Genetic

Diseases
Oleh :
Rizki Widya Nur

Pembimbing :
dr. Ika Pawitra Miranti, M.Kes, Sp.PA
GENETIC DISEASES

• That humans have about

25,000 protein-coding
genes.
• The unraveling of this
“genetic architecture” is
beginning to unlock secrets
of inherited as well as
acquired human disease.
• Hereditary disorders  derived
from one’s parents, familial.
• Congenital  “present at birth.”

Some congenital diseases are not

genetic (congenital syphilis), not
all genetic diseases are congenital;
(Huntington disease  after the
3rd or 4th decade of life.
NATURE OF GENETIC
ABNORMALITIES
CONTRIBUTING
TO HUMAN DISEASE
Mutations in Protein-Coding Genes

Mutation  permanent changes in

the DNA.
1. Point mutations
Result from the substitution of a
single nucleotide base by a different
base, resulting in the replacement
of one amino acid by another in the
protein product.
2. Frameshift
mutations
occur when the
insertion or
deletion of one
or two base
pairs alters the
reading frame
of the DNA
strand.
3. Trinucleotide repeat mutations
belong to a special category, because these
mutations are characterized by amplification of a
sequence of three nucleotides.
 Alterations in Protein-Coding
Genes Other Than Mutations
Alterations in DNA sequence :
• Amplifications
• Deletions
• Translocations

Cancers often contain somatically acquired

structural alterations.
Ex : “Philadelphia chromosome”—translocation
between the BCR and ABL genes in chronic myeloid
leukemia
 Alterations in Non-Coding
RNAs
That a very large number of genes do
not encode proteins. Instead, the
nonencoded products of these genes—
so-called “non-coding RNAs
(ncRNAs)”—play important regulatory
functions.
Although many distinct families of
ncRNAs exist, the two most important
examples :
 small RNA molecules alled microRNAs
(miRNAs)
 long non-coding RNAs (lncRNAs)
We can turn our attention to the three
major categories of genetic disorders:

Mendelian disorders resulting from

mutations in single Genes

Complex disorders involving multiple

genes as well as environmental
influences

Diseases arising from chromosomal

abnormalities, including changes in the
number or structure of chromosomes.
 Mendelian
Disorders: Diseases
Caused By Single-
gene Defects
Mutations involving single genes
follow one of three patterns of
inheritance :
 autosomal dominant
 autosomal recessive
 X-linked.

A single-gene mutation may have

many phenotypic effects (pleiotropy)
and, conversely, mutations at several
genetic loci may produce the same
trait (genetic heterogeneity).
Estimated Prevalence of Selected Mendelian Disorders
Among Live-Born Infants
 Disorders of Autosomal
Dominant Inheritance

• Manifested in the heterozygous state,

so at least one parent in an index case
usually is affected.
• Both males and females can be affected
• Both sexes can transmit the condition
• When an affected person marries an
unaffected one, each child has one
chance in two of having the disease.
The following features also pertain to autosomal
dominant diseases:

1. With any autosomal dominant disorder, some

patients do not have affected parents.
2. Clinical features can be modified by reduced
penetrance and variable expressivity.
3. In many conditions, the age at onset is delayed, and
symptoms and signs do not appear until adulthood
(as in Huntington disease)
4. In autosomal dominant disorders, a 50% reduction
in the normal gene product is associated with clinical
signs and symptoms. Because a 50% loss of enzyme
activity can be compensated for, involved genes in
autosomal dominant disorders usually do not encode
enzyme proteins.
 Disorders of Autosomal
Recessive Inheritance

are manifested in the

homozygous state. They occur
when both of the alleles at a
given gene locus are mutants.
Therefore, such disorders are
characterized by the following features:
1. The trait does not usually affect the
parents, who are carriers of one
diseased allele, but multiple siblings
may show the disease
2. Siblings have one chance in four of
being affected (i.e., the recurrence risk
is 25% for each birth)
3. If the mutant gene occurs with a low
frequency in the population, there is a
strong likelihood that the affected
patient (the proband) is the product of
a consanguineous marriage
Features generally apply to most
autosomal recessive disorders:
• The expression of the defect tends to
be more uniform than in autosomal
dominant disorders.
• Complete penetrance is common.
• Onset is frequently early in life.
• Although new mutations for recessive
disorders do occur, they are rarely
detected clinically. Because the affected
person is an asymptomatic
heterozygote.
• In many cases, enzymes are affected
by the mutation.
 X-Linked Disorders

