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