Genetic Disorders PDF

Genetic Disorders 1 Genetic Basis of Human Diseases Lifetime frequency of genetic disorders is estimated to be 670 per 1000 Human genetic disorders Chromosomal disorders - structural or numerical alteration in the autosomes and sex chromosomes Disorders related to mutations in single...

Genetic Disorders 1 Genetic Basis of Human Diseases Lifetime frequency of genetic disorders is estimated to be 670 per 1000 Human genetic disorders Chromosomal disorders - structural or numerical alteration in the autosomes and sex chromosomes Disorders related to mutations in single genes with large effects - cystic fibrosis, lysosomal storage diseases, etc. Complex multigenic (polygenic) disorders (most common type of human genetic disorders) - atherosclerosis, diabetes mellitus, hypertension and autoimmune diseases 2 Normal Male Karyotype 3 Cytogenetic Disorders Involving Autosomes 4  Different Genetic Chromosomal Mechanisms TRANSLOCATIONS Balanced reciprocal Centric fusion Robertsonian Lost ISOCHROMOSOMES DELETIONS Fragments INVERSIONS RING CHROMOSOMES Paracentric Pericentric Fragments 5 Down Syndrome (Trisomy 21) Karyotype - 47,XX or XY, +21 Most common chromosomal disorder Incidence with increasing maternal age Caused by nondisjunction (95%), robertsonian translocation (4%), and mosaicism (1%) Clinical features: Intellectual disability (mental retardation), flat facial profile, muscle hypotonia, broad short neck, Simian crease and epicanthic folds, congenital heart disease (40%), duodenal atresia, acute lymphoblastic leukemia (ALL) and Alzheimer disease (100%) 6 47 XY, +21 7 8 Atrioventricular Canal 9  Duodenal Atresia: “Double Bubble Sign” 10  Edwards Syndrome (Trisomy 18) Karyotype - 47,XX or XY, +18 Increased with maternal age Caused by nondisjunction Very poor prognosis due to severe congenital malformations Clinical features: Intellectual disability, low set ears and micrognathia, prominent occiput, flexion of fingers and rocker-bottom feet 11 12 “Rocker-bottom feet” 13 Patau Syndrome (Trisomy 13) Karyotype - 47,XX or XY, +13 Increased with maternal age Caused by nondisjunction Very poor prognosis due to severe congenital Intellectual disability, microencephaly and microphthalmia, arrhinencephaly, cleft lip and palate, polydactyly, cardiac dextroposition and interventricular septal defects 14 15 Cri du Chat (cry of cat) Syndrome Karyotype - 46,XX or XY, 5p- Affected infants up to one year of age have the characteristic cry of a cat Clinical features: Severe intellectual disability, congenital heart anomalies (ventricular septal defects), epicanthic folds, and microcephaly and round facies 16 Normal Male Karyotype 17 Disorders of Sex Development (Differentiation) 18  Factors Affecting Sex Presence or absence of a Y chromosome - testicular development and male gender (SRY - Sex-determining region Y gene [testis determining factor]) Gonadal sex Ductal sex Phenotypic or genital sex - appearance of external genitalia 19  Cytogenetic Disorders Involving Sex Chromosomes (Intersex) 20  Klinefelter Syndrome Karyotype - 47,XXY (90% of cases) Most frequent genetic disease involving sex chromosomes and one of the most common causes of hypogonadism in the male (two or more X chromosomes and one or more Y chromosomes) Clinical features: Testicular atrophy and azoospermia, gynecomastia, and female distribution of hair, increased risk for breast cancer, extragonadal germ cell tumors, and autoimmune diseases (e.g., SLE) 21  Turner Syndrome (Gonadal Dysgenesis) Karyotype - 45, X Definition: complete or partial monosomy of the X chromosome and is characterized primarily by hypogonadism in phenotypic female Second X chromosome is necessary for ovarian development Clinical features: Short stature, primary amenorrhea, infertility, webbing of