Basic Pathology

Congenital
Anomalies
dr. Gara Samara B., SE, MMR
Congenital vs Genetic diseases
Mengenal Kelainan Genetik
Hereditary disorders, familial
Mengenal Kelainan Genetik

Basic Pathology
Kromosom
Mengenal Kelainan Genetik

Basic Pathology
DNA
Mengenal Kelainan Genetik

Basic Pathology
 HEREDITARY, FAMILIAL
and CONGENITAL

Hereditary disorders are derived from one parents,

and are transmitted in the germ line through the
generations, and therefore are Familial.

The term congenital simply implies BORN WITH.

Some congenital diseases ARE NOT GENETIC eq
Congenital syphilis.

NOT ALL GENETIC DISEASE ARE

CONGENITAL. Some diseases begin to manifest
their condition only after 3rd or 4th decade of
life.
 CONGENITAL vs
GENETIC DISEASES

The term congenital simply implies BORN WITH.

Some congenital diseases ARE NOT GENETIC eq

Congenital syphilis.

NOT ALL GENETIC DISEASE ARE

CONGENITAL. Some diseases begin to manifest
their condition only after 3rd or 4th decade of
life.
 3 Major Categories of
GENETIC DISORDERS
1). RELATED TO MUTANT GENES OF LARGE EFFECTS.
Most of these follow the classic mendelian pattern of inheritance
MENDELIAN DISORDERS.

2). DISEASES WITH MULTIFACTOR (POLYGENIC)

INHERITANCE. Such as hypertension, DM.
Multifactorial: influence by both Genetic and Environmental
factors. The genetic component involves results of multiple
genes of small effect, while the environmental contribution
may be small or large.

. 3).DISEASES THAT RESULT FROM GENOMIC OR

CHROMOSOMAL MUTATIONS, associated with
Numerical or Structural Changes in chromosomes
 MUTATIONS

Define as Permanent Change in the DNA

Mutations that affect the GERM CELLS are transmitted
inherited disease
Mutations that arise in SOMATIC CELLS do not cause
Hereditary diseases, but important for the Genesis of Cancer
and some Congenital anomalies

CHROMOSOME MUTATION involving NUMBER or

STRUCTURE of chromosome. Transmitted infrequently
because most are incompatible with survival
Majority of mutations associated with Hereditary diseases is
GENE MUTATION.
 GENE MUTATIONS

Majority of mutations associated with Hereditary

diseases is GENE MUTATION.
Partial or complete deletion of a gene or more often
affect a single base
POINT MUTATION: single nucleotide substitute by
a different base (F5.2)
FRAMESHIFT MUTATION: one or two base pairs
may be inserted into OR deleted from DNA
alteration in the reading frame of the DNA strand.
(f5.3-5.4)
 GENE MUTATION:
point mutations
POINT MUTATION WITHIN CODING SEQUENCE:
A point mutation (single base substitution) may alter the code in a
triplet of bases replace one amino acid by another in gene
product (often term as missense mutation)
Ex: sickle mutation affecting the beta globin of Hb ( CTC for
glutamic acid is changed to CAC for valine) alter
physicochemical properties of Hb sickle cell anaemia
A point mutation may change amino acid codon to stop codon
(nonsense mutation), ex: CAG for glutamine is changed to
UAG for stop codon premature translation of beta globin:
short peptide is rapidly degraded. Lack of beta globin chains
Thalassemia
 GENE MUTATION:
point mutations
POINT MUTATION WITHIN NONCODING SEQUENCES:
Transcription of DNA is initiated and regulated by promoter and
enhancer sequences. Point mutation or deletion involving these
regulatory sequences may interfere the total lack of
transcription, ex: certain form of hereditary haemolytic anaemia.
Point mutation within intron interfere with normal mRNA
transcript, failure to form the mature mRNA translation can
not take place, gene product is not synthesized.

