Genetic disorders Dr.K.V.Bharathi. Normal karyotype Study of chromosomes karyotyping A karyotype is...
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Transcript of Genetic disorders Dr.K.V.Bharathi. Normal karyotype Study of chromosomes karyotyping A karyotype is...
![Page 1: Genetic disorders Dr.K.V.Bharathi. Normal karyotype Study of chromosomes karyotyping A karyotype is the standard arrangement of a photographed, stained.](https://reader033.fdocuments.us/reader033/viewer/2022061305/55140a42550346dd488b4d42/html5/thumbnails/1.jpg)
Genetic disorders
Dr.K.V.Bharathi
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Normal karyotype
• Study of chromosomeskaryotyping
• A karyotype is the standard arrangement of a photographed, stained chromosomes pairs which are arranged in order of decreasing length
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When chromosomes are preparing to divide, the DNA When chromosomes are preparing to divide, the DNA replicates itself into two strands called chromatidsreplicates itself into two strands called chromatids
Replicating chromosome The same chromosome under normal conditions
Centromere
Telomere
Telomere
The two chromatids
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Chromosome nomenclature
• Two arms– p (petite) small and q (follows p in alphabet)
• 1-22 = autosome numbers
• X, Y = sex chromosomes
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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)
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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).
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What is the difference between an What is the difference between an Autosome and a Sex-chromosome?Autosome and a Sex-chromosome?
AutosomesAutosomes are the first 22 are the first 22 homologous pairs of human homologous pairs of human chromosomes that do not chromosomes that do not influence the sex of an influence the sex of an individual.individual.
Sex ChromosomesSex Chromosomes are the 23 are the 23rdrd pair of chromosomes that pair of chromosomes that determine the sex of an determine the sex of an individual.individual.
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• Sperm determines genotypic sex by contributing either an X or a Y chromosome during fertilization.
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46,XX = female46,XX = female 46,XY = male46,XY = male
Giemsa banding (G-banding)
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Three classes of chromosome
• Metacentric - centromere in middle
• Submetacentric - centromere distant from middle
• Acrocentric - centromere at end
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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..).
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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)
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• 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))
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Aneuploidy results from the failure of chromosomes to separate normally during cell division:
Meiotic Nondisjunction
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NORMAL SEPARATION
NORMAL ZYGOTE
First meiotic division
Second meiotic division
Gametes
Fertilization
Zygotes
4N
2N
N
2N
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NONDISJUNCTION
TRISOMIC ZYGOTE MONOSOMIC ZYGOTE
First meiotic division
Second meiotic division
Gametes
Fertilization
Zygotes
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• Aneuploidy usually results from non-disjunction
• 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
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Structural abnormalities of chromosomes
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Six main types
• Deletion• Ring chromosome• Duplication• Isochromosome• Inversion
– paracentric & pericentric
• Translocation– Robertsonian & reciprocal
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• 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
Deletion
Beforedeletion
Afterdeletion
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Two types of deletion
Interstitial Terminal
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Ring chromosomeBreaks 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).
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Epilepsy, mental retardation and craniofacial abnormalities
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IsochromosomeIsochromosomeMirror image chromosome
Loss of one arm with duplication of other
Loss of p-arm Duplication of q-arm
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InversionTwo breaks in one chromosome
The fragment generated rotates 180o and reinserts into the chromosome
Pericentric - involves p and q armPericentric - involves p and q arm Paracentric - involves only one armParacentric - involves only one arm
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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
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Reciprocal Translocation• Involves two chromosomes • One break in each chromosome• The two chromosomes exchange broken segments
Before translocation After translocation
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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
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Homologous acrocentric, i.e. chromosome 14
+ =
lost
Non-homologous acrocentric, i.e. chromosomes 14 & 21
+ =
lost
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A balanced chromosome 14 & 21 A balanced chromosome 14 & 21 Robertsonian translocationRobertsonian translocation
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Mutations
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What is mutation?
• A mutation may be defined as a permanent change in the DNA.
• These structural DNA changes affect protein expression & function.
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Mutations affect protein synthesis
Transcription: Mutated DNA will produce faulty mRNA leading to the production of a faulty protein.
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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 .
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• 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.
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Mutagens are agents that cause mutations. They include:1. High Temperatures 2. Toxic Chemicals (pesticides, etc)3. Radiation (nuclear and solar)
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Types of mutationsChromosomal mutation: affecting whole or a part of a chromosome
Gene mutation: changes to the bases in the DNA of one gene
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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).
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Gene Mutations: DNA base alterations
Point mutation- eg:sickle cell anemiaInsertionDeletionInversionFrame Shifts
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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
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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!