the neck (hygroma), preductal coarctation of aorta, and hydrops fetalis 22  Short stature TURNER SYNDROME Low posterior hairline Webbing of neck Incidence: 1 in 3000 female births Karyotypes: Classic: 45,X Coarctation of Defective aorta second X Broad chest chromosome: 46,X,i(Xq) and widely 46,XXq– spaced nipples 46,XXp– Cubitus valgus 46,X, r(X) Mosaic type: 45,X/46,XX Streak ovaries, infertility, amenorrhea Pigmented nevi Peripheral lymphedema at birth 23 Turner Syndrome 24 Intersex (Hermaphrodism) True hermaphrodite Individual with the presence of both ovarian and testicular tissue (ovitestis) Pseudohermaphrodite Disagreement between gonadal and phenotypic sex Female pseudohermaphrodite Male pseudohermaphrodite 25  Autosomal Recessive Disorders In homozygous individuals, the clinical manifestations tend to be more uniform Complete penetrance is common Age of onset is frequently early in life Enzymes rather than structural proteins are usually affected by the mutation 26 27 Cystic Fibrosis (Mucoviscidosis) CF is the most common lethal genetic disease in whites (CF frequency= 1 in 2500 live births; carrier rate = 1 in 20 in the US) Defect - cystic fibrosis transmembrane conductance regulator (CFTR) 70% of worldwide CF cases involve a deletion of a single amino acid (508) located on chromosome 7q31.2 28 Cystic Fibrosis (Mucoviscidosis) Six Classes of Cystic Fibrosis Mutations (>1800 disease- associated mutations involving the CFTR protein) Class I: Defective protein synthesis Class II: Abnormal protein folding, processing, and trafficking (deletion 3 nucleotides coding for phenylalanine at amino acid 508) Class III:Defective regulation Class IV: Decreased conductance Class V: Reduced abundance Class VI: Altered function in regulation of ion channels 29 Cystic Fibrosis (Mucoviscidosis) Pathology involving epithelial tissues (exocrine glands and eccrine sweat glands) Pancreas Lungs Liver Brunner gland Salivary glands 30  NORMAL CYSTIC FIBROSIS LUMEN OF Cl– Na+ Cl– Na+ SWEAT DUCT CFTR ENaC NORMAL CYSTIC FIBROSIS AIRWAY Normal mucus Dehydrated mucus Cl– Na+ H 2O Cl– Na+ H2 O 31 Cystic Fibrosis 32 Cystic Fibrosis of the Pancreas 33 Cystic Fibrosis of the Pancreas 34 Cystic Fibrosis of the Liver and Bile Ducts 35 Cystic Fibrosis of the Lung: Bronchiectasis 36 Cystic Fibrosis of the Lung: Bronchiectasis 37 Cystic Fibrosis (Mucoviscidosis) Clinical features Intestinal obstruction due to meconium ileus Malabsorption syndrome Chronic pulmonary infections Aspermia in males Recurrent or persistent pulmonary infections are responsible for 80-90% of deaths 38  Phenylketonuria (PKU) Decreased phenylalanine hydroxylase leads to accumulation of phenylalanine Clinical features - intellectual disability, photosensitivity, eczema and convulsions Normal at birth and clinical manifestations become evident by 3 days of age 39  Phenylketonuria 2 2 2 Phenylalanine Phenylalanine hydroxylase Tyrosine Thyroxine Adrenaline Melanin Noradrenaline 40 Alkaptonuria (Ochronosis) Homogetisic oxidase deficiency blocks the metabolism of phenylalanine-tyrosine leading to the accumulation of homogentisic acid Homogentisic acid binds to collagen in connective tissue, tendons and cartilage Oxidation of homogentisic acid leads a blue-black pigmentation (ochronosis) Complications - severe degenerative joint disease due to homogentisic acid binding to collagen in articular cartilage, intervertebral disc, knees, shoulders and hips Urine turns black due oxidation of homogentisic acid 41  Albinism Tyrosinase deficiency results in decreased production of melanin Increased risk for basal cell and squamous cell carcinomas 42 Glycogen Storage Diseases Definition - a deficiency in an enzyme necessary for glycogen metabolism leading to accumulation of glycogen in various tissues including