Kelainan Genetik

dr. Zainuri Sabta N

Departemen Anatomi
Fakultas Kedokteran UII

GENETIC DISORDERS AND

HEREDITARY DISORDERS
Currently around 4,000 genetic disorders are known, with more being
discovered. Most disorders are
quite rare and affect one person in every several thousands or
millions. Cystic fibrosis is one of the most
common genetic disorders; around 5% of the population of the United
States carry at least one copy of
the defective gene.

Chromosom
Kromosom manusia
dibedakan dalam 2 tipe,
yaitu Autosom* dan
Kromosom seks**. Dari 46
kromoson didalam inti sel
tubuh manusia , maka 44
buah atau 22 pasang
merupakan autosom, dan
sepasang seks kromoson
dibedakan atas 2 macam
yaitu Kromosom X dan
Kromosom Y.
Perempuan homogametic (XX)
Laki-laki heterogametic (XY)
*Kromosom yang tiada hubungan dengan penetuan jenis kelamin
**Sepasang kromosom yang menentukan jenis kelamin

What is genetic disorder?

Adalah suatu kondisi penyakit

yang disebabkan oleh adanya

abnormalitas satu atau beberapa
gen atau chromosom.

Penyebab Kelainan
Genetik
42% unknown
8% Taratogen Obat :
Thalidomide ,
Warfarin ,
Tetracycline
3% Kondisi
Maternal Diabetes,

Pengkategorian kelainan genetik:

1.

Single gene disorders including Mendelian Disorders (i.e, follow

mendelian order of inheritance i.e. Autosomal and Xlinked and Y
linked) and NonMendelian disorders (i.e, do not follow mendelian
orderof inheritance e.g. mitochondrial inheritance)
2. MULTIFACTORIAL INHERITANCE DISORDER/POLYGENIC
(COMPLEX) DISORDER
3. Disorders with variable modes of transmission
4. Cytogenetic disorder: including autosomal disorders and sex
chromosome disorders.

1.Single Gene Disorders

Disebabkan oleh mutasi dari single gene tertentu.
- satu atau kedua chromosome.
A
B

Subtipe:
Autosomal dominant
Misal: Huntingtons disease, Homologs
Marfan syndrome
C
Autosomal recessive
Misal: Sickle cell anemia,
Cystic fibrosis

a
b

From Dad

D
From Mom

X-linked dominant trait

Misal: Hypophosphatamia,
X-linked recessive trait
Misal: Hemophilia A, Duchenne muscular dystrophy, Color blindness,
Muscular dystrophy, Androgenetic alopecia and also includes G6PD
deficiency.

Y-linked
Misal: Male infertility
Mitochondrial (also known as maternal inheritance),
Misal: Lebers Hereditary Optic
Neuropathy

Autosomal dominant inheritance pattern:

Either parent can be dominant D, and
normal gene is n, here just for the
example, the father is dominant I.e.
affected, It is possible to construct a
pattern with the mother to be dominant
too but its not shown here

Autosomal recessive inheritance pattern:

recessive gene is d and normal gene
is N

XLinked recessive inheritance pattern:

Mitochondrial Inheritance pattern:

Because only egg cells contribute
mitochondria to the developing embryo,
only females can pass on mitochondrial
conditions to their children
A mitochondrial gene disease is
transmitted :
solely by women.
to all her descents.
Often the genetic defect is not present
in allbut in a fraction only of
mitochondria transmitted
to the next generation; then according to
the number of gene mutations in
mitochondria.
variable expressivity.

Marfan syndrome (autosomal dominant)

Marfan syndrome is an autosomal dominant genetic disorder of the
connective tissue characterized by disproportionately long limbs, long thin
fingers, a relatively tall stature and a predisposition to cardiovascular
abnormalities, specifically affecting the heart valves and aorta. The disease
may also affect numerous other structures and organs including the lungs,
eyes, dural sac surrounding the spinal cord, and hard palate. It is named
after Antoine Marfan, the French pediatrician who first described it in 1899.
Pathogenesis: Marfan syndrome has been linked to a defect in the FBN1
gene on chromosome 15,[6] which encodes a glycoprotein called fibrillin1.
Fibrillin is essential for the formation of the elastic fibers found in connective
tissue, as it provides the scaffolding for tropoelastin.[3] Elastic fibers are
found throughout the body but are particularly abundant in the aorta,
ligaments and the ciliary zonules of the eye, consequently these areas are
among the worst affected. Without the structural support provided
by fibrillin many connective tissues are weakened, which can have severe
consequences for support and stability.
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Sickle Cell Disease

PATHOLOGY

Photo Source: Del Mar Image Library; Used with

permission

Normal RBC has a flexible, round shape

RBC w/HbS has a normal shape until its O2

delivered to tissue, then sickle shape occurs

Stiff, non-pliable cant flow freely
Trapped in small vessels = causes vasoocclusions, tissue ischemia and infarctions
painful episodes, most common area is joints
Hemolysis of RBC- lifespan down to 20 days
Compensatory mechanism is increased
reticulocytes

14

Cystic fibrosis (autosomal recessive)

Cystic fibrosis (CF), also called mucoviscidosis, is a hereditary

disease that affects the entire body, causing progressive

disability and early death.
Cystic fibrosis is one of the most common lifeshortening,
childhoodonset inherited diseases. In the United States, 1 in
3900 children are born with CF
Difficulty breathing and insufficient enzyme production in the
pancreas are the most common symptoms.

