Genetic Disorders I PDF

Pathophysiology Course- PHMU 534 Lecture 1 Genetic Diseases 1 Assoc. Prof. Nabila Hamdi MD, PhD in Molecular Pathology  Outlin I. INTRODUCTION e II. MENDELIAN DISORDERS: DISEASES CAUSED BY SINGLE-...

Pathophysiology Course- PHMU 534 Lecture 1 Genetic Diseases 1 Assoc. Prof. Nabila Hamdi MD, PhD in Molecular Pathology  Outlin I. INTRODUCTION e II. MENDELIAN DISORDERS: DISEASES CAUSED BY SINGLE- GENE DEFECTS 1. Transmission Patterns 2. Diseases Caused by Mutations in Genes Encoding Structural Proteins (Marfan syndrome) 3. Diseases Caused by Mutations in Genes Encoding Receptor Proteins (FHC) 4. Diseases Caused by Mutations in Genes Encoding Channels (CF) III. COMPLEX MULTIGENIC DISORDERS IV. CYTOGENETIC DISORDERS 1. Chromosomal Abnormalities 2. Cytogenetic Disorders Involving Autosomes 3. Cytogenetic Disorders Involving Sex Chromosomes IV. SINGLE-GENE DISORDERS WITH ATYPICAL PATTERNS OF INHERITANCE 4. Triplet Repeat Mutations 5. Diseases Caused by Mutations in Mitochondrial Genes 2  Competenc ies of the pathophysiological Demonstrate understanding mechanisms of genetic disorders. Utilize the proper medical terms in pharmacy practice. Integrate knowledge from fundamental sciences to relate the mechanisms of disease to their clinical manifestations and possible complications. Recognize the role of physicians as members of the health care professional team and perform responsibilities in compliance with the professional structure. Apply the principles of body function and basis of genomics in health and disease states to manage genetic diseases. Relate etiology, epidemiology, pathophysiology, laboratory 3 diagnosis, and clinical features of diseases to understand their General Organization of the Human Genome Humans have only about 30,000 protein-coding genes, far fewer than the 100,000 previously estimated and almost half the number in the lowly rice plant!! 4  Genetic Abnormalities Contributing to Human Diseases Mutatio ns (SNP Copy number  Predictors of s) changes  Amplificati response to thera on Markers Protein-Coding  Deletion py for complex Genes  Translocat diseases ions Epigenetic Modulation of geneChanges expression in the absence of alterations in DNA sequence  Hypermethylation  Histone modifications 5   Genetic Abnormalities Contributing to Human Diseases Mutations  Point mutations (substitution of a single nucleotide base by a different base) “Missense” “Nonsense” mutations mutations (sickle cell (Thalassemia 6  Genetic Abnormalities Contributing to Human(addition  Frameshift mutations Diseases or deletion of one or two base pairs) No shift! Protein with missing a.a  Trinucleotide repeat Cystic Fibrosis mutations Fragile X syndrome: Increased tandem repeats of CGG within FMR1 gene. Huntington disease: Increased tandem repeats of CAG in a gene located on 4p16.3. 7  Important Terms “Hereditary disorders” are derived from one’s parents and transmitted in the gametes through the generations and therefore they are familial. “Congenital” implies present at birth. Some congenital diseases are not genetic (congenital syphilis…). Not all genetic diseases are congenital (Huntington disease begins after 3rd or 4th decade). 8 Mendelian Transmission Patterns ? ? Autosomal dominant Human Genetics 9 https://www.uic.edu/classes/bms/bms655/lesson4.html/ Recurrenc e?? 50% 50% affect norm ed al Punnet square 1 0  Mendelian Transmission Patterns  Disorders of Autosomal Dominant Inheritance Manifested in the heterozygous state. Both males and females are affected, and both can transmit the condition (50% chance). Reduced penetrance: some persons inherit the mutant gene but are phenotypically normal. Variable expressivity: a trait is consistently associated with a mutant gene but is expressed differently among persons carrying the gene. The age at onset is delayed, and symptoms and signs do not appear until adulthood. 