• Heterozygous female carriers

transmit them only to sons,
who of course are hemizygous
for the X chromosome.
• Heterozygous females rarely
express the full phenotypic
change, because they have the
paired normal allele.
• An affected male does not
transmit the disorder to sons,
but all daughters are carriers.
Diseases Caused
by Mutations in
Genes Encoding
Structural
Proteins
 Marfan Syndrome

• Autosomal dominant
• Disorder of connective tissues
• Manifested in the skeleton, eyes, and
cardiovascular system.
• Caused by an inherited defect in an
extracellular glycoprotein called
fibrillin-1
 Fibroblas LOCUS
15q21

FIBRILIN - FB N1
1 GENE

Serve as scaffolding
for the deposition of
Microfibrils tropoelastin

Extracelluler matrix Distributed in the body, they

are particularly abundant in
the aorta, ligaments, and the
ciliary zonules
• Arachnodactyly
• Hyperextensibility of joints
• Kyphoscoliosis
• Pectus excavatum
• Ectopia lentis
• Cystic medionecrosis
• Floppy valve syndrome
Ehlers-Danlos Syndromes

Ehlers-Danlos syndromes
(EDSs) are a group of diseases
characterized by defects in
collagen synthesis or
structure.

-> autosomal dominant and

recessive patterns.
There are approximately 30 distinct
types of collagen; all have
characteristic tissue distributions and
are the products of different genes. To
some extent, the clinical heterogeneity
of EDS can be explained by mutations
indifferent collagen genes.

Tissues rich in collagen, such as skin,

ligaments, and joints,frequently are
affected in most variants of EDS.
Clinical features :
 Fragile
 Hyperextensible skin
vulnerable to trauma
 Hypermobile joints
 Ruptures involving colon,
cornea, or large arteries.
 Diaphragmatic hernias
The molecular bases for three of the
more common variants are as follows:

1. Deficient synthesis of type III

collagen. (autosomal dominant)
COL3A1 gene -> Collagen type III ->
blood vessels, bowel wall.
2. Deficiency of the enzyme lysyl
hydroxylase. (autosomal recessive)
->congenital scoliosis and ocular
fragility.
3. Deficient synthesis of type V collagen
(autosomal dominant) -> mutations
in COL5A1 and COL5A2 ->classical
EDS.
Diseases Caused
By Mutations In
Genes Encoding
Receptor Proteins
Or Channels
Familial hypercholesterolemia

“Receptor disease” caused by loss-of-

function mutations in the gene encoding
the LDL receptor, which is involved in the
transport and metabolism of cholesterol.

Loss-of-function LDL receptor  elevated

levels of cholesterol  premature
atherosclerosis  increase the risk of
myocardial infarction.
 Normal Cholesterol Metabolism

