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Genetic disease

Genetic disease. Ahmad abu alsamen MD. Genetic diseases. traditionally - 3 types of diseases 1. genetically determined 2. environmentally determined 3. 1. + 2. up to 20% of pediatric in-patients have genetic abnormality about 50% of spontaneous abortuses have chromosomal aberration

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Genetic disease

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  1. Genetic disease Ahmad abu alsamen MD

  2. Genetic diseases • traditionally - 3 types of diseases • 1. genetically determined • 2. environmentally determined • 3. 1. + 2. • up to 20% of pediatric in-patients have genetic abnormality • about 50% of spontaneous abortuses have chromosomal aberration • only mutations that are not lethal are reservoir of genetic diseases

  3. Terminology • hereditary= derived from parents • familial= transmitted in the gametes through generations • congenital = present at birth (not always genetically determined - e.g. congenital syphilis, toxoplasmosis) • Not all genetical diseases are congenital - e.g. Huntington disease - 3rd to 4th decade of life • Classification • 3 groups of genetic diseases • 1. Disorders with multifactorial inheritance (polygenic) • 2. Monogenic(mendelian) disorders • 3. Chromosomal aberrations

  4. 1. Disorders with multifactorial inheritance (polygenic) • influence of multiple genes + environmental factors • relatively frequent - Diabetes mellitus - Hypertension (see Circulation) - Gout - Schizophrenia (Psychiatry) - Congenital heart disease - certain forms (see Heart) - Some types of cancer (ovarian, breast, colon) • often familial occurrence - probability of disease is in • 1st degree relatives 5-10%; • 2nd degree relatives - 0,5-1%

  5. 2. Monogenic (mendelian) disorders • mutation of 1 gene, mendelian type of inheritance • today about 5000 diseases • Autosomal dominant • Autosomal recessive • X-linked

  6. Autosomal dominant disorders • both homozygotes and heterozygotes are affected • usually heterozygotes (inherited from one parent) • both males and females are affected • transmission from one generation to the other • 50% of children are affected

  7. Familial hypercholesterolemia • is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol") • (= subgroup of hyperlipoproteinemia) • most frequent mendelian disorder - 1:500 • mutation of gene encoding LDL-receptor (70% of plasma cholesterol) • heterozygotes 2-3× elev. of plasma cholesterol levels • homozygotes 5× elevation of plasma cholesterol levels • heterozygotes asymptomatic until adulthood - xanthomas along tendon sheets, coronary AS • homozygotes - xanthomas in childhood, death due to MI by the age of 15Y

  8. 2. Autosomal recessive • majority of mendelian disorders • only homozygotes are affected, heterozygotes (parents) are only carriers • 25% of descendants are affected • onset of symptoms often in childhood • frequently enzymatic defect • testing of parents and amnial cells

  9. Cystic fibrosis • 1:2000 live births - most common lethal genetic disease in white population • defect in the transport of chloride ions across epithelia increased absorption of Na+ and water to the blood • widespread defect in the exocrine glands - abnormally viscid mucous secretions • blockage of airways, pancreatic ducts, biliary ducts

  10. Pancreatic abnormalities (85%) - dilatation of ducts, atrophy of exocrine part, fibrosis • Pulmonary lesions - dilatation of bronchioles, mucus retention, repeated inflammation, bronchiectasis, lung abscesses, emphysema and atelectasis (100%) • GIT - meconium ileus (newborns) (25%), - biliary cirrhosis (2%) • Male genital tract - sterility (obstruction of vas deferens, epididymis, seminal vesicles) (95%)

  11. Clinical symptomatology • recurrent pulmonary infections • pancreatic insufficiency, malabsorption syndrome (large, foul stool), hypovitaminosis A, D, E, K, poor weight gain • high level of sodium in the sweat - "salty" children - mother's diagnosis • death usually in 3. decade due to respiratory failure

  12. Trisomy 21 (Down syndrome) • most frequent • Down syndrome, trisomy 21 is a genetic condition caused by an extra chromosome. Most babies inherit 23 chromosomes from each parent, for a total of 46 chromosomes. • - 1:700 births; parents have normal karyotype • maternal age has a strong influence: • <20 y. 1:1550 live births • >45 y. 1:25 live births • most frequently is abnormality in ovum (ovum is under long-time influence of enviroment

  13. Clinical symptoms • mental retardation (IQ 25-50) • flat face + epicanthus • congenital heart defects • neck skin folds • skeletal muscle hypotonia • hypermobility of joints • increased risk of acute leukemias • mortality 40% until 10Y (cardiac complications) • Less frequent disorders • Trisomy 18 (Edwards syndrome)1:8000 • Trisomy 13 (Patau syndrome)1:15000

  14. Paraneoplastic syndrome Major Forms of Underlying Cancer Causal Mechanism Endocrinopathies Cushing syndrome Small cell carcinoma of lung ACTH or ACTH-like substance Syndrome of inappropriateADH secretion Small cell carcinoma of lung; I Antidiuretic hormon Hypercalcemia Squamous cell carcinoma of lung Parathyroid hormone- related Breast carcinoma Renal carcinoma Adult T-cell leukemia/lymphoma Ovarian carcinoma Hypoglycemia Fibrosarcoma Insulin or insulin-like substance Hepatocellular carcinoma Carcinoid syndrom Bronchial adenoma (carcinoid)Serotonin, bradykinin Pancreatic carcinoma Gastric carcinoma

  15. Paraneoplastic syndrome Polycythemia Renal carcinoma Erythropoietin Cerebellar hemangioma Hepatocellular carcinoma Acanthosis nigricans Gastric carcinoma; Immunologic secretion of epidermal growth factor Lung carcinoma Uterine carcinoma • Hypertrophic osteoarthropathy and Bronchogenic carcinoma Unknown clubbing of thefinger

  16. Occupational Cancers -- Agents or Groups of Agents Human Cancer Site Typical Use or Occurrence Arsenic and arsenic Lung, skin compounds, hemangiosarcoma electrical and semi conductor devices, Asbestos Lung, mesothelioma; used for many gastrointestinal tract applications because of esophagus, stomach, fire, heat, and friction large intestine resistance ;

  17. Occuptionl cancer • Benzene Leukemia, Hodgkin Principal component use as lymphoma in printing and , paint, rubber, dry cleaning, adhesives and coatings, and detergents. Beryllium and beryllium compounds Lung Missile fuel and space vehicles Cadmium and cadmium compounds Prostate Uses include yellow pigments and phosphors. Found in solders. Used inbatteries Chromium compounds Lung Component of metal alloys, paints, pigments, and preservatives Ethylene oxide Leukemia Ripening agent for fruits and nuts. Nickel compounds Nose, lung , ceramics, and batteries. Byproductof stainless steel arc welding Radon Lung From decay of minerals containing uranium. Vinyl chloride Angiosarcoma, liver Refrigerant. Monomer for vinyl polymers. Adhesive for plastics. Formerly inertaerosol propellant in pressurized containe

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