1 1 Mendelian Transmission Patterns Autosomal recessive Human Genetics https://www.uic.edu/classes/bms/bms655/lesson4.html/ 1 2  Autosomal recessive Recurrenc e?? Autosomal Recessive Inheritance. Image: U.S. National Library of Medicine 1 3 https://slideplayer.com/slide/ 13780606/ 1 4  Mendelian Transmission Patterns  Disorders of Autosomal Recessive Inheritance Manifested in the homozygous state: when both of the alleles at a given gene locus are mutants. There are skipped generations. The trait does not usually affect the parents, but siblings may show the disease (consanguineous marriage!) The recurrence risk is 25% for each birth. Complete penetrance is common. Onset is frequently early in life. fo 1 5 Mendelian Transmission Patterns X-linked recessive 1 6 X-linked recessive ANATOMY AND PHYSIOLOGY Chapter 28. Development and Inheritance 1 7  Mendelian Transmission Patterns  X-linked Disorders All sex-linked disorders are X-linked. Most X-linked disorders are X-linked recessive Transmitted by heterozygous female carriers only to sons. Heterozygous females rarely express the full phenotypic change. Sons of heterozygous women have one chance in two of receiving the mutant gene (50%). An affected male does not transmit the disorder to sons, 1 but all daughters are carriers. 8 http://hihg.med.miami.edu/code/http/modules/education/Design/Print.asp?CourseNum= 2&LessonNum=4 Mitochondrial Inheritance 1 9  Marfan Syndrome http://quizlet.com/2752374/connective-tissue-fl ash-cards/ The structural protein fibrillin is mutated. It is a glycoprotein, secreted by fibroblasts and the major component of microfibrils found in the extracellular matrix. Microfibrils serve as scaffolding for the deposition of tropoelastin, an integral component of elastic fibers. Microfibrils sequester TGF-beta. Microfibrils are particularly abundant in the aorta, ligaments, and the 2 ciliary zonules that support the ocular lens. 0  Marfan Syndrome Fibrillin is encoded by the FBN1 gene, which maps to chromosomal locus 15q21. Molecular diagnosis of Marfan syndrome is not yet feasible: more than 600 distinct causative mutations in the very large FBN1 gene have been found. Autosomal dominant with variable expressivity (it is believed to be related to different allelic mutations in the FBN1 gene. The prevalence of Marfan syndrome is estimated to be 1 per 5000. Approximately 70% to 85% of cases are familial. parent s. The rest are sporadic, arising from de novo FBN1 mutations in2 1  https:// www.physio-pedia.com/Marfan_Syndrome Long fine (a) Thumb Sign; (b) Wrist Sign http://temasek68.blogspot.com/2009_06_01_arc hive.html fingers “Spider fingers” Arachnodactyl y https:// www.physio-pedia.com/Marfan_Syndrome  Hypermobile  Elongated habitus with joints abnormally long legs, Skeletal 2 2  Pectus excavatum (deeply depressed) https://awarnessofmarfansyndrom.weebly.com/nervous- system.html http://ratedmedicine.wordpress.com/high-arche d-palate/ Pectus craniatum (prodruding, pigeon- http://www.hughston.com/hha/a_12  High-arched breast) _2_4.htm  Spinal palate  Chest https://healthjade.com/marfan-syndrome/ deformities Skeletal deformities 2 3  Marfan Syndrome Chapter 73 Cataract: Clinical Types http://quizlet.com/3969760/3-orbit-and-eyeball-fl MANUEL B. DATILES III and BENJAMIN V. ash-cards/ MAGNO  Bilateral dislocation, or subluxation, of the lens secondary to weakness of its suspensory ligaments. Occular problems 2 4  http://www.hughston.com/hha/a_12_2_4.htm  Fragmentation of the elastic fibers in the tunica media of the aorta predisposes to aort aneurysmal dilation and ic dissection.  Aortic rupture is the most common Cardiovascular cause of death. 