Transcript Genetic disorders - Welcome to nky.wikidot.com

Genetic disorders
Dr.K.V.Bharathi
Normal karyotype
• Study of chromosomeskaryotyping
• A karyotype is the standard arrangement
of a photographed, stained chromosomes
pairs which are arranged in order of
decreasing length
When chromosomes are preparing to divide, the DNA
replicates itself into two strands called chromatids
Replicating chromosome
Telomere
Centromere
The two
chromatids
Telomere
The same chromosome
under normal conditions
Chromosome nomenclature
• Two arms
– p (petite) small and q (follows p in alphabet)
• 1-22 = autosome numbers
• X, Y = sex chromosomes
Cytogenetic terminology
• Short arm p and long arm q
• Each Chromosome is divided into 2 or
more regions
• Each region is subdivided into bands
and sub-bands
• Total no of chromosomes is given first
followed by sex chromosome and finally
description of abnormality in ascending
order.eg:47,XY,+21 ,and Xp 21.2
• 46,XY,del(16)(p11.2 p13.1)
The normal human karyotype
• Somatic cells: 22 pairs of autososmes &
1 pair of sex chromosomes (46,XX or
46,XY).
• The normal karyotype is diploid (2 copies
of each chromosome).
• Sperm & eggs carry 23 chromosomes &
are haploid (one copy of each
chromosome).
What is the difference between an
Autosome and a Sex-chromosome?

Autosomes are the first 22
homologous pairs of human
chromosomes that do not
influence the sex of an
individual.

