GENETIC DISORDERS

Dr. Winny Natacia Leiwakabessy, Mkes,

SpPA
Genetic disorders

Disorders related to mutations in single genes with large

effects

Chromosomal disorders

Complex multigenic disorders

Mutasi

Point mutations within coding sequence

●
Point mutation: a single base is substituted with a different base
●
Alter the code in a triplet base replacement of one amino acid by another in gene product
●
= missense mutation
●
Conservative missense mutation: jika asam amino yang digantikan secara biokomia mirip dg
original perubahan kecil thd fungsi dari protein
●
Nonconservative missense mutation. Contoh: siclkle mutation affecting -globin chain of
hemoglobin
Mutasi
 Nonconservative missense mutation.
 Contoh: siclkle mutation affecting
-globin chain of hemoglobin
 Nucleotide triplet CTC (or GAG in
MRNA), mengkode glutamic acid
 CTC  CAC (or GUG in MRNA)
mengkode valine
 Merubah properti fisikokimia
hemoglobin  sickle cell anemia
Mutasi
 Point mutations within coding sequence
 Merubah sebuah codon as. Amino menjadi
sebuah chain terminator atau stop codon.
 Contoh : -globin
 Point mutation: affecting the codon for
glutamine (CAG) cretaes a stop codon (UAG) if
U is subtituted for C  change leads to
premature termination of -globin gene
translation & short peptide that is produce is
rapidly degraded  severe anemia B
thalasemia.
Mutasi

Mutations within noncoding sequence

Deletions and insertions

Trinucleotide-repeat mutations
Mutasi

Deletions and insertions

●
Small deletions or insertions involving the coding sequence can have two possible effects on the
encoded protein.
●
If the number of base pairs involved is three or a multiple of three, the reading frame will remain intact,
and an abnormal protem lacking or gaining one or more amino acids will be synthesized (Fig. 5-2).
●
If the number of affected codmg bases is not a multiple of three, this will result in an alteration of the
reading frame of the DNA strand, producing what is referred to as a frameshift mutation (Figs. 5-3 and
5-4).
 Gambar 9. Contoh mutasi
Substitusi
A G C T T A C A G
A G C T C A C A G
Delesi
A G C T T A C A G
A G C T -- A C A G
Insersi
A G C T T A C A G
A G C TAT A C A G
Inversi
A G C T T A C A G
G A C A T T C G A
Mutasi

Trinucleotide-repeat mutations

●
Trinucleotide-repeat mutations belong to a special
category of genetic anomaly.
●
These mutations are characterized by amplification of a
sequence of three nucleotides.
Hereditar ●
are derived from one's parents
and are transmitted in the germ
y line through the generations
disorders and therefore are familial.

conge ●

●
simply implies "born with."
Some congenital diseases are not genetic;
For example, congenital syphilis.

nital
●
Not all genetic diseases are congenital
●
individuals with Huntington disease, begin to
manifest their condition only after they 20s or 30s
Mendelian Disorder
 Mengikuti pola pewarisan Mendel
 Ekspresi mutasi 1 buah gen dgn efek
besar
 Dasar molekuler & biokimia:
 Defek ensim & konsekuensinya
 Defek reseptor & sistem transport
 Defek fungsi, struktur, jumlah protein non
ensim
 Pola pewarisan: autosomal dominan,
autosomal resesif, X-linked
Biochemical and Molecular Basis of
Single-Gene (Mendelian) Disorders
 The mechanisms involved in single-gene
disorders can be classified into four
categories:
1. enzyme defects and their consequences;

2. defects in membrane receptors and

transport systems;
3. alterations in the structure, function, or
quantity of nonenzyme proteins;
4. mutations resulting in unusual reactions to
drugs.
Biochemical and Molecular Basis of
Single-Gene (Mendelian) Disorders

Enzyme Defects and Their Consequences

 Mutations may result in the synthesis of an
enzyme with reduced activity or a reduced
amount of a normal enzyme. Konsekuensi:
 Accumulation of the substrate
 An enzyme defect can lead to a metabolic
block and a decreased amount of end
product
 Failure to inactivate a tissue-damaging
substrate
 PENYAKIT AKIBAT DEFEK
PROTEIN STRUKTURAL
 Sindroma Marfan
 Penyakit jaringan konektif
 Kelainan skeleton, okuler,
kardiovaskuler
 Mutasi gen fibrilin (15q21.1)
 Fibrilin : glikoprotein disekresi
fibroblast & microfibriller network ECM
& berperan dalam deposisi elastin
 Marfan
syndrome

