THE ROLE OF HERED
ITY IN PATHOLOGY
ASS. BEGER T.A.

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.

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.

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.

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

MUTATION
is sudden and spontaneous cha
nges in DNA.
Mutations are caused by mutag
ens.

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

CLASSIFICATION OF MUTATI
ONS
1) nuclear
2) cytoplasmic

1. Spontaneous
2. Induced - occurs under the
influence of mutagens

1. Generative (occur in sex cell
s)
2. Somatic (occur in somatic ce
lls)

1. chromosome mutation
2. genomic mutation
3. gene mutation.

Chromosome mutation
is change of structure of chromo
somes.
TYPES:

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

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.

NONDISJUNCTION
NORMAL NONDIS. MI NONDIS. MII

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.

GENETIC DISEASES:
1.chromosome (resulting from
chromosome and genome muta
tions)
2. gene (resulting from gene mu
tations)

CHROMOSOME DISEASES
resulting from chromosome mutation:
cat cry syndrome
partial deletion of
the short arm of
chromosome 5.

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

(resulting from genome mutation)
NUMERIC ANOMALIES
OF AUTOSOMES:
DOWN SYNDROME
47,XX/Y,+21
PATAU SYNDROME
47,XX/Y,+13
EDWARDS SYNDROME
47,XX/Y,+18
NUMERIC ANOMALIES
OF SEX
CHROMOSOMES:
TURNER SYNDROME
45,X
KLINEFELTER SYNDROME
47,XXY
XYY SYNDROME
(SUPERMALE) 47,XYY
XXX SYNDROME
(SUPERFEMALE) 47,XXX

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

• mental retardation
• macroglossia
• male hypogenitalism
• denture defects
• short, broad hands,
brachydactyly
• immune system
defects
• higher risk of
tumour diseases
(leukemia)

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

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

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)

KLINEFELTER SYNDROME
47,XXY
• tall stature
• average intelligence
• male psychosexual
orientation
• poor beard
growth
• hypoplastic testes,
cryptorchism
• sterility -
azoospermia
• gynaecomastia

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

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

GENE GENETIC DISEASES:
(resulting from gene mutations)
autosomal recessive disorder
autosomal dominant disorder
autosomal codominant disorder
X-linked recessive disorder
Y-linked recessive disorder

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)

AUTOSOMAL DOMINANT DIS
ORDERS:
Marfan syndrome
Familial hypercholesterolemia
Hereditary spherocytosis
Von Willebrand disease

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.

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).

Autosomal Recessive Disorders:
- Sickle cell anemia
- Thalassemia
- Myeloperoxidase deficiency
- Phenylketonuria
- Glycogen storage disease Ia (von
Gierke disease)
- Alkaptonuria

Phenylketonuria

Phenylketonuria
PKU patients have
light pigmentation
and are physically
and mentally
retarded.

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

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.

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.

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.

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.

X-linked recessive disorders
Hemophilia A
In general symptoms
are internal or
external bleeding
episodes.
Y-linked recessive
disorders
hypertrichosis
of ears

METHODS:
1.cytogenetic analysis
2.clinico-genealogical method
3.study of dermatoglyphics
4.Twin Studies
5.biochemical method
6.immunogenotypic analysis
7.population genetic and statistical
methods
8.prenatal diagnostics
9.modelling

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.

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.

Sensitivity of specific organs to teratogenic agents
at critical stages of human embryogenesis

Diathesis
is a hereditary predisposition of
the body to a disease, a group o
f diseases, an allergy, or anothe
r disorder.

TYPES OF DIATHESIS:
1. arthritism, gouty diathesis
2. lymphohypoplastic diathesis
3. exudative diathesis
4. asthenic diathesis

ARTHRITISM, GOUTY DIATHE
SIS
increased excitability
obesity
predisposition to joint disease, s
kin disease,
gout,
rheumatism

LYMPHOHYPOPLASTIC DIAT
HESIS
muscular hypotrophy
pharyngitis,
lymphocytosis,
splenomegaly,
predisposition to autoimmune di
seases

EXUDATIVE DIATHESIS
predisposition to inflammation a
nd allergy

ASTHENIC DIATHESIS
general adynamia
vasomotor lability
ptosis internal organs

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ENTION