Sex Chromosomes are the 23rd
pair of chromosomes that
determine the sex of an
individual.
• Sperm determines genotypic sex by
contributing either an X or a Y
chromosome during fertilization.
46,XX = female
46,XY = male
Giemsa banding (G-banding)
Three classes of chromosome
• Metacentric centromere in middle
• Submetacentric centromere distant
from middle
• Acrocentric centromere at end
Uses of karyotype analysis:
1. Genotypic sex ( identification of X & Y
chromosomes).
2. Ploidy ( euploid, aneuploid or polyploid).
3. Chromosomal structural defects
(translocation, isochromosome, deletion
etc..).
Some definitions
• Haploid (n)- refers to a single set of
chromosomes (23 in humans).Sperm &
eggs are haploid.
• Diploid (2n)- refers to a double set of
chromosomes (46 in humans). Somatic
cells are diploid.
• Euploid- refers to any multiple of the
haploid set of chromosomes (from n-8n)
• Polyploid- refers to any multiple of the
haploid set of chromosomes> diploid (2n).
• Aneuploid- refers to karyotypes that do not
have multiples of the haploid set of
chromosomes.
• Monosomy- refers to an aneuploid
karyotype with one missing chromosome
(XO in Turner’s syndrome).
• Trisomy- refers to an aneuploid karyotype
with one extra chromosome (trisomy 21 in
Down’s syndrome))
Aneuploidy results from the failure
of chromosomes to separate
normally during cell division:
Meiotic Nondisjunction
4N
First meiotic
division
NORMAL SEPARATION
2N
Second meiotic
division
Gametes
N
Fertilization
Zygotes
2N
NORMAL ZYGOTE
First meiotic
division
NONDISJUNCTION
Second meiotic
division
Gametes
Fertilization
Zygotes
TRISOMIC ZYGOTE
MONOSOMIC ZYGOTE
• Aneuploidy usually results from nondisjunction
• Chromosomes or chromatids fails to
separate
• An error of mitotic or meiotic spindle
attachment to centromere
• May occur in either the maternal or the
paternal germ cells
• More commonly arises in the mother
• Frequency of non-disjunction increases
with maternal age
Structural abnormalities of
chromosomes
Six main types
•
•
•
•
•
Deletion
Ring chromosome
Duplication
Isochromosome
Inversion
– paracentric & pericentric
• Translocation
– Robertsonian & reciprocal
Deletion
• Involves loss of part of a
chromosome
• Results in monosomy of
that chromosomal
segment
• Clinical effects due to
– Insufficient gene products
– Unmasking of mutant
alleles on normal
chromosome
Before
deletion
After
deletion
Two types of deletion
Terminal
Interstitial
Ring chromosome
Breaks occur in both arms of a chromosome.
The two broken ends anneal; the two acentric fragments
are lost.
Results in double deletion (in p and in q).
Epilepsy, mental retardation and craniofacial abnormalities
Isochromosome
Mirror image chromosome
Loss of one arm with duplication of other
Loss of p-arm
Duplication of q-arm
Inversion
Two breaks in one chromosome
The fragment generated rotates 180o and reinserts
into the chromosome
Pericentric - involves p and q arm
Paracentric - involves only one arm
Translocation - exchange of
chromosomal material between two or more
chromosomes
• Reciprocal
• Robertsonian
• If no essential chromosome material lost
or genes damaged then the individual is
clinically normal
• However, there is an increased chance of
chromosomally unbalanced offspring
Reciprocal Translocation
•
•
•
Involves two chromosomes
One break in each chromosome
The two chromosomes exchange broken segments
Before translocation
After translocation
Robertsonian translocation
• Named after W. R. B. Robertson who first
identified them in grasshoppers in 1916
• Most common structural chromosome
abnormality in humans
– Frequency = 1/1000 livebirths
• Involves two acrocentric chromosomes
• Two types
– Homologous acrocentrics involved
– Non-Homologous acrocentrics involved
Homologous acrocentric, i.e. chromosome 14
lost
+
=
Non-homologous acrocentric, i.e. chromosomes 14 & 21
lost
+
=
A balanced chromosome 14 & 21
Robertsonian translocation
Mutations
What is mutation?
• A mutation may be defined as a
permanent change in the DNA.
• These structural DNA changes affect
protein expression & function.
Mutations affect protein synthesis
Transcription:
Mutated DNA will
produce faulty
mRNA leading to
the production of a
faulty protein.
Somatic & Germ cell mutations
Mutations that occur in somatic cells
such as skin cells or hair are termed
Somatic.
Germline mutations occur only in the
gametes. These mutations are more
threatening because they can be passed
to offspring .
• Germline mutations can be transmitted to
future generations.
• Those that occur in somatic cells may
contribute to the pathogenesis of
neoplasia.
• Drugs, chemical & physical agents that
increase the rate of mutation act as
carcinogens.
Mutagens are agents that cause
mutations. They include:
1. High Temperatures
2. Toxic Chemicals (pesticides, etc)
3. Radiation (nuclear and solar)
Types of mutations
Chromosomal mutation:
affecting whole or a part
of a chromosome
Gene mutation: changes
to the bases in the DNA of
one gene
Major types of genetic mutations
1. Point mutations: Single base substitutions .
