lecture of med 2

1. GENETIC
DISORDERS
PROF. DR. FLORENCIO C. DIZON
PATHOLOGY

3. DNA recombinant technology
 Molecular basis of disease
 Production of human biologically active agents
 Gene therapy
 Disease diagnosis

4. Structure of DNA
 is double helix, with about 10
nucleotide pairs per helical
turn.
 Each spiral strand, composed
of a sugar phosphate
backbone and bases
connected by hydrogen
bonding (non- covalent)
adenine (A) with thymine (T)
and guanine (G) with
cytosine (C).

5. Base Pair - A More Detailed Picture

6. The Genetic Code

7. Human Chromosomes
 formed from a single DNA
molecule that contains many
genes.
 a centromere attach the DNA
to the mitotic spindle.;
 a telomere located at each end
of the linear chromosome

8. Chromosomes
 hold our genes.
 Genes are the individual instructions that
tell our bodies how to develop
 there are 50,000 to 100,000 genes that are
located on 46 chromosomes.
 These 46 chromosomes occur as 23 pairs.
 The first 22 pairs are labelled longest to
shortest.
 The last pair are called the sex
chromosomes labeled X or Y.

9. Chromosomes
 Each chromosomes has a p and q arm
 p (petit) is the short arm and q is
the long arm.
 chromosomes like 13, 14, and 15
have very small p arms.
 the q arm is always put on the
bottom and the p on the top. The
arms are separated by a region
known as the centromere, which is a
pinched area of the chromosome.

10. Karyotype
 photograph of the
chromosomes from one
cell.
 The cells analyzed are
usually white blood cells
 chromosomes can be seen
as banded strings under
1,000 x magnification.
 Cytogenetics the study of
chromosomes.

11. International Standard of
Cytogenetic Nomenclature.
 method of describing chromosomes and
chromosome abnormalities.
 some examples:
 46,XX - Normal Female Karyotype
46,XY - Normal Male Karyotype
 These descriptions say there are 46 chromosomes
and that it is a male or female.
 46,XX,del(14)(q23)
 Female with 46 chromosomes with a deletion of
chromosome 14 on the long arm (q) at band 23.

12. GENETIC DISORDERS
 CYTOGENETIC DISORDERS
 MENDELIAN DISORDERS
 MULTIFACTORIAL INHERITANCE
 SINGLE GENE DISORDERS

13. Cytogenetic disorder
 Chromosomes mutation
 Abnormal number or alterations in the structure
of one or more chromosomes
 Euploid –exact multiple of haploid
 Aneuploid – error occurs in meiosis a cell
acquire a complement that is not exact multiple
of 23

14. Mutation of Chromosomes
 A permanent structural
alteration in DNA. In
most cases, such DNA
changes either have no
effect or cause harm,
but occasionally a
mutation can improve
an organism's chance
of surviving and
passing the beneficial
change on to its
descendants.

15. Mutation
 Permanent change in DNA
 Change in number of chromosomes
 Genome mutations
 Change in the stuctures of chromosomes
 Chromosome mutations
 Gene mutations

16. Gene Mutation
 Complete or partial deletion of gene affecting
one gene
 Point mutation
 Insertion or deletion of one or two base pairs –
frameshift mutation

17. Chromosomes deletion
 when a part of a chromosome(s) has
been deleted.
 A deletion can occur on any
chromosome, at any band, and can
be any size (large or small).
 What a deletion causes depends on
how big a piece is missing and what
genes are missing in the section

18. Deletion
 loss of a segment of a
chromosome.
 This can be terminal,
or it can be interstitial
(within the long arm or
the short arm).
 cri-du-chat syndrome
(5p-). involve the loss
of the distal end of the
short arm.

19. Translocations
 abnormalities which occur when
chromosomes break and the
fragments rejoin to other
chromosomes
 the long arms of chromosome 7
and 21 have broken off and
switched places.
 a normal 7 and 21, and a
translocated 7 and 21. This
individual has all the material
needed, just switched around
(translocated)

20. Abnormalities in Chromosome
Structure
 Translocations
 most clinically significant
 involves two nonhomologous chromosomes (e.g.,
chromosome 2 and chromosome 6). Following a break
in each of the chromosomes, and subsequent reunion, a
segment of chromosome 2 becomes attached to
chromosome 6

21. Duplication
 extra chromosomal
segment within the same
homologous
chromosome
 an extra chromosomal
segment on another
nonhomologous
chromosome.