triglycerides cholesterol

intestial
chylomicrons mucosa

blood muscle and fat

Hydrolyzed by lipoprotein
lipase

Some of the cholesterol enters the

metabolic pool (to be described), and
some is excreted as free cholesterol
or as bile acids into the biliary tract.
These can be divided into five categories.:
1. Class I, are uncommon, and they are
associated with complete loss of receptor
synthesis.
2. Class II, the most prevalent type, the receptor
protein is synthesized, but its transport from the
endoplasmic reticulum to the Golgi apparatus is
impaired because of defects in protein folding.
3. Class III, produce receptors that are
transported to the cell surface but fail to bind
LDL normally.
4. Class IV, give rise to receptors that fail to
internalize within clathrin pits after binding to
LDL
5. Class V, encode receptors that can bind LDL
and are internalized but are trapped in
endosomes because dissociation of receptor and
bound LDL does not occur.
 Cystic Fibrosis
 Disorder of epithelial ion transport
affecting fluid secretion in exocrine
glands and the epithelial linings of
the respiratory, gastrointestinal,
and reproductive tracts.
 Reduced production, or abnormal
function of an epithelial chloride
channel protein encoded by the
CFTR gene.
CFTR protein  reabsorb luminal chloride
ions and augment sodium reabsorption
through the epithelial sodium channel
(ENaC)  decreased reabsorption of
sodium chloride  hypertonic (“salty”)
sweat.
CF -> decreased chloride secretion and
increased sodium and water reabsorption in
the airways -> dehydration of the mucus
layer coating epithelial cells  defective
mucociliary action and mucous plugging.
M
O
R
P
H
O
L
O
G
Y
Diseases Caused
by Mutations in
Genes Encodin
Enzyme Proteins
 Phenylketonuria
(PKU)
 PKU results from mutations that
cause a severe lack of the enzyme
phenylalanine hydroxylase (PAH).

• Usually, by 6 months of life, severe

mental retardation becomes all too
evident.
• Seizures, other neurologic abnormalities,
decreased pigmentation of hair and skin,
and eczema often accompany the mental
retardation in untreated children.
• Hyperphenylalaninemia and the resultant
mental retardation can be avoided by
restricting phenylalanine intake early in
life.
The biochemical abnormality in PKU is an
inability to convert phenylalanine into
tyrosine.
Protein
Synthesis

Phenylalanine

Phenylalanine
Hydroylase enzym
Tyrosine Melanin

Urine,
Sweat
 Galactosemia

• Autosomal recessive disorder

• Mutation in the gene encoding the
enzyme galactose-1 phosphate
uridyltransferase (GALT) -> convert
galactose to glucose
• Galactose-1-phosphate and other
metabolites, including galactitol,
accumulate in many tissues, including
the liver, spleen, lens of the eye,
kidney, and cerebral cortex.
• Clinical features : jaundice,
liver damage, cataracts,
neural damage, vomiting and
diarrhea, and E. coli sepsis,
Aminoaciduria.
• Dietary restriction of
galactose for at least the
first 2 years of life, can
prevent at least some of the
more severe complications.
 Lysosomal Storage Diseases

Lysosomes  breakdown of complex

substrates, such as sphingolipids and
mucopolysaccharides, into soluble end
products.
 Lysosomal Storage
Diseases
Tay-sachs Disease (Gm2 Gangliosidosis: Deficiency In
Hexosaminidase Β Subunit)

Niemann-Pick Disease Types A and B

Gaucher disease

Mucopolysaccharidoses
 Tay-sachs Disease (Gm2
Gangliosidosis: Deficiency In
Hexosaminidase Β Subunit)

• Accumulation of gangliosides
• Absence of hexosaminidase A
• GM2 ganglioside accumulates in many
tissues (e.g., heart, liver, spleen,
nervous system)
• Involvement of neurons in the central
and autonomic nervous systems and
retina dominates the clinical picture.
• The accumulation of GM2 occurs within
neurons, axon cylinders of nerves, and glial
cells throughout the CNS. Affected cells
appear swollen and sometimes foamy.

(A) Under the light microscope, a large

neuron has obvious lipid vacuolation.
• Electron microscopy shows whorled
onionskin-like configurations within
lysosomes composed of layers of membranes.