2. Frameshift mutations: base pair insertions or
deletions that change the codon reading frame.
3. Large deletions: can result in loss of gene or
juxtapose genes to create a hybrid that encodes
a new “fusion” protein.
4. Expansion of trinucleotide repeats: can arise
in genes that have repeated sequences.
Affected patients can have 100s or 1000s of
repeats (normal:10-30).
Gene Mutations: DNA base
alterations
Point mutation- eg:sickle cell anemia
Insertion
Deletion
Inversion
Frame Shifts
Point mutation - when a base is
replaced with a different base.
CGG CCC AAT to CGG CGC AAT
Guanine for Cytosine
Insertion - when a base is added
CGG CCC AAT to CGG CGC CAA T
Guanine is added
Deletion - the loss of a base
CGG CCC AAT to CGG CCA A T
loss of Cytosine
Frame Shift mutations
• A frame shift mutation results from a base
deletion or insertion. Each of these
changes the triplets that follow the
mutation.
CGG CCC AAT to CGG CGC CAA T
• Frame shift mutations have greater
effects than a point mutation because
they involve more triplets.
• This in turn changes the amino acids of the
protein!
Classification of genetic disorders
1.Gross chromosomal abnormalities
2.Diseases with multifactorial inheritance
3.Disorders related to mutant genes of large
effect
Cytogenetic disorders involving
autosomes
Common types of trisomy
• Trisomy 21 - Down's Syndrome
- karyotype 47, XX +21 or 47, XY+21
- frequency about 1 in 600 births
• Trisomy 18 - Edward's Syndrome
- karyotype 47, XX +18 or 47, XY+18
- frequency about 1 in 8,000births
• Trisomy 13 - Patau's Syndrome
- karyotype 47, XX +13 or 47, XY+13
- frequency about 1 in 10,000 births
• Sex chromosome trisomies
- 47, XXY (Klinefelter Syndrome), 47,XXX,
47,XYY
• Triploidies of other chromosomes
– Rare
– usually incompatible with life
• - Polysomy X e.g. XXXX
– - Frequency about 1 in 1000
Trisomy 21(Down’s syndrome)
 The
most common malformation
 Incidence: 1 per 660 live births, closely
related to maternal age
 Mother’s age<30 year risk:1 per 5000
 Mother’s age>35 year risk:1 per 250
Clinical findings
•
•
•
•
•
•
•
Flattened face
Mental retardation
Congenital heart disease:50%endocardial
cushion,ASD,AV malformation,VSD
10 to 20 fold increased risk of developing
leukemia
Infection are common
Premature agingall patints older than 40 will
have Alzheimer disease(degenerative disorder
of brain)
Musculoskeletal problems
Trisomy 21
Normal karyotype
Trisomy 18(Edwards syndrome)
Trisomy 18
• Incidence :1 in
8000 births
• Karyotypes:
– 47,xx+18
– 46,xx/47,xx+18
Micrognathia and prominent occiput
Trisomy 13(Patau syndrome)
Trisomy 13
• Incidence :1 in
15,0000
• Karyotypes:
– Trisomy13
type:47xx+13
– Translocation
type:46,xx,+13,der(13;1
4)(q10;q10)
– Mosaic
type:46,xx/47,xx,+13
Cleft lip
Cleft palate
Rockerbottom feet
Cytogenetic diorders involving sex
chromosomes
• They cause chronic problems relating to
sexual development and fertility
• They are often difficult to diagnose at
birth,and many are recognised at the time
of puberty
• Higher the number of x chromosomes,
greater the likelihood of mental retardation
Lyon hypothesis
:
• In somatic cells of a female
only one of the X
chromosomes is active
• X-inactivation
– Occurs early in embryonic life
– Is random
• either paternal or maternal X
– Is complete
– Is permanent
– Is clonally propagated through
mitosis
Mary Lyon
Y chromosome
• Regardless of the number of X
chromosomes, the presence of single Y
determines male sex
• The gene that indicates testicular
development is sry gene (sex determining
region Y gene)
• Located on distal arm of Y chromosome
Turner syndrome
• Partial monosomy of X chromosome
• Hypogonadism in phenotypic females
• Karyotype:45,X
Mosaic patients with 45,X /46,XX
• Cystic hygromas, Congenital heart disease
(coarctation of aorta and bicuspid aortic valve),
failure to develop secondary sexual
characterstics
• Mental status is usually normal
Klinefelter syndrome
• 47,XXY
• Results from meiotic nondisjunction
• The discovery of the karyotype of
Klinefelter was the first demonstration
that sex in humans is determined by
the presence of the Y rather than the
number of X chromosomes
• Male hypogonadism
Klinefelter syndrome
• Lower IQ than sibs
• Tall stature
• Poor muscle tone
• Reduced secondary
sexual characteristics
• Gynaecomastia
(male breasts)
• Small testes/infertility
• Plasma gonadotropin levels( FSH) and
estrodiol is elevated
• Testosterone levels are decreased
• Testicular tubules are totally atrophied
• Some shows primitive tubules
Hermaphroditism
• Genetic sex is determined by the presence or
absence of Y chromosome
• Gonadal sex is based on histological
characteristics of gonads
• Phenotypic sex is based on the appearance of
external genitalia
• True hermaphrodite implies the presence of
both ovarian and testicular tissue
• Pseudohermaphrodite represents disagreement
between the phenotypic and gonadal sex
(eg:female pseudohermophrodite has ovaries
but male external genitalia)
Transmisson patterns of single gene
disorders
• Autosomal dominant
• Autosomal recessive
• X-linked
Autosomal Traits