the liver, cardiac and skeletal muscle Type I (von Gierke disease) - deficiency of glucose-6- phosphatase = hepatomegaly and hypoglycemia Type II (Pompe disease) - deficiency of lysosomal glucosidase (acid maltase) = hepatomegaly, cardiomegaly, skeletal muscle hypotonia Type V (McArdle syndrome) - deficiency of muscle phosphorylase = exercise-induced muscle cramps 43 44  NORMAL Glycogen Glucose Various tissues Blood Muscle glucose Glycolysis Glucose Energy Glycogen GLYCOGEN STORAGE DISEASE—HEPATIC TYPE Glycogen Glucose Low blood glucose GLYCOGEN STORAGE DISEASE—MYOPATHIC TYPE Glycolysis Glucose Low energy Glycogen output 45  Normal Myocardium Glycogen Accumulation A B 46 Glycogen storage disease Type Ia (von Gierke Disease) Glucose-6-phosphatase deficiency Glycogen Phosphorylase Glycogen Phosphogluco- Glucose-6- Glucose-6- phosphatase Glucose Glucose-1- mutase phosphate phosphate 47 Glycogen storage disease Type V (McArdle Disease) Phosphorylase deficiency Glycogen Phosphorylase Glycogen Phosphogluco- Glucose-6- Glucose-6- phosphatase Glucose Glucose-1- mutase phosphate phosphate 48 Lysosomal Storage Disorders 49  Synthesis and Intracellular Transport of Lysosomal Enzymes 50 Pathogenesis of Lysosomal Storage Disorders 51  a. Enzyme defect: deficiency of hexosaminidase A b. Leads to the accumulation of GM2 ganglioside in the lysosomes of the CNS and retina c. Genetic defect: mutation of HEXA gene on chromosome 15 Table 6-2. Lysosomal Storage Diseases Disease Enzyme Deficiency Accumulating Substance Tay-Sachs disease Hexosaminidase A GM2 ganglioside Niemann-Pick disease Sphingomyelinase Sphingomyelin Gaucher disease Glucocerebrosidase Glucocerebroside Fabry disease α-Galactosidase A Ceramide trihexoside Metachromatic Aryl sulfatase A Sulfatide leukodystrophy Hurler syndrome α-1-Iduronidase Dermatan sulfate Heparan sulfate Hunter syndrome L-Iduronosulfate sulfatase Dermatan sulfate Heparan sulfate 52  Tay-Sachs Disease (GM2-Gangliosidosis Type 1) Increased prevalence among Ashkenazic Jews (1:30) Deficiency of hexosaminidase A Accumulation of GM2-ganglioside in the nervous system: Neurons, autonomic nervous system, peripheral nervous system and retina (cherry-red spot) Clinical features: progressive motor incoordination and weakness, mental obtundation, blindness and progressive dementia 53  The GM2 gangliosidoses Disease Tay-Sachs disease & Sandhoff disease & Activator later-onset variants later-onset variants deficiency Affected gene a (chr 15) b (chr 5) activator (chr 5) Polypeptide a subunit b subunit activator Isozyme: subunits Hex A: ab Hex B: bb activator Active enzyme ab GM2 ganglioside complex N-acetylgalactosamine - galactose - glucose - ceramide NANA Cleavage site 54 Tay-Sachs Disease Ganglioside GM2 β-N-acetyl hexosaminidase Ganglioside GM3 55 Tay-Sachs Disease 56 “Cherry-red spot” 57  Neimann-Pick Disease Deficiency of sphingomyelinase Accumulation of sphingomyelin and cholesterol in all phagocytic cells and neurons Several types Types A and B - deficient activity of the enzyme Types C - primary defect in intracellular transport of free cholesterol from the lysosomes to the cytoplasm 58 Lipids 59 60  Niemann-Pick Disease Sphingomyelin H 20 Sphingomyelinase (lysosomal hydroxylase) Ceramide Phosphocholine 61 Niemann-Pick Disease 62 Niemann-Pick Disease 63 Niemann-Pick Disease 64 Niemann-Pick Disease 65 Niemann-Pick Disease 66 Niemann-Pick Disease 67 Niemann-Pick Disease 68 “Zebra bodies” 69 70 71  Gaucher Disease Deficiency of glucocerebrosidase (most common lysosomal storage disorder) Accumulation of glucocerebroside in reticuloendothelial cells - liver, spleen and bone marrow Several types Type I - chronic non-neuronopathic form (99%) Type II - CNS neurons (acute neuropathic form) Type III (juvenile) - involves the brain and