?
 Disorders Associated with Defects
in Receptor Proteins

Familial Hypercholesterolemia

• Familial hypercholesterolemia is an autosomal dominant

disorder caused by mutations in the gene encoding the LDL
receptor
• Patients develop hypercholesterolemia as a consequence
of impaired transport of LDL into the cells
• In heterozygotes, elevated serum cholesterol greatly
increases the risk of atherosclerosis and resultant coronary
artery disease; homozygotes have an even greater increase
in serum cholesterol and a higher frequency of ischemic
heart disease. Cholesterol also deposits along tendon
sheaths to produce xanthomas
Lysosomal Storage Diseases
 Inherited mutations leading to
defective lysosomal enzyme
functions gives rise to:
 accumulation and storage of complex
substrates in the lysosomes
 defects in autophagy resulting in
cellular injury
Lysosomal Storage Diseases
 Tay-Sachs disease is
 caused by an inability to metabolize
GM2 gangliosides due to lack of the a
subunit of lysosomal hexosaminidase.
 GM2 gangliosides accumulate in the
central nervous system and cause:
 severe mental retardation,
 blindness,

 motor weakness,
 death by 2 to 3 years of age.
Lysosomal Storage Diseases
 Niemann-Pick disease types A and B
 caused by a deficiency of sphingomyelinase.
 In the more severe type A variant,
accumulation of sphingomyelin in the
nervous system results in neuronal damage.
 Lipid also is stored in phagocytes within the
liver, spleen, bone marrow, and lymph
nodes, causing their enlargement.
 In type 8 , neuronal damage is not present.
Lysosomal Storage Diseases
 Niemann-Pick disease type C
 caused by a defect in cholesterol
transport and resultant accumulation of
cholesterol and gangliosides in the
nervous system.
 Affected children most commonly
exhibit ataxia, dysarthria, and
psychomotor regression.
Lysosomal Storage Diseases
 Gaucher disease
 results from lack of the lysosomal enzyme
glucocerebrosidase and accumulation of
glucocerebroside in mononuclear phagocytic
cells.
 In the most common, type I variant, affected
phagocytes become enlarged (Gaucher cells)
and accumulate in liver, spleen,and bone
marrow, causing hepatosplenomegaly and bone
erosion.
 Types II and Ill are characterized by variable
neuronal involvement.
Lysosomal Storage Diseases
 Mucopolysaccharidoses
 result in accumulation of mucopolysaccharides
in many tissues including liver, spleen, heart,
blood vessels, brain, cornea, and joints.
 Affected patients in all forms have coarse
facial features.
 Manifestations of Hurler syndrome include
corneal clouding, coronary arterial and
valvular deposits, and death in childhood.
 Hunter syndrome is associated with a milder
clinical course.
KELAINAN DENGAN PEWARISAN
MULTIFAKTORIAL
 Hasil kombinasi lingkungan dan 2 atau
lebih gen mutan yang berefek aditif.
 Juga terdapat pada fenotip normal
 Komponen genetik memberi efek
tekanan (memperberat ekspresi)
 Contoh: DM, hipertensi, peny.jantung
koroner
 Diagnosis sulit
Chromosomal Disorders
 human somatic cells contain 46
chromosomes; these comprise 22
homologous pairs of autosomes and
two sex chromosomes, XX in the
female and XY in the male.
 Deletion refers to loss of a portion of a
chromosome.
 A ring chromosome is a special form of
deletion. It is produced when a break
occurs at both ends of a chromosome
with fusion of the damaged ends
 Inversion refers to a rearrangement that
involves two breaks within a single
chromosome with reincorporation of the
inverted, intervening segment.
 Isochromosome formation results
when one arm of a chromosome is
lost and the remaining arm is
duplicated, resulting in a
chromosome consisting of two short
arms only or of two long arms.
 In a translocation, a segment of one
chromosome is transferred to
another.
 Kelainan sitogenetik pada autosom

 TRISOMI 21 (Sindroma Down)

 Paling sering, penyebab utama retardasi mental
 Nondisjunction pada meiosis
 Klasik: 47,XX,+21
 Translocation type : 46,XX,-14,+t(14q21q)
 Mosaic type : 46,XX/47,XX,+21
Gbr 14. Gambaran klinik Sindroma Down
TRISOMI 21. A simian crease is seen on the
hand of this child with Down syndrome. A
single crease extends transversely across
TRISOMI 21 (47, XY, +21) also known as Down syndrome. Additions or
deletions of genetic material are generally lethal in utero, but Trisomy
21 is an example of one form of addition in which the fetus may
occasionally survive
Down Syndrome
Kelainan sitogenetik pada kromosom
sex
 SINDROMA TURNER
Monosomi komplit/parsial dari
kromosom X
 Khas: hipogonadisme pada fenotip wanita
 Klasik : 45,X
 Mosaic : 45,X/46,XX
 Webbing of neck

Broad chest Coarctation aorta

spaced nipples
Cubitus valgus

Streak ovaries

Nevi Lymphedema

Gbr 15. Gejala klinik Sindroma Turner

Turner Syndrome (monosomy X, with
karyotype 45, X). Women with Turner's
syndrome can live relatively normal lives,
Sindrom Klinefelter
Hipogonadismepria, 2 atau lebih
kromosom X dan 1 atau lebih Y
Gejala klinik: long legs, atrophy testis,
penis kecil, sex sekunder (-)
FSH,estradiol meningkat, testosteron
menurun
47,XXY (klasik)
46,XY/47,XXY (mosaik)
48,XXY/48,XXXY (mosaik)
Klinefelter's syndrome with a 47, XXY karyotype.
A non-dysjunctional event in meiosis (maternal or
paternal) left two X chromosomes in an ovum or
PENUTUP
 Kelainan genetik : masih banyak
yang belum terungkap demikian
pula patogenesisnya

 Dengan makin berkembangnya

biotech.molekuler --- diagnosis
(terutama prenatal/genetic
counseling) --- preventif & kuratif