2 5  https:// www.heart-valve-surgery.com/aortic-valve-regurgitation-symptom s.php  Dilation of the aortic valve ring, giving rise to aortic incompetence Cardiovascular abnormalities 2 6  http://www.cardiachealth.org/mitral-valve-prolapse-mvp  The cardiac valves, especially the mitral valve, may be excessively distensible and regurgitant (floppy valve syndrome), giving rise to mitral valve prolapse and congestive cardiac failure. Mitral valve prolapse Cardiovascular abnormalities 2 7  Familial Hypercholesterolemia Among the most common Mendelian disorders. The frequency of the heterozygous condition is 1 in 500 in the general population. It is caused by a mutation in the LDL receptor gene (LDLR) that encodes the receptor for low-density lipoprotein (LDL). 70% of total plasma cholesterol is transported in the form of LDL. 2 8  Familial Hypercholesterolemia Normal Cholesterol Metabolism  The endogenous synthesis of cholesterol and LDL begins in the liver.  75% LDLR are located on hepatocytes.  Two thirds of the resultant LDL particles are metabolized by the LDL receptor pathway, and the rest is metabolized by a receptor for oxidized LDL (scavenger receptor).  Monocytes and macrophages have receptors for chemically modified (e.g., acetylated or oxidized) LDLs. 2 9  LDL binding Internalizati on Stati Lysosom ns al hydrolysi s Regulator y actions HMG-CoA reductase: 3-hydroxy-3-methylglutaryl–coenzyme A reductase The LDL receptor pathway and regulation of 3 cholesterol metabolism 0  Familial Hypercholesterolemia Normal Cholesterol Metabolism The cholesterol not only is used by the cell for membrane synthesis but also takes part in intracellular cholesterol homeostasis by a sophisticated system of feedback control: 1. It inhibits the activity of the enzyme 3-hydroxy-3- methylglutaryl–coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in the synthetic pathway. 2.It stimulates the formation of cholesterol esters for storage of excess cholesterol. 3. It downregulates the synthesis of cell surface LDL receptors, thus protecting cells from excessive accumulation of cholesterol. 3 1  Familial Hypercholesterolemia  Pathogenesis Mutations in the LDL receptor protein impair the intracellular transport and catabolism of LDL. The transport of IDL into the liver is impaired, so greater proportion of plasma IDL is converted into LDL. Excessive levels of serum cholesterol (reduced catabolism and excessive biosynthesis). Marked increase of cholesterol traffic into the monocyte- macrophages and vascular walls (scavenger receptor). Appearance of skin xanthomas and premature 3 atherosclerosis. 2 http://medicinexplained.blogspot.com/2011/06/xanthomas-in -tendon-and xanthelasmata.html Clinical manifestations of familial hypercholesterolemia (A)Corneal arcus and xanthelasma http://www.mdguidelines.com/coronary-athero sclerosis (C extensor (B) tendontendon and D) Achilles xanthomas 3 xanthomas 3  Familial Hypercholesterolemia Pathogenesis An autosomal dominant disease.  Heterozygotes  have a two- to three-fold elevation of plasma cholesterol levels.  remain asymptomatic until adult life, when they develop xanthomas along tendon sheaths and coronary artery disease.  Homozygotes  may have an excess of a five-fold elevation.  develop cutaneous xanthomas in childhood and often die of myocardial infarction before the age of 20 years. Analysis of LDL receptor gene has revealed 3 more than 900 different 4  Familial Hypercholesterolemia  Pathogenesis Class I mutations: complete loss of receptor synthesis (uncommon). Class II mutations: LDLR is synthesized, but not transported from the endoplasmic reticulum to the Golgi apparatus (most prevalent). Class III mutations: LDLR are transported to the cell surface but fail to bind LDL normally. Class IV mutations: LDLR fail to internalize after binding to LDL. 3 5  Cystic Fibrosis  Pathogenesis CF is the most common lethal genetic disease that affects white populations (1 in 3200 live births in the US). CF follows an autosomal recessive transmission, and does not affect heterozygote carriers. Phenotypic variation results partly from diverse mutations in the CF-associated gene and tissue-specific effects of loss of this gene’s function. Abnormal