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○Disease is a pathophysiological response2

to internal or external factors.
○Disorder is a disruption to regular bodily
Terminologies structure and function.
GENETIC ○Syndrome is a collection of signs and
DISEASES symptoms associated with a specific health-
related cause.
○Condition is an abnormal state of health
that interferes with normal or regular
feelings of wellbeing.

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Developmental diseases
○hereditary = derived from
parents A. Those that arise spontaneously during gestation
Kinds of ◦ e.g failure of testis to descend
TERMINOLOGIES ○familial
= transmitted in the Congenital
gametes through generations diseases B. Those that are secondary to environmental
○congenital = present at birth problems

(not always genetically ◦From trauma

◦From poisons (teratogenic agents)
determined - e.g. congenital
◦From poor nutrition of mother during gestation
syphilis, toxoplasmosis)

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CLASSIFICATION ○1.Disorders with multifactorial

OF GENETIC inheritance
DISEASES
○2. Monogenic (mendelian) . Disorders with
disorders multifactorial
○3. Chromosomal aberrations inheritance

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7 Diabetes Mellitus
Type 1 Type 2
Age onset Juvenile onset Adult onset
Genetics 60%-65% 10%
HLA region on 6p21 chromosome Insulin receptor gene
Insulin gene in 11p15 chromosome 19p13 chromosome
Pathogenesis Autoimmunity: Islet cell Insulin resistance
Antibodies Relative insulin deficiency
Severe insulin deficiency
Beta cells Severe depletion Mild depletion

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Gout GOUT
OTHER PREDISPOSING
Partly genetic, associated with ABCG2, FACTORS TREATMENT COMPLICATIONS
SLC2A9 and SLC22A12 genes which
results to impaired metabolism of uric 1. Increased consumption of 1. NSAIDS 1. Arthritis
purines
acid (end product of purine metabolism) 2. Increased production of purines
2. Colchicine 2. Tophi
3. Steroids 3. Urinary calculi
precipitation of monosodium urate 3. Decreased clearance of uric
acids 4. Gouty Nephropathy
crystals inside the joints causing arthritis
4. Obesity and diabetes
formation of large crystalline 5. Chemotherapy and radiation
aggregates - tophi 6. Chronic kidney disease
7. Medications

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Inherited disorder due to

hypoxanthine-guanine
phosphoribosyltransferase
(HGPRT) enzyme deficiency

It is characterized by
moderate intellectual
disability and self-mutilating
behaviors

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Monogenic (Mendelian) AUTOSOMAL

disorders DOMINANT

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Marfan Syndrome
Genetic disorder of
the connective tissue
Involves: Tall stature
with long slim limbs,
Low tone muscles,
Little subcutaneous or
skin fat, 60% scoliosis
and prone to Heart
disorders

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Familial
Ehlers-Danlos syndrome hypercholesterolemia
Group of genetic defect of collagen
fibrils - several types - both autosomal Type 2 familial dyslipidemia
dominant and recessive
most frequent mendelian disorder -
hyperextensibility of skin, 1:500 Xanthelasma
hypermobility of joints, joint mutation of gene encoding LDL-receptor
dislocations, vulnerability, rupture of (Chromosome 19)
large vessels, colon, cornea
Reduction of LDL uptake in the liver, thus
Vascular type (Type III collagen) may LDL accumulates in the blood
result to vascular fragility/ rupture, Artherosclerosis
bruising

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Progeria Syndrome
Hutchinson-Gilford Progeria
Syndrome or premature aging
disease.
Point mutation in position
1824 of LMNA gene
(Chromosome 1), cytosine is
replaced with thymine
Noticeable 18-24 months of
age.
Life expectancy 8-21 years with
an average of 14 years
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HEREDITARY Colon Cancer

Hereditary nonpolyposis
BREAST CANCER colorectal cancer (HNPCC)
5-10% of patients
Chromosome 17 or 13
Chromosome 5
Mutations in MSH2 and
BRCA1 and BRCA2 gene mutation MLH1, genes that code
increases the risk to about 45-65% for mismatch repair
proteins, are
responsible for about
90% of cases.

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Cystic fibrosis
1:2000 live births - most common
lethal genetic disease in white
population
AUTOSOMAL defect in the transport of chloride ions
RECESSIVE across epithelia - increased absorption
of Na+ and water to the blood
widespread defect in the exocrine
glands - abnormally viscid mucous
secretions
blockage of airways, pancreatic ducts,
biliary ducts
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Phenylketonuria (PKU) Galactosemia

Inborn error of metabolism: a group of genetic
disease which are caused by single genes that defect of galactose metabolism;
code for enzyme which are important for due to
metabolism
galactose-1 phosphate uridyl
absence of enzyme phenylalanine-hydroxylase transferase (GALT)(most common)
(PAH) due to a PAH gene (Chromosome 12)
mutation. galactokinase (GALK)
Phenylalanine accumulates in blood and brain Uridine diphosphate galactose-4 -
epimerase (GALE)
Results to mental disorder, intellectual
instability, seizures, motor and behavioral
problems Jaundice, hepatomegaly, easy
Physical symptoms: musty odor urine bruisability, galactosuria, E. coli
sepsis. Cataract, hypotonia and
Treatment: diet, supplements
sensory neural deafness