Color blindness (Xlinked recessive)

Color blindness, (also known as Dyschromatopsia) or color

vision deficiency, in humans is the inability to perceive

differences between some or all colors that other people can
distinguish. It is most often of genetic nature, but may also occur
because of eye, nerve, or brain damage, or due to exposure to
certain chem
Color blindness is usually classed as disability; however, in
selected situations color blind people may have advantages
over people with normal color vision. It is a Xlinked Recessive
genetic disorder.icals.

Color Blindness

Biology, Sixth Edition

Cri du Chat Syndrome

A chromosomal deletion is responsible for cri du chat (cats
cry) syndrome, which has a frequency of one in 50,000 live
births (Fig. 19.12). An infant with this syndrome has a
moon
face, a small head, and a cry that sounds like the meow of
a
cat because of a malformed larynx. An older child has an
eyelid fold and misshapen ears that are placed low on the
head. Severe mental retardation becomes evident as the
child matures. Akaryotype shows that a portion of one
chromosome
5 is missing (deleted), while the other chromosome
5 is normal, as are all the other chromosomes.

Sex Chromosomal Inheritance

Too Many/Too Few Sex Chromosomes

Norm
al

Abnormal sex chromosomal inheritance.

a.Female with Turner (XO) syndrome, which
includes a web neck, short stature, and
immature sexual features.
b.A male with Klinefelter (XXY) syndrome, which
is marked by small testes and breast development

Individuals sometimes are born with the

sex
chromosomes XO (Turner syndrome),
XXY
(Klinefelter syndrome), XXX (poly-X
syndrome), and XYY (Jacob syndrome).
No matter how many X chromosomes
there are, an individual with a Y
chromosome develops into a male.

Table 3 - Syndromes Associated with Aneuploidy of the Sex

Chromosomes
Karyotype

Syndrome

Frequency

Description

45,X (XO)

Turner
syndrome

1/5000 female
live births

Phenotypic female,
gonadal dysgenesis and
sexual immaturity after
puberty, infertility

XXY

Klinefelters
syndrome

1/1000 male
live births

Phenotypic male, gonadal

dysgenesis and sexual
immaturity after puberty,
infertility

XYY
(XXYY)

XYY syndrome

1/1000 male
live births

Phenotypic male,
behavioral abnormalities

2.Multifactorial
inheritance disorders
Kelainan ini disebabkan oleh kombinasi dari
variasi gen-gen kecil, yang terjadi karena
pengaruh faktor lingkungan dan lifestyle.
Misal: asthma
autisme
autoimmune diseases such as multiple sclerosis
cancers
cleft palate
diabetes
heart disease
hypertension
inflammatory bowel disease
mental retardation
obesity

3. Disorders With Variable Modes

of Transmission
Heredity malformations are congenital malformations
which may be familial and genetic or may be acquired by
exposure to teratogenic agents in the uterus. Heredity
malformations are associated with several modes of
transmission. Some multifactorial defects are cleft lip,
congenital heart defects, pyloric stenosis etc. Certain
congenital malformations are either multifactorial or by a
single mutant gene (thus
a different class of their own).

Cleft Lip/Palate

May present as single defect or combined

Non-union of tissue and bone of upper lip and
hard/soft palate during fetal development
CL-failure of nasal & maxillary processes to fuse
at 5-8 weeks gestation
CP-failure of palatine planes to fuse 7-12 weeks
gestation
Cleft interferes with normal anatomic structure of
lips, nose, palate, muscles depending on severity
and placement
Open communication between mouth and nose
with cleft palate

CLEFT LIP & CLEFT PALATE:

Operative Care
Cleft lip surgery by 4 weeks & again at 4-5

yrs
Cleft palate surgery at 6-24 months of age,
usually done by 1 year so speech will not be
affected
Protect suture lines- priority
Monitor for infection

Clean Cleft Lip incision

Pain Management
Cleft Palate starts feedings 48-hour post-op:
Clear and advance to soft diet
No straws, pacifiers, spouted cups
Rinse mouth after feeding

HIRSHSPRUNGS
Aganglionic megacolon
No ganglion cells at affected
area usually at
rectum/proximal portion of
lower intestine
Absence of peristalsis leads to
intestinal distension, ischemia
& maybe enterocolitis

