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Genetic disorders Dr.K.V.Bharathi.

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Presentation on theme: "Genetic disorders Dr.K.V.Bharathi."— Presentation transcript:

1 Genetic disorders Dr.K.V.Bharathi

2 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

3 When chromosomes are preparing to divide, the DNA
replicates itself into two strands called chromatids Replicating chromosome The same chromosome under normal conditions Telomere Centromere The two chromatids Telomere

4 Chromosome nomenclature
Two arms p (petite) small and q (follows p in alphabet) 1-22 = autosome numbers X, Y = sex chromosomes

5 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,XY,+21 ,and Xp 21.2 46,XY,del(16)(p11.2 p13.1)

6 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).

7 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.

8 Sperm determines genotypic sex by contributing either an X or a Y chromosome during fertilization.

9 46,XX = female 46,XY = male Giemsa banding (G-banding)

10 Three classes of chromosome
Metacentric - centromere in middle Submetacentric - centromere distant from middle Acrocentric - centromere at end

11 Uses of karyotype analysis:
Genotypic sex ( identification of X & Y chromosomes). Ploidy ( euploid, aneuploid or polyploid). Chromosomal structural defects (translocation, isochromosome, deletion etc..).

12 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)

13 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))

14 Aneuploidy results from the failure of chromosomes to separate normally during cell division: Meiotic Nondisjunction

15 4N 2N N 2N NORMAL SEPARATION NORMAL ZYGOTE First meiotic division
Second meiotic division N Gametes Fertilization 2N Zygotes NORMAL ZYGOTE

Second meiotic division Gametes Fertilization Zygotes TRISOMIC ZYGOTE MONOSOMIC ZYGOTE

17 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

18 Structural abnormalities of chromosomes

19 Six main types Deletion Ring chromosome Duplication Isochromosome
Inversion paracentric & pericentric Translocation Robertsonian & reciprocal

20 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

21 Two types of deletion Terminal Interstitial

22 Ring chromosome Breaks occur in both arms of a chromosome
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).

23 Epilepsy, mental retardation and craniofacial abnormalities

24 Isochromosome Mirror image chromosome
Loss of one arm with duplication of other Loss of p-arm Duplication of q-arm

25 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

26 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

27 Reciprocal Translocation
Involves two chromosomes One break in each chromosome The two chromosomes exchange broken segments Before translocation After translocation

28 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

29 + = + = Homologous acrocentric, i.e. chromosome 14
lost + = Non-homologous acrocentric, i.e. chromosomes 14 & 21 lost + =


31 A balanced chromosome 14 & 21 Robertsonian translocation

32 Mutations

33 What is mutation? A mutation may be defined as a permanent change in the DNA. These structural DNA changes affect protein expression & function.

34 Mutations affect protein synthesis
Transcription: Mutated DNA will produce faulty mRNA leading to the production of a faulty protein.

35 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 .

36 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.

37 Mutagens are agents that cause mutations. They include:
1. High Temperatures 2. Toxic Chemicals (pesticides, etc) 3. Radiation (nuclear and solar)

38 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

39 Major types of genetic mutations
Point mutations: Single base substitutions . Frameshift mutations: base pair insertions or deletions that change the codon reading frame. Large deletions: can result in loss of gene or juxtapose genes to create a hybrid that encodes a new “fusion” protein. Expansion of trinucleotide repeats: can arise in genes that have repeated sequences. Affected patients can have 100s or 1000s of repeats (normal:10-30).


41 Gene Mutations: DNA base alterations
Point mutation- eg:sickle cell anemia Insertion Deletion Inversion Frame Shifts

42 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

43 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!

44 Classification of genetic disorders
1.Gross chromosomal abnormalities 2.Diseases with multifactorial inheritance 3.Disorders related to mutant genes of large effect

45 Cytogenetic disorders involving autosomes

46 Common types of trisomy

47 Trisomy 21 - Down's Syndrome
- karyotype 47, XX +21 or 47, XY+21 - frequency about 1 in 600 births

48 Trisomy 18 - Edward's Syndrome
- karyotype 47, XX +18 or 47, XY+18 - frequency about 1 in 8,000births

49 Trisomy 13 - Patau's Syndrome
- karyotype 47, XX +13 or 47, XY+13 - frequency about 1 in 10,000 births

50 Sex chromosome trisomies
- 47, XXY (Klinefelter Syndrome), 47,XXX, 47,XYY Triploidies of other chromosomes Rare usually incompatible with life

51 - Polysomy X e.g. XXXX - Frequency about 1 in 1000

52 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

53 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


55 Trisomy 21 Normal karyotype



58 Trisomy 18(Edwards syndrome)

59 Trisomy 18 Incidence :1 in 8000 births Karyotypes: 47,xx+18


61 Micrognathia and prominent occiput

62 Trisomy 13(Patau syndrome)

63 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

64 Cleft lip

65 Cleft palate

66 Rockerbottom feet

67 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

68 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

69 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

70 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




74 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


76 Klinefelter syndrome Lower IQ than sibs Tall stature Poor muscle tone
Reduced secondary sexual characteristics Gynaecomastia (male breasts) Small testes/infertility

77 Plasma gonadotropin levels( FSH) and estrodiol is elevated
Testosterone levels are decreased Testicular tubules are totally atrophied Some shows primitive tubules

78 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

79 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)

80 Transmisson patterns of single gene disorders
Autosomal dominant Autosomal recessive X-linked

81 Autosomal Traits Genes located on Autosomes control Autosomal traits and disorders. 2 Types of Traits: Autosomal Dominant Autosomal Recessive

82 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)

83 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

84 Autosomal Dominant Inheritance

85 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

86 Skeletal Marfan syndrome, Osteogenesis imperfecta, Achondroplasia Metabolic Familial hypercholesterolemia, Acute intermittent porphyria

87 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.