DELETIONS AND INSERTIONS involving coding sequence

alteration of the reading frame frameshift mutations.
 CHROMOSOME
MUTATIONS

CHROMOSOME MUTATION involving

NUMBER or STRUCTURE of chromosome.
Transmitted infrequently because most are
incompatible with survival

Majority of mutations associated with Hereditary

diseases is GENE MUTATION.
 3 Major Categories of
GENETIC DISORDERS
1). RELATED TO MUTANT GENES OF LARGE EFFECTS.
Most of these follow the classic mendelian pattern of inheritance
MENDELIAN DISORDERS.

2). DISEASES WITH MULTIFACTOR (POLYGENIC)

INHERITANCE. Such as hypertension, DM.
Multifactorial: influence by both Genetic and Environmental
factors. The genetic component involves results of multiple
genes of small effect, while the environmental contribution
may be small or large.

. 3).DISEASES THAT RESULT FROM GENOMIC OR

CHROMOSOMAL MUTATIONS, associated with
Numerical or Structural Changes in chromosomes
Pendahuluan

Kromosom, dari bahasa Yunani:

(chroma, warna) dan
(soma, tubuh)
Kromosom merupakan rangkaian utas
DNA (dari satu molekul DNA) yang
sangat panjang dan kontinyu,
berisi banyak gen, elemen regulator
dan sekuens nukleotida pengisi
lainnya.
DISEASES RELATED TO
MUTANT GENES OF LARGE
EFFECTS
MENDELIAN DISORDERS

Most of these follow

Mendelian patterns of Inheritance
Mendelian disorders
All mendelian disorders are the result of
expressed mutations of single gene of large
effect
The number of mendelian disorders known has
grown, listed more than 4500 disorders.
Estimated that every individual is a carrier of 5
to 8 deleterious genes. Fortunately most of
these are recessive
About 80% of these mutations are familial
Mendelian disorders

Genetic defect (mutations) formation of

abnormal protein (gene product) phenotypic
effects
Single gene disorders:
Enzyme deffect
Defect membrane receptor and transport system
Alternation in the structure, function, or
quantity of non enzyme proteins
Mutations resulting in unusual reactions to drugs
Mendelian disorders

Mutation Enzyme deffect: reduced activity,

reduced amount of normal enzyme
Ex: enz phenylalanine hydroxylase
phenylketonuria
Hexosaminidase Tay-Sachs disease
Adenosine deaminase Severe Combined
Immunodeficiency
Mendelian disorders

Defect membrane receptor and transport system

Many biologically actve substances transported
across cell membrane.
Ex: reduced synthesis or function of low density
lipoprotein (LDL) receptors defective
transport LDL into the cells, secondary excessive
cholesterol synthesis by complex mechanism
Familial hypercholesterolaemia
Ex: Vit D receptors vit D resistent rickets
Ex: transport oxygen (Hb) thalassemia (alfa,
beta)
Ex: ions cystic fibrosis
Mendelian disorders

Alternation in the structure, function, or

quantity of non enzyme proteins
Ex: defect structure of globin molecule
haemoglobinopathies, sickle cell anaemia.
Ex: reduced amount of struturally normal Hb
(alfa or beta globin chains) Thalassemia
Ex: collagen Osteogenesis imperfecta
Ex: dystrophin muscular dystrophia
Ex: Fibrilin marfan syndrome
Mendelian disorders

Mutations resulting in unusual reactions to drugs

Enzyme defficiencies after exposure of affected
individual to certain drugs Pharmacogenetic
Ex:Def enz G6PD. In normal condition, G6PD
does not result in disease. On administration of
primaquine (antimalaria) severe haemolytic
anaemia
Transmission pattern of single-
gene disorders
Mutations involving single gene typically follow
one of 3 pattern: autosomal dominant,
autosomal recessive, and X-linked.