(B) A portion of a neuron under the electron

microscope shows prominent lysosomes with
whorled configurations just below part of the
nucleus.
Niemann-Pick Disease
Types A and B

Type A and type B Niemann-Pick

diseases are related entities
characterized by a primary
deficiency of acid
sphingomyelinase and the
resultant accumulation of
sphingomyelin.
Type A
severe deficiency of
sphingomyelinase, the breakdown of
sphingomyelin into ceramide and
phosphorylcholine is impaired, and
excess sphingomyelin accumulates
in phagocytic cells and in neurons.
Type B
associated with mutant
sphigomyelinase with some residual
activity, have organomegaly but no
neurologic manifestations.
 Gaucher Disease

 Results from mutation in the gene

that encodes glucocerebrosidase
 The resultant deficiency of this
enzyme leads to an accumulation of
glucocerebroside, an intermediate in
glycolipid metabolism, in the
mononuclear phagocytic cells.
In Gaucher disease, the
degradation stops at the level
of glucocerebrosides, which
accumulate in macrophages.
 (Chronic Manifestations Emerge later
TYPE 1

TYPE 2

TYPE 3
nonneuronopathi appear during and are
c form.)
infancy (acute milder
Osteopenia, focal infantile (chronic
lytic lesions, and
osteonecrosis) in neuronopathic neuronopathic
70% to 100% of form) and are form).
cases, and more severe
hepatosplenome
galy.
Gaucher cells with abundant
lipid-laden “wrinkled”
cytoplasm.

Electron micrograph of Gaucher

cells with elongated distended
lysosomes.
Patients with Gaucher disease have a
20 fold higher risk of developing
Parkinson disease (compared to
controls) and 5–10% of patients with
Parkinson disease have mutations in
the gene encoding glucocerebrosidase.
 Mucopolysaccharidoses
Characterized by defective
degradation and excessive storage
of mucopolysaccharides in
various tissues, including liver,
spleen, heart, blood vessels, brain,
cornea, and joints.
 CLINICAL FEATURES
• Hepatosplenomegaly
• Skeletal deformities
• Lesions of heart valves
• Subendothelial arterial deposits, particularly
in the coronary arteries
• Lesions in the brain
• Coarse facial features
• Clouding of the cornea
• Joint stiffness
• Mental retardation
• Urinary excretion of the accumulated
mucopolysaccharides often is increased.
 • Hurler syndrome
• Caused by a deficiency of α-L-iduronidase
MPS Type • Resesif Autosom
1

• Hunter syndrome
• Caused by a deficiency of L-iduronidase - sulfatase
• Its mode of inheritance (X-linked)
MPS Type • The absence of corneal clouding, and often its milder
2 clinical course.
 Glycogen Storage
Diseases (Glycogenoses)

An inherited deficiency of

any one of the enzymes
involved in glycogen
synthesis or degradation
can result in excessive
accumulation of glycogen
or some abnormal form of
glycogen in various tissues.
Glikog
enesis
Diseases Caused by
Mutations in Genes
Encoding Proteins
That Regulate Cell
Growth
• Two classes of genes, protooncogenes
and tumor suppressor genes, regulate
normal cell growth.

• Mutations affecting these genes, most

often in somatic cells, are involved in
the pathogenesis of tumors.

• Mutations affecting certain tumor

suppressor genes are present in all cells
of the body, including germ cells.
 COMPLEX
MULTIGENIC
DISORDERS
o Caused by interactions
between genetic variants and
environmental factors.
o Environmental influences,
however, significantly modify the
phenotypic expression of complex
traits.
o For example, type 2 diabetes
mellitus.
 Cytogenetic disorders

 Cytogenetic disorders
result from alterations in
the number or structure
of chromosomes and may
affect autosomes or sex
chromosomes.
A karyotype is a photographic representation of a
stained metaphase spread in which the
chromosomes are arranged in order of decreasing
length.
 Numeric Abnormalities

• In humans, the normal chromosome

count is 46 (i.e., 2n =46).
• When nondisjunction the gametes formed
have extra chromosome (n + 1) or one
less chromosome (n − 1).
• Trisomic (2n+ 1)
• Monosomic (2n − 1)
• Monosomy autosome -> incompatible
with life, trisomies autosomes and
monosomy sex chromosomes ->
compatible with life.
Structural Abnormalities

Structural changes in the

chromosomes typically result
from chromosomal breakage
followed by loss or
rearrangement of material.
Translocation  transfer of a part of one chromosome to another
chromosome

Ischromosomes  when the centromere divides horizontally rather

than vertically.
Deletion  loss of a portion of a chromosome.
Inversions  are two interstitial breaks
in a chromosome, and the segment
reunites after a complete turnaround.

