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Genetic disorders Dr.K.V.Bharathi 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 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 agingall 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 macromoleculescell organelles become largelysosomal 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 sizeimparting 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 bonedegenerative 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 Thank you