88 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.

89 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

90 Disorder System Metabolic Hematopoietic Endocrine Skeletal Nervous
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.

91 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

92 X-Linked Inheritance

93 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

94 Single gene disorders 1.With classical (Mendelian) inheritance 2.With non-classical inheritance •Mitochondrial genes •Trinucleotide repeats •Genetic imprinting

95 Single-Gene “Mendelian” Disorders
Structural proteins –Osteogenesis imperfecta and Ehlers-Danlos(collagens); Marfan syndrome (fibrillin); Duchenne and Becker muscular dystrophies (dystrophin) Enzymes and inhibitors Lysosomalstorage diseases; PKU (phenylalanine hydroxylase); Alpha-1 antitrypsin deficiency Receptors Familial hypercholesterolemia (LDL receptor) Cell growth regulation Neurofibromatosis type I (neurofibromin); Hereditary retinoblastoma (Rb) Transporters Cystic fibrosis (CFTR); Sickle cell disease (Hb); Thalassemias(Hb)

96 Marfan syndrome (defect in the structural proteins)
Is a disorder of connective tissues, manifested by changes in skeleton,eyes and cardiovascular system Autosomal dominant

97 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.

98 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

99 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



102 Subluxation of the lens
Marfan Syndrome Subluxation of the lens

103 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




107 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

108 Tay-Sachs disease (Gm2 gangliosidosis: Hexosaminidase α-subunit deficiency)

109 Cause of Tay-Sachs The absence of a vital enzyme called Hexosamindase A (Hex-A) Absence of Accumulation of GM2 in neurons Hex-A This syndrome is named for Warren Tay an ophthalmologist who first described a patient with symptoms and Bernard Sach, a neurologist, who described cellular changes caused by the disease a few years later. Tay-Sachs is caused by the absence of Hexosamindase A (Hex-A). Usually, this enzyme causes a fatty substance called GM2 ganglioside to accumulate in cells, especially in the nerve cells of the brain. However, the absence of Hex-A this does not happen leading several developmental problems. (1,2) Involvement of CNS, ANS and retina common

110 Gene Location Chromosome 15 showing location of the syndrome
The gene that controls the production of Hex-A is found on Chromosome 15. The picture above shows its location. (3)

111 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 At birth, babies affected with Tay-Sachs appear normal. After about six months, their development begins to slow. By two years of age, child are often affected by seizures and have fading mental functions. The syndrome continues to progress until blindness, mental retardation, paralysis and overall non-responsiveness result. Children usually die within the first four years of life. (1,2,7)

112 Microscopy: neurons are ballooned with cytoplasmic vacuoles having lysosomes filled with gangliosides EM: Whorled configuration with lysosomes composed of “onion skin” layer of membranes

113 Ballooned out neuron

114 Detection Methods: Amniocentesis Chorionic villus sampling
Blood samples to detect carriers Amniocentesis: Amniocentesis is done by removing and testing a small quantity of the fluid that surrounds the fetus in the uterus. This procedure is done at approximately the 16th week of pregnancy. Chorionic villus sampling: Choronic villus sampling is performed by the 10th week and usually provides a test answer much sooner than amniocentesis. The cell sample is obtained by withdrawing a small bit of the developing afterbirth. Blood samples to detect carriers: Bloods samples can be collected and tested for carriers by looking at the gene that is responsible for the production of Hex-A on chromosome 15. (7)

115 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.

116 Niemann –pick disease (type A and B)
Deficiency of sphingomyelinase accumulation of sphingomyelin

117 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

118 Type B Patients have organomegaly but no CNS involvement
Survive to adulthood.

119 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

120 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

121 Clinical Features: Evident by 6 months
Protuberant abdomen Failure to thrive, vomiting, fever, Deterioration of psychomotor function Death by 2 yrs

122 Gaucher disease Autosomal recessive
Mutation in the gene encoding glucocerebrosidase Most common Glucocerebroside accumulates in phagocytic cells 3 types

123 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

124 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.

125 Gaucher cells (Phagocytic cells with a “crumpled tissue paper” appearance)



128 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

129 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

130 Clinical features Failure to thrive Vomiting, diarrhea Hepatomegaly
Opacification of lens (cataracts) Aminoaciduria

131 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

132 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

133 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

134 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.

135 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 :deficiency of glucose-6-phosphatase

136 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

137 Emphasize on: Down’s syndrome Turner’s syndrome Klinefelter syndrome
Marfan syndrome Gaucher’s disease

138 Thank you

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