AUTOSOMAL DOMINANT DISORDERS

AUTOSOMAL RECESSIVE,
X-LINKED
Transmission pattern of single-gene disorders:
AUTOSOMAL DOMINANT DISORDERS

Manifest in the heterozygote state, at least one parent is

usually affected, male or female can affected, both can
transmit the condition
If an affected person marries unaffected, every child has
one change in two of having the disease
In addition, the characteristic as follows:
Some patients do not have affected parents, their
disorder caused by new mutation involving eggs or
sperm. Their siblings are neither affected. Many new
mutations seem to occur in germ cells of relatively older
fathers.
Transmission pattern of single-gene disorders:
AUTOSOMAL DOMINANT DISORDERS

Some individual inherit the mutant gene, but

phenotypically normal. This is referred as reduced
penetrance. This is important for genetic counseling.
If a trait is seen in all individuals carrying mutant gene,
but expressed differently among individual, it is called
variable expressivity. Example: manifestations of
neurofibromatosis range from brownish spots to multiple
skin tumor and skeletal deformities
In many conditions, the age of onset is delayed, symptom
and signs do not appear until adult hood
Two major categories of nonenzyme proteins are usually
affected in autosomal dominant disorders:
Transmission pattern of single-gene disorders:
AUTOSOMAL DOMINANT DISORDERS

Some individual inherit the mutant gene, but

phenotypically normal. This is referred as reduced
penetrance. This is important for genetic counseling.
If a trait is seen in all individuals carrying mutant gene,
but expressed differently among individual, it is called
variable expressivity. Example: manifestations of
neurofibromatosis range from brownish spots to multiple
skin tumor and skeletal deformities
In many conditions, the age of onset is delayed, symptom
and signs do not appear until adult hood
Two major categories of nonenzyme proteins are usually
affected in autosomal dominant disorders:
Transmission pattern of single-gene
disorders:
AUTOSOMAL RECESSIVE
DISORDERS

The trait does not affect the parents, siblings

may show the disease
Onset is frequently early in life
Transmission pattern of single-
gene disorders:
X-LINKED DISORDERS

All sex-linked disorders are X-linked

Almost all X-linked recessive
DISEASES WITH
MULTIFACTORIAL (POLYGENIC)
INHERITANCE
Influence by both
Genetic and Environmental
Factors
Included most common diseases in
human: hypertension and DM
DISEASES THAT RESULT FROM
GENOMIC OR CHROMOSOMAL
MUTATIONS
associated with
Numerical or Structural
Changes in chromosomes
Kromosom
Kromosom pertama kali diamati pada
tanaman oleh ahli botani Swiss Karl Wilhelm
von Nageli (1817-1891) tahun 1842. Dan pada
cacing Askaris oleh ilmuwan Belgia Edouard
Van Beneden (1846-1910).

Sifat-sifat kromatin pada binatang

(Salamander) dijelaskan secara detail oleh ahli
anatomi Walter Flemming (1843-1905), penemu
mitosis pada tahun 1882.

Nama kromosom kemudian dicetuskan oleh

ahli anatomi Belanda Heinrich von Waldeyer.
 Morfologi kromosom

Kariotipe
Kromosom, Kromatin, Kromatid

(1) Chromatid. One of the two

identical parts of the chromosome
after S phase.
(2) Centromere. The point where the
two chromatids touch, and where
the microtubules attach.
(3) Short arm.
(4) Long arm.
Morfologi
Dua kromatid bersatu pada sentromer
Klasifikasi kromosom berdasarkan panjang,
letak sentromer dan ada atau tidaknya
satelit
Letak sentromer :
1. Metasentris
2. Submetasentris
3. Akrosentris
 Nomenklatur

Cara mengidentifikasi
kromosom :
1. ukuran
2. pola setelah pengecatan
3. posisi sentromer