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Glycogen storage
diseases (glycogenoses)
deficiency of any one of the enzymes
involved in degradation or synthesis of
glycogen

depending on the type of defect - tissue

distribution, type of accumulated product
12 forms skeletal muscle only
biopsy: PAS, Best's carmine

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Lysosomal storage diseases Functions of lysosomes:

Function of lysosomes;
Autophagy, A. Autophagy: hydrolytic digestion of cells own worn
Heterophagy, Protein out, damaged or unwanted cytoplasmic material.
degradation, Apoptosis
B. Heterophagy: Digestion of exogenous material
defect of lysosomal
C. Role in protein degradation: The protein that
enzymes. If one enzyme undergo turn over is digested. It is acted upon by
is defective, a product proteinases Lysosomes
accumulates within the
cells and eventually kills D. APOPTOSIS :programmed death of cell
it

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Gaucher disease
Tay-Sachs disease defect of glucocerebrosidase
(gangliosidosis) accumulation of glucocerebroside
1. Due to deficiency β- Gaucher cells - spleen (red pulp), liver
hexosaminidase A (sinuses), bone marrow
2. Enzyme responsible for -Crumpled tissue paper;lipid filled
breakdown of gangliosides. macrophages
3. GM2 Gangliosides in large -Symptoms can include:
amount deposits in cells. easy bleeding and bruising, fatigue,
4. neurons and glial cells of CNS anemia, weak bones, bone and joint
- mental retardation, pain, and enlargement of the spleen
blindness or liver

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Niemann-Pick
disease
defect of sphingomyelinase
accumulation of cholesterol and
sphingomyelin in spleen, liver,
BM, LN, lungs - massive
visceromegaly
Histiocytes (foamy cells) - severe
neurological deterioration
death during first 4-5 years

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Mucopolysacharidoses
MP synthesized in the connective tissue by
fibroblasts - part of the ground substance
several clinical variants (I-VII)
involvement of liver, spleen, heart (valves,
coronary arteries), blood vessels
Symptoms: coarse facial features (gargoylism-
), clouding of the cornea, joint stiffness,
mental retardation
usually death in childhood (cardiac
complications)
most frequent Hurler syndrome and Hunter
syndrome

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CHROMOSOMAL
ABERRATION

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CHROMOSOMAL ABERRATION
1. alternations in the number or structure
of chromosomes
2. autosomes or sex chromosomes: 22
pairs of autosomes, 2 sex chromosomes
(XX or XY)
3. Detected through Karyotyping: cell
cycle arrested in metaphase (colchicin)
- staining by Giemsa method (G-bands)
- photographed
4. cytogenetic disorders are relatively
frequent (1:160 newborns; 50% of
spontaneous abortions)
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1. Numerical abnormalities
euploidy - normal 46 (2n)
A. polyploidy : spontaneous abortion
-Triploidy (3n)
-Tetraploidy (4n)
B. aneuploidy
monosomy (2n-1) - autosomal - incompatible with life
- sex chromosomal - compatible with life
trisomy (2n+1) - 47 - compatible with life
Tetrasomy: gain 2 chromosomes

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Triploidy and Tetraploidy 2. Structural abnormalities

breakage followed by loss or
rearrangement
1-2% of all pregnancies
Scarcely any triploids Translocation: a portion is transferred to
are born alive another chromosome
Arise from double Inversions
fertilization Deletions: a portion is missing
Insertions
Duplication: extra genetic material due to
duplication of a portion of chromosome
Rings Isochromes

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Trisomy 21 / Down Syndrome

Nondisjunction Genetic Disorders (1:800)

One of the cause of Aneuploidy Individuals have partial or total addition of

When chromosomes don't chromosome number 21
separate properly during meiosis.
Symptoms
results in gametes w/ too many
or few chromosomes. Mental retardation distinctive eyes
enlarged tongue short stature
Downs syndrome/Trisomy 21
enlarged heart low body tone
Patau syndrome/Trisomy 13 decreased life expectancy small ears
Slanted palpebral Fissures Flat face
Edwards syndrome/Trisomy 18

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Trisomy 13
Patau syndrome
(1:10000)

Symptoms
defects of eye, nose, lip, and forebrain
Polydactyly (more then 5 fingers or toes)
hyperconvex fingernails (arches down)

Only 18% survive the first year

Survivors have severe mental
defects
seizures

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Trisomy 18- Edwards syndrome

(1:3000)
Clenched hand
Low Arch Dermal - the crease on tip the 5th finger is
missing.
80% die w/in first two months
Only 10% survive the first year

Usually feeble (weakness)

Limited capacity for survival
Resuscitation (artificial breathing)
often performed at birth
apneic episodes neonatally (stop
breathing during sleep)

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Sex linked Nondisjunction Genetic Disorders