22. Causes of Chromosomal Disorders
 ionizing radiation, autoimmunity, virus infections and
chemical toxins
 Most cases of simple aneuploidy - monosomy or
trisomy - are likely due to meiotic non-
disjunctions.

23. Euploidy vs aneuploidy
 Euploidy normal
number of structurally
normal chromosomes.
Euploid human females
have 46 chromosomes
(44 autosomes and two
X chromosomes).
 Aneuploidy having less
than or more than the
normal diploid number
of chromosomes,
 the most frequently
observed type of
cytogenetic
abnormality.

24. Aneuploidy is due to
nondisjunction
 failure of normal separation of a
chromosome pair when the eggs
or sperm are formed during
meiosis.
 The pairs of chromosomes are
separated (segregation) during
meiosis 1.
 During meiosis 2, a second
division of the chromosomes
occurs resulting in the formation
of four sperm, or one egg and
three polar bodies, each with 23
chromosomes.
 Nondisjunction can occur in
meiosis 1 or meiosis 2.

25. Monosomy vs Trisomy
Monosomy is lack of one of
a pair of chromosomes.
An individual having only one
chromosome 6 is said to have
monosomy 6.
A common monosomy seen in
many species is X
chromosome monosomy, also
known as Turner's syndrome.
Monosomy is most commonly
lethal during prenatal
development.
 Trisomy is having three
chromosomes of a particular
type.
 A common autosomal trisomy in
humans in Down syndrome, or
trisomy 21, in which a person
has three instead of the normal
two chromosome 21s.
 Trisomy is a specific instance
of polysomy, a more general
term that indicates having more
than two of any given
chromosome.

26. Chromosomal abnormalities
 Most chromosomal abnormalities result in
spontaneous abortion.
 As many as 50 60% of spontaneous abortions
are shown to have an underlying chromosomal
abnormality.
 These abnormalities are numerical (aneuploidy)
or structural (rearrangement).

27. Cytogenetic disorder involving
autosomes
 Down syndrome
 Edwards syndrome
 Patau syndrome

28. Down’s syndrome
 Trisomy 21
 Most common chromosomal disorder
 Major cause of mental retardation
 1/25 for mothers > 45
 maternal age strong influence

29. Chromosome analysis reveals a 47, XY,
+21 karyotype typical for Down
syndrome.

30. Trisomy 21
-flat facial pofile
-epicanthal folds
-oblique palpebral fissures
- severe mental retardation
- congenital heart disease
- 10 x acute leukemia
- > 21 y/o develop
Alzeimers disease
- abnormal immune
response

31. Edwards syndrome
 The clenched fingers that
are overlapping are
typical for trisomy 18.
 Micrognathia
 Mental retardation
 Low set ears
 Congenital heart defects
 Renal malformations

32. Patau syndrome
 Midline defects, such as
the cleft lip shown here,
are typical (but not
specific)
 Microphthalmia
 Microcephaly
 Umbilical hernia
 Rocker bottom feet

33.  Postaxial polydactyly, as
shown here, is quite
characteristic for trisomy
13.

34.  Trisomy 13 has many
midline defects. Here is
cyclopia, with a single slit
for an eye (but no actual
eye present). A
protruding proboscis is
also seen.

35. Cytogenetic disorder involving
sex chromosomes
 Klinefelters syndrome
 Turners syndrome
 Hermaphroditism.

36. Klinefelters syndrome
 Male hypogonadism
 47 XXY
 Most frequent sex chromosome disorders
 Increase length between soles and pubic bones
 Small atrophic testes, Reduced spermatogenesis
 Lack of secondary sex characteristics
 FSH elevated

37. Klinefelter's syndrome
 47, XXY karyotype. A
non-dysjunctional event
in meiosis (maternal or
paternal) left two X
chromosomes in an
ovum or a sperm.
 Infertility results from
absent sperm.
 About half have
gynecomastia.

38. Turners syndrome
 Monosomy of X
 Hypogonadism of phenotypic females
 Edema
 Swelling of the nape, cystic hygroma
 Neck webbing
 Coarctation of aorta
 Streak ovaries

39. Turners syndrome
 Fetal hydrops indicates a
poor prognosis, regardless of
the cause, and in about a
third of stillbirths, the cause
for hydrops is not found.
However, chromosomal
abnormalities should be
considered, and foremost
among them should be
Turner's syndrome.

40.  Here is the 45, X
karyotype of monosomy
X (Turner's syndrome).

41.  After puberty, the ovaries
should develop into
plump 3 to 5 cm ovoid
organs, but these
"streak" ovaries are
typical for Turner's
syndrome.

42. Thank you