visceral organs Engorged phagocytic cells are called "Gaucher cells" 72 Gaucher Disease Type I Glucosylcerebroside H 20 Glucosyl ceraminidase (lysosomal hydroxylase) Glucose Ceramide 73 74  Autosomal Dominant Disorders May be delayed age of onset of clinical features Mutations usually involve complex structural proteins or regulatory proteins 75 Familial Hypercholesterolemia Probably the most frequent mendelian disorder Mutations in cholesterol metabolism (LDL receptor disorder) Premature atherosclerosis of the coronary arteries, cerebral and peripheral arteries, and skin xanthomas 76 LDL Receptor Pathway and Regulation of Cholesterol Metabolism Protein LDL Cholesterol esters LDL receptor ApoB-100 Plasma membrane Coated pit Clathrin Recycling vesicle Coated Golgi vesicle Endosome apparatus Synthesis of Synthesis of LDL receptors cholesterol DNA HMG CoA reductase Lysosome RNA Inhibits Inhibits Amino acids Oversupply of Receptor Cholesterol cholesterol Stimulates Cell membrane, steroid hormones, Endoplasmic Receptor Ribosome Storage of and bile acids reticulum protein cholesterol esters 77  Endoplasmic Golgi apparatus reticulum 2 3 1 4 LDL Classification of LDL Receptor Mutations 5 Endosome Coated pit Mutation Synthesis Transport Binding Clustering Recycling class I X II X III X IV X V X 78  Marfan Syndrome Genetic disorder of connective tissue involving the fibrillin gene on chromosome 15 Clinical manifestations: Skeletal abnormalities (tall due to long extremities, lax joints and pigeon chest) Ocular (lens subluxation) Cardiovascular (cystic medial degeneration of the aorta) 79 Marfan Syndrome: Aorta 80 Marfan Syndrome: Aorta - Elastin Stain 81  Ehlers-Danlos Syndromes Definition - clinically and genetically heterogeneous group of disorders due to some defect in collagen synthesis or structure Inheritance patterns include x-linked, and autosomal dominant and recessive Most variants of EDS often affects the skin, ligaments and joints rich in collagen Clinical manifestations: Hyper-extensible skin and hypermobile joints Internal complications - rupture of the colon and large arteries (EDS type IV - type III collagen), ocular fragility with rupture of cornea and retinal detachment (EDS type VI - lysly hydroxylase [type I and III collagens]) and diaphragmatic hernia (EDS type 1) 82  Neurofibromatosis Type 1 Frequency - 1 in 3,000 Neurofibromatosis-1 (NF-1) gene is on chromosome 17q (neurofibromin - tumor suppressor inhibits RAS activity) Clinical manifestations: Multiple neural tumors (neurofibromas) attached to nerve trunks Numerous pigmented skin lesions - “cafe au lait” spots or light brown macules Pigmented iris hamartomas - Lisch nodules Skeletal lesions - scoliosis, intraosseous cystic lesions, etc Increased risk - meningiomas, optic gliomas and pheochromocytomas 83 Neurofibromatosis Type 1 84 Neurofibromatosis Type 1 85 Neurofibromatosis Type 1 86 Neurofibromatosis Type I: Lisch Nodules 87 Neurofibromatosis Type 2 Less frequent than type 1 Neurofibromatosis-2 (NF-2) gene is on chromosome 22q12 (merlin normally restricts the cell-surface expression of growth factor receptors such as EGFR) Clinical manifestations: Bilateral acoustic neuromas (schwannomas) with or without skin tumors “Cafe au lait” spots are present without Lisch nodules 88 von Hippel-Lindau Disease Characterized by a variety of benign and malignant tumors VHL gene is located on chromosome 3p25.3 Clinical manifestations: Retinal hemangioblastoma (von Hippel tumor) Hemangioblastoma of cerebellum, medulla oblongata or spinal cord (Lindau tumor) Angiomas and cysts involving a variety of visceral organs 50% of patients with VHL disease develop bilateral multiple renal cell carcinomas and other tumors 89 Bilateral Multicentric Renal Cell Carcinomas 90 Bilateral Multicentric