Konstitusi kromosom :
1. nomor kromosom
2. lengan
3. region
e.g. 13q12
Jumlah Kromosom
Spesies # Spesies #
Tikus Putih 16 Manusia 46
Merpati 16 Siput 24
Cacing tanah 36 Rubah Tibet 36
Kucing 38 Babi 38
Tikus 40 Celurut 42
Kelinci 44 Hamster 44
Gorilla 48 Domba 54
Gajah 56 Sapi 60
Keledai 62 Kuda 64
Anjing 78 Ayam 78
Kupu-kupu 380
Kelainan struktur kromosom #1
Delesi : bagian dari kromosom
ada yang hilang atau terhapus
e.g. Jacobsen syndrome (11q)

Duplikasi : bagian dari

kromosom terduplikasi,
menghasilkan ekstra material
genetik. E.g. Charcot-Marie-
Tooth disease type 1A (17)

Inversi : bagian dari kromosom

berpindah tempat ke atas atau
bawah sehingga material
genetik menjadi inverted
Kelainan struktur kromosom #2

Insersi

Translokasi
Kelainan jumlah kromosom

Monosomi

Trisomi
 Aberasi Kromosom
Beberapa kelainan struktur kromosom tidak mengakibatkan
kelainan bawaan, seperti translokasi atau inversi, tapi
meningkatkan kemungkinan mempunyai anak dengan
kelainan kromosom.

Kelainan jumlah kromosom atau kromosom set (aneuploidi)

biasanya fatal, atau memberikan penyakit genetik.

Cri du chat
Klinefelter's syndrome
Wolf-Hirschhorn syndrome
Jacobsen syndrome Turner syndrome

XYY syndrome
Down syndrome
Edward's syndrome
Patau syndrome Triple-X syndrome
Cri du Chat
Cri du chat syndrome / deletion 5p syndrome /5p minus
Pertama kali dijelaskan oleh Jrme Lejeune th 1963.
1 : 20,000 - 50,000 kelahiran hidup, lebih sering pada
perempuan.
Cri du Chat
Karakteristik
Tangisan mengeong --> perkembangan abnormal laring
Karakter Fisik: Underweight, mikrosefal, hipotonia,
round face, lowset ear, strabismus, facial asimetri
Malformasi jantung

Perkembangan lebih lanjut:

Retardasi mental
Autis
Hipersensitivitas terhadap suara
Bersifat sosial dan periang
Wolf-Hirschhorn syndrome
Disebabkan oleh delesi parsial dari lengan pendek kromosom 4

Karakteristiknya retardasi pertumbuhan berat dan mental

retardasi.
Jacobsen Syndrome
Jacobsen Syndrome / 11q deletion merupakan kelaianan
yang merupakan hasil delesi dari daerah terminal
kromosom 11 (11q24.1)

Mengakibatkan mental retardasi ringan, wajah khas dan

beberapa problem fisik termasuk kelainan jantung dan
perdarahan (Paris-Trousseau syndrome)

Sindroma ini pertama kali dikenali oleh Petra Jacobsen

th 1973, 1 : 100,000 kelahiran
Down Syndrome
Sindroma Down / Down's Syndrome / Trisomi 21
Merupakan kondisi yg terjadi akibat adanya ekstra
kromosom 21.
Pertama kali ditemukan oleh John Langdon Down, tahun
1866.
 Down Syndrome
Karakteristik Fisik
Fissura mata mendatar
Hidung rata, makroglossia, leher pendek
hipotoni
simian crease
Penyakit jantung kongenital
Retardasi mental ringan
(IQ 5070) sampai sedang (IQ 3550)
Edward's Syndrome
Trisomy 18 / Edwards Syndrome
Trisomi paling sering setelah Down Syndrome.
Mengakibatkan BBLR, mikrosefal, low-set ears, penyakit
jantung dan malformasi organ
Survival rate Edwards Syndrome sangat rendah.
Setengahnya mati dalam kandungan. Pada kelahiran hidup
hanya 50% hidup sampai 2 bulan, 5-10% sukses sampai
umur 1 tahun
Penyebab utama
kematian adalah apneu
dan kelainan jantung.
 Patau Syndrome
Patau syndrome / Trisomi 13
Karakteristik: mental retardasi, mata sipit, bibir/palatum
sumbing, hipotonia
1 : 10,000 angka kelahiran hidup
Semakin tua, resiko wanita mempunyai bayi dengan Patau
syndrome meningkat
Klinefelter's Syndrome
Klinefelter's syndrome / XXY syndrome
Merupakan kondisi yang disebabkan oleh kegagalan
disjungsi kromosom, mengakibatkan laki-laki mempunyai
2 kromosom X
Dinamakan oleh Dr. Harry Klinefelter, peneliti di
Massachusetts General Hospital, Boston, Massachusetts,
1942
Klinefelter's Syndrome