• Turner syndrome

• Klinefelter syndrome

• Fragile-X syndrome

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Klinefelter Syndrome
Turner Syndrome
XXY
Females with only one X sex
chromosomes First sex chromosome abnormality
Physical Characteristics to be reported
Short stature Tall, thin relatively long legs
Web neck
Infertile appear normal until puberty
Normal intelligence Hypogonadism (sex hormones are
Low posterior hairline not released)
broad chest with widely spaced Infertile due to undeveloped sex
nipples
elevated frequency of renal (kidney) organs
and cardiovascular anomalies significantly reduced IQ

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Fragile X Syndrome
In males the lower portion of the
X chromosome appears
constricted in a karyotype.
Moderate mental retardation
Fragile site - chromatin fails to
condense during mitosis
Females who carry the trait
may also show symptoms
long face with a prominent jaw,
large prominent ears, high
arched palate; flattened nasal
bridge; Prominent forehead

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Genomic Imprinting
The expression of the disease phenotype depends on whether it
has been inherited from the father or from the mother.
Rare genetic disorder in which 7 genes on chromosome 15 (q11-
13 are deleted or unexpressed
Prader-Willi Syndrome: maternal chromosome
Angelman’s Syndrome: paternal chromosome

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Prader-Willi Syndrome Angelman’s Syndrome

Obesity “Happy Puppets”
Small hands and feet disorder
Short stature Mental
Mental retardation Retardation
Do not produce the chemical that Can understand
tells them they are full
only simple
Severely over weight
commands
Their crave for food can be so
server that parents have to lock Inappropriate
their refrigerators laughter
Inherited from the mother

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PRENATAL DIAGNOSIS Genetic Counseling

Genetic counseling can help parents determine the
is the science of likelihood of their child being born with a genetic disorder
identifying structural Genetic counselors study the family histories of both
parents
or functional Create pedigree charts to trace the passage of traits
abnormalities-birth Medical geneticists analyze blood tests to determine if
defects-in the fetus parents are carriers of certain genetic disorders
Genetic counseling usually can NOT determine whether or
not a child will be born with a genetic disorder

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INDICATIONS FOR PRENATAL ETIOLOGY OF BIRTH DEFECTS

DIAGNOSIS
1. Malformation 2. Deformation
•advanced maternal age family history of other congenital
structural abnormalities an intrinsic abnormality "programmed" caused when a genetically normal fetus develops
•previous child with a chromosome in development, regardless of whether a abnormally because of mechanical forces imposed by
abnormality •abnormalities identified in precise genetic etiology is known the uterine environment
pregnancy
•family history of a chromosome spina bifida normal limb that develops contractures because of
abnormality •Other high risk factors prolonged oligohydramnios
(consanguinity ,poor obst.,history,
•family history of single gene maternal illnesses
disorder
•family history of a neural tube
defect

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Diagnosing Genetic Disorders

ETIOLOGY OF BIRTH DEFECTS
There are several ways to determine whether a
3. Disruption 4. Others child will have a genetic disorder
which is a more severe change in form or Syndrome: trisomy 18 Two main ways to diagnose:
function that occurs when genetically normal
tissue is modified as the result of a specific
Analysis of fetal cells
insult Amniocentesis
Chorionic villus biopsy
an amniotic band causing a cephalocele or
limb-reduction abnormality Imaging techniques
Ultrasonography (computerized image)
Fetoscopy (direct observation)

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Amniocentesis
Amniocentesis
Amniocentesis
Amniotic fluid is the fluid that surrounds a
fetus inside the uterus
Also contains fetal cells
A sample of amniotic fluid is taken and cells
are grown in a lab
Can be used to make a karyotype – takes 10 days to
grow enough cells
Detects chromosome abnormalities
Can be analyzed for defective alleles
Detects other genetic disorders
Cannot be conducted until the 14th week
of pregnancy

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Chorionic Villus Biopsy

Ultrasonography
Chorionic villus biopsy
Chorionic villi are structures that help Uses high-frequency sound waves which bounce
maximize the surface area for nutrient and off of tissue
gas exchange between a mother and Depending on the density of tissue, waves “echo”
developing fetus (they are part of the back at different wavelengths and are used to
placenta) produce a computerized image called an
The villi develop from fetal cells and echogram
therefore have the same chromosomes as
the fetus & amniotic fluid Used in most pregnancies to detect the position
and anatomy of the fetus
A sample of these cells can be taken and
analyzed as in amniocentesis Used with amniocentesis to reduce risk of injury
Karyotyping
Can also help doctors detect abnormalities such
Tests for recessive alleles as congenital heart defects
• Can be done as early as the 9th
week of pregnancy

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Acardiac Twin or Twin Reversal Arterial

Fetoscopy Perfusion Sequence
A small incision is made in a
pregnant woman’s abdomen
An endoscope tube is inserted
through the incision
Has a camera on the end that
shows an image on a monitor
Instruments can be inserted
through the endoscope to
perform additional procedures

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Developing Cures for Genetic

Disorders

Gene therapy
Introducing normal genes into
the cells of people with defective
This is the end….
alleles Use your knowledge to be compassionate and kind
Using viruses to inject alleles into cells
towards others.
Enclosing alleles in droplets of fat, which
are taken into cells by endocytosis

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