Treatment
Mild-mod: stool softeners &
rectal irrigations
Mod-severe: single or 2-step
surgery
Colostomy with later pullthrough
Photo Source: Del Mar Image Library; Used with
permission

4. Cytogenetic Disorders:
These may be from alterations in the number or structure of the
chromosomes and may affect autosomes or sex chromosomes.
E.g. Fragile X chromosome. It is characterized by mental retardation
and an inducible cytogenetic abnormality in the X chromosome. It is
one of the most common causes of mental retardation. The
cytogenetic alteration is induced by certain culture conditions and is
seen as a discontinuity of staining or constriction of in the long arm of
the Xchromosome.
Other disorders include Downs Syndrome in which the number of
chromosomes is increased by a third
21st chromosome and hence a total of 47 chromosomes occur.

Fragile X Syndrome
Males outnumber females by about 25% in
institutions for the mentally retarded. In some
of these males, the X chromosome is nearly
broken, leaving the tip hanging by a flimsy
thread. These males are said to have fragile X
syndrome
Fragile X syndrome occurs in one in 1,000
male births
and one in 2,500 female births. As children,
fragile X syndrome individuals appear to be
normal except they may behyperactive or
autistic. Their speech is delayed in
development and is often repetitive in nature.
As adults, they are short in stature with a long
face. The jaw is prominent, and there are big,
usually protruding ears
Malesalso have large testicles. Stubby hands,
lax joints, and a heart defect may also be
seen. The symptoms, including mental
retardation, are not as severe in females.

Trisomy
Faktor umur ketika
melahirkan juga
berpengaruh, misalnya pada
Kasus Sindroma Down
trisomi 21, biasanya lahir
sebagai anak terakhir
keluarga besar, atau dari
usia ibu yang lanjut, nondisjunction terjadi pada
meiosis I menghasilkan
ovum yang mengandung 2
buah autosom nomor 21 dan
bila ovum ini dibuahi oleh
sperma normal yang
membawa nomor 21 maka
terbentuklah zigot trisomi 21

Non-disjunction
Nondisjunction of chromosomes during
Down
Syndrome
meiosis.

a. Nondisjunction can occur during meiosis I

if homologous
chromosomes fail to separate and
b. during meiosis II if the sister
chromatids fail to separate completely. In either
case, certain
abnormal gametes carry an extra chromosome (n
1) or lack a
chromosome (n 1).

Down syndrome occurs when

the egg has an extra
chromosome 21 due to
nondisjunction in either meiosis
I or meiosis II. Characteristics
include a wide, rounded face
and narrow, slanting eyelids.
Mental retardation to varying

Downs Syndrome
Most common cause of
cognitive impairment
(moderate to severe)
1 in 600 live births
Risk factor- pregnancy in
women over 35 yrs old
Cause - extra chromosome 21
(faulty cell division)
Causes change in normal
embryogenesis process
resulting in:

Cardiac defects, GI conditions,

Endocrine disorders,
Hematologic
abnormalities, Dermatologic
changes

Physical features: small

head, flat facial profile, broad

30

Talipes (Clubfoot)
Most common type is when foot is pointed

downward and inward

Often associated with other disorders
May be due to decreased movement in
utero
Treatment requires surgical intervention
Serial casting is begun shortly after birth
and usually lasts for 8-12 weeks
Priority nursing interventions are skin
care and facilitating normal growth and
development

Osteogenesis Imperfecta (OI)

Inherited disorder of connective tissue and

excessive fragility of bones

Pathologic fractures occur easily
Incidence of fractures decrease at puberty related
to increased hormones making bones stronger
Treatment is supportive: careful handling of
extremities, braces, physical therapy, weight
control diet, stress on home safety
Surgical techniques for correcting deformities
and for intermedullary rodding

Spina Bifida:
Occulta and Cystica
(meningocele and myelomeningocele)
Etilogy is unknown, but genetic &

Photo Source: Del Mar Image Library; Used with

permission

environmental factors considered.

Maternal intake of folic acid
Exposure of fetus to teratogenic
drugs
The severity of clinical
manifestations depend on the
location of the lesion.
T12 - flaccid lower extremities,
sensation, lack of bowel control and
dribbling urine
S 3 and lower - no motor impairment
Other complications may occur.
Hydrocephalus (80-90%)
Orthopedic issues such as scoliosis,
kyphosis, club foot
Urinary retention
Skin breakdown/Trauma

33

CONCLUSION
A genetic disorder is a disease caused in
whole or in part by variation or mutation
of a gene.
May or may not be heridetary.
Currently about 4,000 genetic disorders
are known, with more being discovered.

Reff
http://learn.genetics.utah.edu/units/disorders/whatare

gd/
http://learn.genetics.utah.edu/units/disorders/
http://www.ornl.gov/sci/techresources/Human_Geno
me/medicine/assist.shtml
http://www.noah-health.org/en/genetic/

THANK YOU!!!