Renal Cell Carcinomas 91 Table 6-1. General Characteristics of Autosomal Dominant and Recessive Diseases Autosomal Recessive Autosomal Dominant Onset Early uniform onset Variable onset (infancy/childhood) (may be delayed into adulthood) Penetrance Complete penetrance Incomplete penetrance with variable expression Mutation Usually an enzyme protein Usually a structural protein or receptor Requires Mutation of both alleles Mutation of one allele F. AUTOSOMAL RECESSIVE DISORDERS 1. Cystic fibrosis (mucoviscidosis) a. Most common lethal genetic disorder in Caucasians b. Defect: mutation of the chloride 92 channel protein, cystic fibrosis transmembrane Table 6-1. General Characteristics of Autosomal Dominant and Recessive Diseases Autosomal Recessive Autosomal Dominant Onset Early uniform onset Variable onset (infancy/childhood) (may be delayed into adulthood) Penetrance Complete penetrance Incomplete penetrance with variable expression Mutation Usually an enzyme protein Usually a structural protein or receptor Requires Mutation of both alleles Mutation of one allele F. AUTOSOMAL RECESSIVE DISORDERS 1. Cystic fibrosis (mucoviscidosis) a. Most common lethal genetic disorder in Caucasians b. Defect: mutation of the chloride 93 channel protein, cystic fibrosis transmembrane  X-Linked Diseases Arm Region Band Sub-band 3 2 2 2 Ocular albinism 1 3 p 1 2 Chronic granulomatous disease 1 Duchenne muscular dystrophy 4 3 Menkes syndrome 1 1 2 1 1 1 2 Testicular feminization 1 2 3 X-linked severe combined immunodeficiency 1 2 1 3 X-linked agammaglobulinemia Fabry disease 1 q 2 2 3 3 2 4 5 6 Lesch-Nyhan syndrome 7 Hemophilia B, Hunter syndrome Fragile X syndrome 8 Hemophilia A G6PD deficiency X-CHROMOSOME 94  Triple Repeat Mutations Promoter UTR Intron Exon UTR 5' 3' Expansions Sequences CCCCGCCCCGCG CGG GAA CAG CTG 12 mer triplet triplet triplet triplet Disease Myoclonus* Fragile-X Friedreich Huntington Myotonic epilepsy syndrome ataxia disease dystrophy 95 Triple Repeat Mutations 96  Fragile-X Syndrome Mutation leading to a long repeating sequence of three nucleotides (CGG) on Xq involving FMR-1 gene Second most common genetic cause of intellectual disability after Down syndrome Clinical features Intellectual disability in most males and carrier females (30%) Long face with a large mandible Large everted ears Macro-orchidism (large testes) in 80% of post-pubertal males 97  Huntington Disease Age - 20 to 50 years Huntingtin gene is located on chromosome 4p16.3 Increased repeats of CAG encoding polyglutamine region of the protein Pathology - bilateral atrophy of the caudate nucleus, lateral and third ventricles become dilated, frontal lobe atrophy, severe loss of neurons with pronounced fibrillary gliosis Clinical - extrapyramidal or choreiform movements and a progressive dementia 98 Huntington Disease 99  Genomic Imprinting Definition Certain maternal and paternal genes have functional differences leading to differential expression of these genes in the offspring Probably due to an epigenetic mechanism Differential DNA methylation of maternal and paternal genes during gametogenesis 100  MATERNAL PATERNAL (M) (P) Imprinted Prader-Willi Active Prader-Willi gene(s) gene(s) Active Angelman Imprinted Angelman gene (UBE3A) gene (UBE3A) Deletion in maternal Deletion in paternal chromosome chromosome (M) (P) (M) (P) Active Prader-Willi Imprinted Prader-Willi Site of deletion gene(s) gene(s) Site of deletion Inactive UBE3A Active UBE3A gene gene ANGELMAN SYNDROME PRADER-WILLI SYNDROME 101  Genomic Imprinting Clinical Features Prader-Willi syndrome Intellectual disability, short stature, muscle hypotonia, obesity, small hands and feet, and hypogonadism Angelman syndrome (happy puppet syndrome) Intellectual disability, seizures, ataxia and inappropriate laughter 102