function of an epithelial chloride channel protein encoded by the CF transmembrane conductance regulator (CFTR) gene at chromosomal locus7q31.2. Mutations in the CFTR gene render the epithelial membranes relatively impermeable to chloride ions. In the sweat reduction glandsecretion of chloride ducts, loss intoof CFTR function leads to 3 decreased reabsorption 6  Cystic Fibrosis A chloride channel defect in the sweat duct causes increased chloride and sodium concentration in sweat. Decreased chloride secretion and increased sodium and water reabsorption in the airways, lead to dehydration of the mucus layer, defective mucociliary action, and mucous plugging predisposing to recurrent pulmonary infections. T 3 7 h  Cystic Fibrosis  More than 1300 disease-causing mutations have been identified.  The most common severe CFTR mutation is a deletion of three nucleotides coding for phenylalanine at amino acid position 508 (ΔF508) (misfolding and total loss of the CFTR).  Worldwide, ΔF508 mutation is Concept Version 10 Created by Boundless- Cystic fibrosis found in approximately 70% of patients with CF. 3 8  Cystic Fibrosis Morphology  Pulmonary changes: the most serious complications of CF Viscous mucus secretions lead to obstruction and infection of the air passages. Bronchioles are often distended with thick mucus. chronic Superimposed infectionsgive rise to bronchitis severe bronchiectasis. and Development of lung abscesses is common. Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the three most common organisms responsible for lung infections. 3 9  http://discovermagazine.com/2013/september/14-doorwa y-to-a-cure http://www.nhlbi.nih.gov/health/health-topics/to pics/brn/ http://www.myinterestingfacts.com/cystic-fibro 4 sis-facts/ 0 http://www.bennettsbrigade.com/additional-info/  Cystic Fibrosis Morphology Pancreatic abnormalities (85- 90%) In the milder cases, there may be only accumulations of mucus in the small ducts, with dilation of the exocrine glands. In more advanced cases, the ducts are Pancreatic insufficiency, totally plugged, causing pancreatitis, atrophy recurrent chronic of acute the exocrine glands later pancreatitis, and https:// www.cff.org/ progressive diabetes fibrosis. Impairment of fat absorption (avitaminosis) Malabsorption of proteins and fats (large, gain), poor weight 4 foul-smelling edema. stools; 1  Cystic  MorphologyFibrosis Infertility & azoospermia are found in 95% of the affected males who survive to adulthood. Congenital bilateral absence of vas deferens is a characteristic finding in adult patients with CF. Thick viscid plugs of mucus also  GIT: may be found in the small intestine of infants causing small bowel obstruction, known as meconium ileus (5% to 10%). Severe hepatic involvement is encountered in less than 10% of patients. Bile canaliculi are plugged by Pinterest Meconium Ileus Rosh Review | Nursing notes, mucinous material, Nursing flashcards 4 accompanied by portal 2  Cystic Genotype Fibrosis Description Possible symptoms Wild-type / Wild- Homozygote Unaffected type ∆508F / ∆508F Homozygote Severe lung disease pancreatic insufficiency ∆508F / W1204X Compoun No lung disease d pancreatic heterozyg insufficiency Genetic and Nutrition Cystic Fibrosis - Disease Outcome h ote ttp://www.nchpeg.org/nutrition/index.php?option=com_content&view=article&id=462&Itemid R117H / R117H =564&limitstart=5 Homozygote Congenital bilateral What about absence of the vas ∆508F/WT?? deferens No lung or pancreas The combination of mutations on disease the two alleles influences the overall phenotype, as well as organ-specific manifestations. 4 3  Referenc es Robbins Basic Pathology, 10th edition, by Vinay Kumar, Abul K. Abbas and Jon C. Aster. Elsevier, ISBN: 9780323353175, 2018. ROBBINS Basic Pathology 9th Edition ROBBINS Basic Pathology 8th Edition Source of the cover image: http://www.biologyreference.com/Fo-Gr/Genetic-Diseases. html 4 4