Genes located on Autosomes control
Autosomal traits and disorders.
2 Types of Traits:
 Autosomal Dominant
 Autosomal Recessive
Autosomal Dominant Traits

If dominant allele is present on the autosome, then the
individual will express the trait.

A = dominant a = recessive

What would be the genotype of an individual with an
autosomal dominant trait?
– AA and Aa (Heterozygotes are affected)
Autosomal Dominant Inheritance







Are manifested in heterozygous state
One parent of an index case is usually affected
Both males and females are affected and both can transmit
the condition
50% chance of affected heterozygote passing gene to
children
A new mutation in the gene resulting in the offspring being
first affected and then may be inherited in a dominant
fashion
Dominant genes may exhibit lack of penetrance, which is
an all or none phenomenon; either the gene is expressed or
not expressed
May show variable expressivity with different family
members showing different manifestations of the trait
Autosomal Dominant Inheritance
System
Nervous
Disorder
•Huntington disease.
•Neurofibromatosis.
•Myotonic dystrophy.
•Tuberous sclerosis.
Urinary
•Polycystic
kidney disease
•Familial polyposis coli
•Hereditary
spherocytosis
•Von Willebrand disease
G.I.T
Hematopoietic
Skeletal
•Marfan syndrome,
•Osteogenesis
imperfecta,
•Achondroplasia
Metabolic
•Familial
hypercholesterolemia,
•Acute intermittent
porphyria
Autosomal Recessive Traits

If dominant allele is present on the autosome, then the
individual will not express the trait.

In order to express the trait, two recessive alleles
must be present.
• A = dominant a = recessive
• What would be the genotype of an individual
with an autosomal recessive trait?
– aa
• What would be the genotype of an individual
without the autosomal recessive trait?
– AA or Aa
– Aa – called a Carrier because they carry the
recessive allele and can pass it on to offspring,
but they do not express the trait.
Autosomal Recessive Traits








Heterozygotes are Carriers with a normal phenotype.
Most affected children have normal parents. (Aa x Aa)
Two affected parents will always produce an affected child.
(aa x aa)
Close relatives who reproduce are more likely to have affected
children.
Both males and females are affected with equal frequency.
Pedigrees show both male and female carriers.
Complete penetrance is common
Onset is early in life
System
Disorder
Metabolic
•Cystic fibrosis,
•Phenylketonurua,
•Galactosemia,
•Homocystinuria,
•Lysosomal storage diseases,
•Α1-antitrypsion deficiency,
•Wilson disease,
•Hemochromatosis,
•Glycogen stroage diorders
Hematopoietic
Sickle cell anaemia,
Thalassemia.
Endocrine
Congenital adrenal hyperplasia
Skeletal
Alkaptonuria
Nervous
Neurogenic muscular atrophies,Friedreich ataxia,
Spinal muscular atrophy.
X-Linked Inheritance