Gejala dan Tanda

Pria XXY hampir selalu steril
Ginekomasti timbul pada 1/3 penderita.
Meningkatkan resiko kanker payudara,
penyakit paru, DM, rheumatoid artritis dan
osteoporosis.
Kebanyakan orang tidak menunjukkan gejala
yang spesifik
Turner Syndrome
Turner syndrome merupakan sekumpulan kelainan akibat
monosomi X, disebut juga 45,X or 45,X0
1 : 2.500 angka kelahiran bayi perempuan hidup.
Pada Turner syndrome, karakteristik seksual perempuan
ada namun tidak berkembang.

Gejala:
Perawakan pendek
Dada lebar (shield chest) dan puting susu jauh
satu sama lain
Steril
Amenore
XYY Syndrome
XYY syndrome adalah aneuploidi
(khususnya trisomi) dari kromosom sex
dimana laki-laki menerima kromosom Y
ekstra, menjadikan kariotipenya 47,XYY.
Beberapa ahli genetik (Allanson &
Graham 2002) mempertanyakan
penggunaan istilah sindrome yang tidak
tepat untuk kondisi penyakit karena
fenotipenya normal dan mayoritas (97%)
laki-laki di Inggris tidak menyadarinya.
Mempunyai resiko kesulitan belajar yang
lebih tinggi, rata-rata penderita IQ
berbeda 10-15 poin dari normal
Triple-X Syndrome
Triple X syndrome / triplo-X / trisomy X /
XXX syndrome / 47,XXX aneuploidy

Merupakan variasi kromosom yang

ditandai dengan adanya ekstra kromosom
X pada setiap sel dari perempuan

Perempuan dengan kondisi ini tidak

mempunyai resiko kesehatan

Dapat mengalami ketidakteraturan haid,

kadang-kadang juga meningkatkan resiko
kesulitan belajar dan keterlambatan
bicara dan bahasa
PRENATAL SCREENING #1

Relatively simple, non invasive, examine mothers blood

Test measure level of three markers:
Serum alpha fetoprotein (MSAFP)
Chorionic gonadotropin (hCG)
Unconjugated estriol (uE3)
This measurement are not a definitive test.
PRENATAL SCREENING #2
AMNIOCENTESIS
The removal and analysis of a small sample of fetal
cells from the amniotic fluid
Cannot be done until the 14-18th week of pregnancy
Lower risk of miscarriage than CVS

CHORIONIC VILLUS SAMPLING

Extraction of a tiny amount of fetal tissue at 9 to 11
weeks of pregnancy
The tissue is tested for the presence of extra material
from chromosome 21
Carries a 1-2% risk of miscarriage
PRENATAL SCREENING #3

PERCUTANEOUS UMBILICAL BLOOD

SAMPLING (PUBS)
Most accurate method used to confirm the result of
CVS or amniocentesis
The tissue is tested for the presence of extra material
from chromosome 21
PUBS cannot be done untill the 18-22nd week
Carries the greatest risk of miscarriage

CURRENT TECHNIQUES:
Cell culture and karyotyping; 99% correct
CYTOGENETIC AND MOLECULAR
DIAGNOSIS

DNA analysis
Detection of inherited mutations that underline the
development of genetic disease
Direct gene diagnosis DNA sequencing
Cytogenetic analysis:
Cell culture and karyotyping; 99% correct
SELAMAT SURFING
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