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Classification of genetic disorders
1.Gross chromosomal abnormalities 2.Diseases with multifactorial inheritance
3.Disorders related to mutant genes of large effect
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Cytogenetic disorders involving autosomes
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Common types of trisomy
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• Trisomy 21 - Down's Syndrome- karyotype 47, XX +21 or 47, XY+21- frequency about 1 in 600 births
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• Trisomy 18 - Edward's Syndrome- karyotype 47, XX +18 or 47, XY+18- frequency about 1 in 8,000births
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• Trisomy 13 - Patau's Syndrome- karyotype 47, XX +13 or 47, XY+13- frequency about 1 in 10,000 births
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• Sex chromosome trisomies- 47, XXY (Klinefelter Syndrome), 47,XXX,
47,XYY
• Triploidies of other chromosomes– Rare– usually incompatible with life
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• - Polysomy X e.g. XXXX– - Frequency about 1 in 1000
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Trisomy 21(Down’s syndrome)
The most common malformation Incidence: 1 per 660 live births, closely
related to maternal ageMother’s age<30 year risk:1 per 5000Mother’s age>35 year risk:1 per 250
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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 agingall patints older than 40 will
have Alzheimer disease(degenerative disorder of brain)
• Musculoskeletal problems
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Normal karyotypeTrisomy 21
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Trisomy 18(Edwards syndrome)
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Trisomy 18
• Incidence :1 in 8000 births
• Karyotypes:– 47,xx+18– 46,xx/47,xx+18
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Micrognathia and prominent occiput
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Trisomy 13(Patau syndrome)
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Trisomy 13
• Incidence :1 in 15,0000• Karyotypes:
– Trisomy13 type:47xx+13
– Translocation type:46,xx,+13,der(13;14)(q10;q10)
– Mosaic type:46,xx/47,xx,+13
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Cleft lip
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Cleft palate
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Rockerbottom feet
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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
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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
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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
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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
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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
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Klinefelter syndromeKlinefelter syndrome
• Lower IQ than sibsLower IQ than sibs
• Tall statureTall stature
• Poor muscle tonePoor muscle tone
• Reduced secondaryReduced secondarysexual characteristicssexual characteristics
• Gynaecomastia Gynaecomastia (male breasts)(male breasts)
• Small testes/infertilitySmall testes/infertility
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• Plasma gonadotropin levels( FSH) and estrodiol is elevated
• Testosterone levels are decreased
• Testicular tubules are totally atrophied
• Some shows primitive tubules
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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
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• 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)
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Transmisson patterns of single gene disorders
• Autosomal dominant
• Autosomal recessive
• X-linked
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Autosomal TraitsAutosomal Traits Genes located on Autosomes control Genes located on Autosomes control
Autosomal traits and disorders.Autosomal traits and disorders.
2 Types of Traits:2 Types of Traits: Autosomal DominantAutosomal Dominant Autosomal RecessiveAutosomal Recessive
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Autosomal Dominant TraitsAutosomal Dominant Traits
If dominant allele is present on the autosome, then the If dominant allele is present on the autosome, then the individual will express the trait.individual will express the trait.
A = dominant a = recessiveA = dominant a = recessive
What would be the genotype of an individual with an What would be the genotype of an individual with an autosomal dominant trait?autosomal dominant trait?– AA and Aa (Heterozygotes are affected)AA and Aa (Heterozygotes are affected)
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Autosomal Dominant InheritanceAutosomal Dominant Inheritance Are manifested in heterozygous stateAre manifested in heterozygous state One parent of an index case is usually affectedOne parent of an index case is usually affected Both males and females are affected and both can transmit Both males and females are affected and both can transmit
the conditionthe condition 50% chance of affected heterozygote passing gene to 50% chance of affected heterozygote passing gene to
childrenchildren A new mutation in the gene resulting in the offspring being A new mutation in the gene resulting in the offspring being
first affected and then may be inherited in a dominant first affected and then may be inherited in a dominant fashion fashion
Dominant genes may exhibit lack of penetrance, which is Dominant genes may exhibit lack of penetrance, which is an all or none phenomenon; either the gene is expressed or an all or none phenomenon; either the gene is expressed or not expressednot expressed
May show variable expressivity with different family May show variable expressivity with different family members showing different manifestations of the traitmembers showing different manifestations of the trait
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Autosomal Dominant InheritanceAutosomal Dominant Inheritance
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System Disorder
Nervous •Huntington disease.•Neurofibromatosis.•Myotonic dystrophy.•Tuberous sclerosis.
Urinary •Polycystic
kidney disease
G.I.T •Familial polyposis coli
Hematopoietic •Hereditary spherocytosis•Von Willebrand disease
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Skeletal •Marfan syndrome,
•Osteogenesis imperfecta,
•Achondroplasia
Metabolic •Familial hypercholesterolemia,
•Acute intermittent porphyria
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Autosomal Recessive TraitsAutosomal Recessive Traits
If dominant allele is present on the autosome, then the If dominant allele is present on the autosome, then the individual will not express the trait. individual will not express the trait.
In order to express the trait, two recessive alleles In order to express the trait, two recessive alleles
must be present.must be present.