Involves particular genes located on the X
chromosome
Disorders more commonly affect males
Heterozygote female will pass the gene to 50% of
her sons who will express the trait, and to 50% of
her daughters who will be carriers for the trait
Affected males pass the gene to all of their
daughters and none of their sons
Hallmark is absence of male to male transmission
X-Linked Inheritance
System
Disease
Musculoskeletal Duchenne muscular dystrophy
Blood
Immune
Metabolic
Nervous
Hemophilia A and B,Chronic
granulomatous disease, glucose -6phophate dehyderogenase
deficiency
Agammaglobulinemia,Wiskottaldrich syndrome
Diabetes insipidus, Lesch-Nyhan
syndrome
Fragile-X syndrome
Single gene disorders
1.With classical (Mendelian) inheritance
2.With non-classical inheritance
•Mitochondrial genes
•Trinucleotide repeats
•Genetic imprinting
Single-Gene “Mendelian” Disorders
1. Structural proteins
– –Osteogenesis imperfecta and Ehlers-Danlos(collagens);
– Marfan syndrome (fibrillin);
– Duchenne and Becker muscular dystrophies (dystrophin)
2. Enzymes and inhibitors
– Lysosomalstorage diseases;
– PKU (phenylalanine hydroxylase);
– Alpha-1 antitrypsin deficiency
3. Receptors
– Familial hypercholesterolemia (LDL receptor)
4. Cell growth regulation
– Neurofibromatosis type I (neurofibromin);
– Hereditary retinoblastoma (Rb)
5. Transporters
– Cystic fibrosis (CFTR);
– Sickle cell disease (Hb);
– Thalassemias(Hb)
Marfan syndrome (defect in the
structural proteins)
• Is a disorder of connective tissues, manifested
by changes in skeleton,eyes and cardiovascular
system
• Autosomal dominant
Pathogenesis
• Marfan syndrome results from inherited defect in
extracellular glycoprotein –fibrillin-1
• Fibrillin is the major component microfibrils
• These fibrils form a basement on which
tropoelastin is deposited to form elastic fibers
• Microfibrils are abundant in aorta, ligaments,and
ciliary zonules of lens
• Mutations of FBN1 are mapped on the
chromosome 15q21.
Morphology
•
Cardiovascular System: Dilatation of
ascending aorta due to cystic medial
necrosis, mitral vale insufficiency,aortic
dissection
•
Eyes: Dislocation of lens (usually
outward and upward) called as ectopia
lentis, severe myopia
•
Musculoskeletal: exceptionally tall with long
extremities and tapering fingers and toes
–
The ratio of upper segment to the lower segment of
the body is lower than normal
– Joint ligaments of hands and feet are lax;typically
thumb can be hyperextended back to the wrist
– The head is dolicocephlic(long headed) with bossing
of frontal eminences
– Pectus excavatum deformity, scoliosis
Marfan Syndrome
Subluxation of the lens
Ehlers-Danlos Syndrome
• A family of disorders with defect in synthesis and
structure of fibrillar collagen characterized by
hyperextensibility of skin, joint hypermobility, early
bruisability
• Mode of inheritence show all three types of
Mendelian patterns
• Orthopaedic problems: joint instability, joint laxity,
arthralgia and scoliosis
Lysosomal storage
disorders(defects in enzymes)
• Key component of intracellular “digestive”
tract
• Composed of acid hydrolases that catalyse
the breakdown of macromolecules
• Inherited deficiency-catabolism of
macromolecules is incomplete
accumulation of partially degraded
macromoleculescell organelles become
largelysosomal storage disease
Tay-Sachs disease (Gm2 gangliosidosis:
Hexosaminidase α-subunit deficiency)
Cause of Tay-Sachs
The absence of a vital enzyme called
Hexosamindase A (Hex-A)
Absence of
Hex-A
Accumulation of GM2 in neurons
Involvement of CNS, ANS and retina common
Gene Location
• Chromosome 15
showing location of
the syndrome
Characteristics
• Birth: Appear normal
• 6 months: Development slows
• 2 years: Seizures and deteriorating mental functions
• 3 years: Blindness, mentally retardation, paralysis and
non-responsiveness.
• Cherry red spot in the macula
• Common in Jews
• Microscopy: neurons are ballooned with
cytoplasmic vacuoles having lysosomes
filled with gangliosides
• EM: Whorled configuration with lysosomes
composed of “onion skin” layer of
membranes
Ballooned out neuron
Detection Methods:
• Amniocentesis
• Chorionic villus sampling
• Blood samples to detect
carriers
In Summary
• Tay-Sachs is a genetic disorder that causes
Hex-A, an enzyme important to the function of
nerve cells, not to be produced.
• Babies with Tay-Sachs often appear normal at
birth, but develop severe symptoms in the first
few years of life.
• There is genetic counseling as well as support
groups available for carriers of Tay-Sachs or