A ring chromosome  After loss of

segments from each end of the
chromosome, the arms unite to form a
ring.
 General Features of
Chromosomal Disorders
• A loss of chromosomal material more
severe defects than does a gain of
chromosomal material.
• Imbalances of sex chromosomes (excess
or loss) are tolerated much better than
are similar imbalances of autosomes.
• Sex chromosomal disorders sometimes
not detected at birth -> Infertility
• In most cases, chromosomal disorders
result from de novo changes  Down
syndrome exception to this principle.
 Cytogenetic
Disorders Involving
Autosomes
THREE MOST COMMON AUTOSOMAL
TRISOMIES

TRISOMY 21 (DOWN SYNDROME)

Down syndrome, characterized by
extra copy of genes on chromosome
21, is the most common of the
chromosomal disorders.

Their chromosome count is 47

The parents of such children are

normal in all respects.
4 %, the extra chromosomal material is present as a
translocation of the long arm of chromosome 21 to
chromosome 22 or 14.
• 21-40 th = develop
neuropathologic
changes (Alzheimer
disease)
• Abnormal immune
responses ->
serious infections
(lungs) and thyroid
autoimmunity
22Q11.2 DELETION SYNDROME
The 22q11.2 deletion syndrome
encompasses a spectrum of
disorders that result from a small
interstitial deletion of band 11 on
the long arm of chromosome 22.

Velocardiofacial syndrome, have mild

immunodeficiency and pronounced
dysmorphology and cardiac defects.

DiGeorge syndrome, When T cell

immunodeficiency and hypocalcemia
are the dominant features.
 Congenital
Heart
Disease

Facial Abnormslit
Dysmorp ies of the
hism, Palate

Clinical
Features

impaired
Thymic
hypoplasia
T cell
immunity

Developm
ental delay
Cytogenetic Disorders
Involving Sex
Chromosomes
• A number of abnormal karyotypes
involving the sex chromosomes,
ranging from 45,X to 49,XXXXY, are
compatible with life.

• In females, one X chromosome,

maternal or paternal, is randomly
inactivated during development (Lyon
hypothesis).
Klinefelter Syndrome (47,XXY)

=> Male hypogonadism that

develops when there are at least
two X chromosomes and one or
more Y chromosomes.
some persons expressed only as
hypogonadism.
 Most patients have a distinctive body
habitus (increase in length between the
soles and the pubic)
Reduced facial, body, and pubic hair and
gynecomastia also are frequently seen.
The testes are markedly reduced in size,
sometimes to only 2 cm in greatest
dimension.
The serum testosterone levels are lower
than normal.
 Turner Syndrome (45,X)

Primary hypogonadism in
phenotypic females, results
from partial or complete
monosomy of the short arm of
the X chromosome.
 SINGLE-GENE
DISORDERS WITH
ATYPICAL PATTERNS
OF
INHERITANCE
Three groups of diseases resulting from
mutations affecting single genes do not
follow the mendelian rules ofinheritance:

Diseases caused by triplet repeat

mutations

Diseases caused by mutations in

mitochondrial genes

Diseases associated with alteration

of imprinted regionsof the genome
 Triplet Repeat Mutation

Occurs in a long repeating sequence

of three nucleotides.
Fragile X syndrome results from a
mutation in the FMR1 gene, which
maps to Xq27.3
 The typical physical phenotype : a
long face with a large mandible,
large everted ears, and large
testicles (macroorchidism).
Fragile X Tremor/Ataxia
• Carrier females  mild cognitive
impairmen, premature ovarian failure
(< 40 years)
• Premutation-carrying males 
progressive neurodegenerative
syndrome (>60) .
• Tremors
• Cerebellar ataxia, may progress to
parkinsonism.
 Mutations in
Mitochondrial Genes
• The mitochondrial DNA  derived
entirely from the ovum  only mothers
transmit mitochondrial genes to their
offspring, both male and female.
• Mitochondrial DNA  encodes enzymes
involved in oxidative phosphorylation 
affect organs most dependent on
oxidative phosphorylation (CNS,
skeletal muscle, cardiac muscle, liver,
and kidney).
 Alterations of Imprinted
Regions
• All humans inherit two copies of each
gene (except, of course, the sex
chromosome genes in males),
carried on homologous maternal and
paternal chromosomes.
• Loss of the functional allele (not
imprinted) by deletions gives rise to
diseases.
• Prader-Willi syndrome
results from deletion of
paternal chromosomal region
15q12 and is characterized by
mental retardation, short
stature, hypotonia, obesity,
and hypogonadism.
• Angelman syndrome
results from deletion of
maternal chromosomal region
15q12 and is characterized by
mental retardation, ataxia,
seizures, and inappropriate
laughter.
A 4-year-old girl has sudden onset of right hip pain. On
examination, the child’s right hip is dislocated. The child
can bend her thumb backward to touch the forearm. Her
skin is noted to be extraordinarily stretchable.
Radiographs of her spine show marked lateral and
anterior curvature. She develops retinal detachments
later in childhood. A sibling is similarly affected. A
mutation in tenascin-X is identified. Which of the
following is the most likely cause for this child’s findings?

A Congenital syphilis
B Deficient collagen synthesis
C Diet lacking in vitamin D
D Multiple congenital anomalies
E Trauma from battering
B .The joints are frequently involved in most variants of
Ehlers-Danlos syndrome (EDS), and tensile strength is
reduced so that skin is hyperextensible, and joints are
hypermobile. Deficiency of the enzyme lysyl hydroxylase can
lead to defects in types I and III collagen and is inherited as
an autosomal recessive disorder. Kyphoscoliosis and ocular
problems also are present in this type of EDS. When EDS-like
features are present, but no collagen gene mutations
identified, then abnormal tenascin-X, a large multimeric
protein of extracellular matrix that affects synthesis and fibril
formation of type VI and type I collagens may be present.
Congenital syphilis can produce abnormalities of bone, such as
saber shin from periosteitis and perichondritis, but does not
affect the skin. Vitamin D deficiency in childhood producing
rickets is accompanied by bowing deformities of long bones,
but not skin abnormalities. The pattern of findings here
suggests a structural gene defect leading to development of
abnormalities, and not congenital anomalies without a specific
cause. Battered children typically have multiple contusions
and fractures, but the skin and bone structure are normal.
Mental retardation has affected several
generations of a family, and most of the affected
individuals have been males. The severity of
mental retardation has increased with each
passing generation. Genetic testing is performed,
and about 20% of the males who have the
genetic abnormality are unaffected. Which of the
following mechanisms is most likely to produce
this genetic condition?

A Frameshift mutation
B Missense mutation
C Mitochondrial DNA mutation
D Point mutation
E Trinucleotide repeat mutation
E . Fragile X syndrome is a condition in which there are 250
to 4000 tandem repeats of the trinucleotide sequence CGG.
Generally, as the number of trinucleotide repeats increases,
the manifestations of the associated conditions worsen or
have an earlier onset. The trinucleotide mutations are
dynamic; because their number increases during oogenesis,
subsequent male offspring have more severe disease
compared with earlier generations. With a frameshift
mutation, one, two, or three nucleotide base pairs are inserted
or deleted. As a result, the protein transcribed is abnormal. A
missense mutation results from a single nucleotide base
substitution, and it leads to elaboration of an abnormal
protein. Abnormalities of mitochondrial DNA, typically
involving genes associated with oxidative phosphorylation, are
transmitted on the maternal side. A point mutation of a single
base pair may affect a single protein.