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• A = dominant a = recessiveA = dominant a = recessive
• What would be the genotype of an individual What would be the genotype of an individual with an autosomal recessive trait?with an autosomal recessive trait?– aaaa
• What would be the genotype of an individual What would be the genotype of an individual without the autosomal recessive trait?without the autosomal recessive trait?– AA or Aa AA or Aa – Aa – called a Aa – called a CarrierCarrier because they carry the because they carry the
recessive allele and can pass it on to offspring, recessive allele and can pass it on to offspring, but they do not express the trait.but they do not express the trait.
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Autosomal Recessive TraitsAutosomal Recessive Traits Heterozygotes are Carriers with a normal phenotype.Heterozygotes are Carriers with a normal phenotype. Most affected children have normal parents. (Aa x Aa)Most affected children have normal parents. (Aa x Aa) Two affected parents will always produce an affected child. Two affected parents will always produce an affected child.
(aa x aa)(aa x aa) Close relatives who reproduce are more likely to have affected Close relatives who reproduce are more likely to have affected
children.children. Both males and females are affected with equal frequency.Both males and females are affected with equal frequency. Pedigrees show Pedigrees show bothboth male and female carriers. male and female carriers. Complete penetrance is commonComplete penetrance is common Onset is early in lifeOnset is early in life
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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.
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X-Linked InheritanceX-Linked Inheritance
Involves particular genes located on the X Involves particular genes located on the X chromosomechromosome
Disorders more commonly affect malesDisorders more commonly affect males Heterozygote female will pass the gene to 50% of Heterozygote female will pass the gene to 50% of
her sons who will express the trait, and to 50% of her sons who will express the trait, and to 50% of her daughters who will be carriers for the traither daughters who will be carriers for the trait
Affected males pass the gene to all of their Affected males pass the gene to all of their daughters and none of their sonsdaughters and none of their sons
Hallmark is absence of male to male transmissionHallmark is absence of male to male transmission
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X-Linked InheritanceX-Linked Inheritance
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System Disease
Musculoskeletal Duchenne muscular dystrophy
Blood Hemophilia A and B,Chronic granulomatous disease, glucose -6-phophate dehyderogenase deficiency
Immune Agammaglobulinemia,Wiskott-aldrich syndrome
Metabolic Diabetes insipidus, Lesch-Nyhan syndrome
Nervous Fragile-X syndrome
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Single gene disorders
1.With classical (Mendelian) inheritance2.With non-classical inheritance •Mitochondrial genes •Trinucleotide repeats •Genetic imprinting
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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)
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Marfan syndrome (defect in the structural proteins)
• Is a disorder of connective tissues, manifested by changes in skeleton,eyes and cardiovascular system
• Autosomal dominant
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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.
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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
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• 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
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Marfan Syndrome
Subluxation of the lens
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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
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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 macromoleculescell organelles become largelysosomal storage disease
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Tay-Sachs disease (Gm2 gangliosidosis: Hexosaminidase α-subunit deficiency)
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Cause of Tay-Sachs
Hex-A Accumulation of GM2 in neuronsAbsence of
Involvement of CNS, ANS and retina common
The absence of a vital enzyme called Hexosamindase A (Hex-A)
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Gene Location
• Chromosome 15 showing location of the syndrome
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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
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• Microscopy: neurons are ballooned with cytoplasmic vacuoles having lysosomes filled with gangliosides
• EM: Whorled configuration with lysosomes composed of “onion skin” layer of membranes
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Ballooned out neuron
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Detection Methods:
• Amniocentesis
• Chorionic villus sampling
• Blood samples to detect carriers
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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.
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Niemann –pick disease (type A and B)
• Deficiency of sphingomyelinase accumulation of sphingomyelin
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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
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Type B
• Patients have organomegaly but no CNS involvement
• Survive to adulthood.
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Morphology
• Accumulation of sphingomyelin in mononuclear phagocytes
• Affected cell become large
• Innumerable small vacuoles of uniform sizeimparting foaminess to the cytoplasm
• Vacuoles stain for fat
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• 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
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• Clinical Features: Evident by 6 monthsProtuberant abdomenFailure to thrive, vomiting,fever,Deterioration of psychomotor functionDeath by 2 yrs
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Gaucher disease
• Autosomal recessive
• Mutation in the gene encoding glucocerebrosidase
• Most common
• Glucocerebroside accumulates in phagocytic cells
• 3 types
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Type I: Chronic non-neuronopathic formStorage 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
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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.
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Gaucher cells (Phagocytic cells with a “crumpled tissue paper” appearance)
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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
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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
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Clinical features
• Failure to thrive
• Vomiting, diarrhea
• Hepatomegaly
• Opacification of lens (cataracts)
• Aminoaciduria
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• 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
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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
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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 bonedegenerative arthropathy
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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.
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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
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• 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
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Emphasize on:
1. Down’s syndrome
2. Turner’s syndrome
3. Klinefelter syndrome
4. Marfan syndrome
5. Gaucher’s disease
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Thank you