parents with an affected child.
Niemann –pick disease (type A and B)
• Deficiency of sphingomyelinase
accumulation of sphingomyelin
Type A
• More severe infantile form with extensive
neurological involvement
• Marked visceral accumulation of
sphingomyelin
• Progressive wasting and early death within
3 years
• Cherry red spot in the macula
Type B
• Patients have organomegaly but no CNS
involvement
• Survive to adulthood.
Morphology
• Accumulation of sphingomyelin in
mononuclear phagocytes
• Affected cell become large
• Innumerable small vacuoles of uniform
sizeimparting foaminess to the
cytoplasm
• Vacuoles stain for fat
• Phagocytic foam cells widely distributed in
spleen ,liver, lymph node, bone marrow,
tonsils, g.i.t,lungs
• Brain: Gyri shrunkened,sulci widened with
vacuolation and ballooning of neurons
• EM: zebra bodies
• Clinical Features: Evident by 6 months
Protuberant abdomen
Failure to thrive,
vomiting,
fever,
Deterioration of psychomotor function
Death by 2 yrs
Gaucher disease
• Autosomal recessive
• Mutation in the gene encoding
glucocerebrosidase
• Most common
• Glucocerebroside accumulates in
phagocytic cells
• 3 types
Type I: Chronic non-neuronopathic form
Storage limited to mononuclear phagocytes throughout the
body
Splenic and skeletal involvement common
Type II: acute neuronopathic ,dominated by
CNS involvement,death by 2 years
TypeIII: intermediate between I and II,
progressive CNS involvement
Morphology
• Glucocerebrosides accumulates in
phagocytic cells
• Distended phagocytic cells (Gaucher)cells
found in spleen
liver,BM,LN,TONSILS,thymus and peyer
patches
• Cells have fibrillary pattern instead of
vacuolated (crumpled tissue paper )and
have eccentrically placed nucleus.
Gaucher cells (Phagocytic cells with a
“crumpled tissue paper” appearance)
Phenylketonuria
• Autosomal recessive disorder
• Deficiency of phenylalanine hydroxylase
hyperphenylalaninemia
• Common in scandinavian people
• Normal at birth
• By 6 months severe mental retardation
• Seizures,decreased pigmentation of hair and
skin
• Mental retardation can be avoided by restriction
of phenylalanine intake early in life
Galactosemia
• Autosomal recessive disorder
• Deficiency of galactose -1-phosphate
uridyl transferase
• Galactose -1-phosphate accumulates in
liver, spleen, kidneys, lens of eye, cerebral
corex
• Alternative metabolic pathways activated,
leading to the production of galacitol
Clinical features
•
•
•
•
•
Failure to thrive
Vomiting, diarrhea
Hepatomegaly
Opacification of lens (cataracts)
Aminoaciduria
• Diagnosis can be suspected by
demonstration in the urine of reducing
sugars
• Many morphological changes can be
prevented by early removal of galactose
from diet
Oochronosis (alkaptonuria)
• First human inborn error of metabolism to
be discovered
• Autosomal recessive
• Lack of homogentisic oxidase blocks
metabolism of phenylalanine-tyrosine at
the level of homogentisic acid
• Homogentisic acid accumulates in the
body
• Large amount is excreted,imparting a
black color to the urine if allowed to stand
Morphology
• The retained homogentisic acid selectively
binds to collagen in connective tissues,
tendons ,cartillage imparting blue black
pigmentation
• Most evident in the ears, nose and
cheeks.
• Wear and tear erosion of abnormal
cartilage leads to denudation of
subchondral bonedegenerative
arthropathy
Mucopolysaccharidoses
• Result from genetic deficiency of enzymes
involved in the degradation of
mucopolysaccharides
• Progressive disorder chacterised by involvement
of multiple organs like liver,spleen, heart and
blood vessels
• Most are associated with coarse facial
features,joint stiffness and mental retardation
• The accumulated mucopolysaccharides are
grnerally found in mononuclear phagocytic
cells,endothelial cells,smooth muscle cells and
fibroblsts.
Glycogen storage diseases
• Hereditary deficiency of one of the
enzymes involved in the synthesis and
breakdown of glycogen.
• Hepatic form: an inherited deficiency of
hepatic enzymes involved in glycogen
metabolism leads to storage of glycogen in
liver and also hypoglycemia.eg :deficiency
of glucose-6-phosphatase
• Myopathic form:in muscles glycogen is
mainly used as a source of energy
• If the enzymes that fuel glycolytic pathway
are deficient, glycogen storage occurs in
muscles.
• eg: deficiency of muscle
phosphofructokinase, muscle
phosphorylase
Emphasize on:
1.
2.
3.
4.
5.
Down’s syndrome
Turner’s syndrome
Klinefelter syndrome
Marfan syndrome
Gaucher’s disease
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