prophase-1(Synapsis, g.rec)
  • Metaphase-1
  • Anaphase-1
  • Telophase-1
  • Equatorial Division (2n-n)
  • Prophase-2
  • Metaphase-2
  • Anaphase-2
  • Telophase-2
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