Genetics disorder introduction

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GENETICS :

GENETICS Down load this ppt from www.drarjunpatho.hpage.com Dr. Arjun Singh M.D. Pathology Associate Professor Index medical college hospital and Research Center, Indore, India

Objectives :

Objectives Introduction of genetics Mendelian Disorder Inborn of Metabolic Disease Gaucher Disease Niemann-Pick Disease Alkaptonuria www.drarjunpatho.hpage.com

Introduction :

Introduction Human genome project Two individual have 99.5% same DNA material Only 0.5% gene responsible for diversity We know only <2% genes of the encoded proteins Frequency of genetic disease is 670- per 1000 Disease only represent tip of iceberg 50% spontaneous abortion is due to chromosomal abnormalities www.drarjunpatho.hpage.com

Genetic disease :

Genetic disease Disease related to the mutation in single genes with large effect (Mendelian disorder) Autosomal dominant disorder Autosomal recessive disorder X-linked disorder Chromosomal disorder Complex multigenic disorder www.drarjunpatho.hpage.com

Mendelian disorder :

Mendelian disorder Single gene disorder can be classified in Enzymes defect and their consequences Defect in membrane receptors and transport systems Alterations in the structure, function, or non-enzymes protiens Mutations resulting in unusual reactions to drugs

Mutation :

Mutation Defined as permanent change in the DNA Point mutation Framshift mutation Point mutation within coding system Mutations within noncoding sequences Deletion and insertion Trinucleotide repeat mutations www.drarjunpatho.hpage.com

Autosomal recessive disorders:

Autosomal recessive disorders Alkaptonuria Albinism Beta thalassemia Congenital adrenal hyperplasia Cystic fibrosis Deafness Ehlers-Danols syndrome Friedreich’s ataxia Glycogen storage diseases Galactosemia www.drarjunpatho.hpage.com

Autosomal recessive disorders:

Autosomal recessive disorders Hereditary emphysema Hemochromatosis Homocystinuria Lysosomal storage disorders Neurogenic muscular atrophies Phenylketonuria Spinal muscular atrophy Sickle cell anemia Wilson’s disease www.drarjunpatho.hpage.com

Autosomal recessive disorders:

Autosomal recessive disorders General features Homozygous Parents clinically normal Only siblings affected Males females equally affected Consanguinity strong factor Because of homozygosity rare in small families In small families disease may skip many generations www.drarjunpatho.hpage.com

Autosomal recessive disorders:

Autosomal recessive disorders Pedigree If both parents heterozygous 25 % homozygous 50 % heterozygous 25 % normal www.drarjunpatho.hpage.com A A O A AA AA O A O AA O A O A O

Autosomal recessive disorders:

Autosomal recessive disorders Pedigree One homozygous, other hetero 50 % affected 50 % normal Resemble with autosomal dominant disorders If two recessive mate 100 % affected www.drarjunpatho.hpage.com A O A O A AA O AA O A O A O A O A O A O

Autosomal dominant disorders:

Autosomal dominant disorders Polycystic kidney disease Familial polyposis coli Hereditary spherocytosis von Willebrand disease Marfan syndrome Osteogenesis imperfecta Ehlers- Danlos syndrome www.drarjunpatho.hpage.com

Autosomal dominant disorders:

Autosomal dominant disorders Achondroplasia Familial hypercholestrolemia Acute intermittent porphyria Huntington disease Neurofibromatosis Myotonic dystrophy Tuberous sclerosis www.drarjunpatho.hpage.com

Autosomal dominant disorders:

Autosomal dominant disorders Disordered affected in heterozygous state At least one of the parent are affected, both male and female affected When a affected person marry with an unaffected one, every child has one chance in two having disease www.drarjunpatho.hpage.com

X-linked disorders:

X-linked disorders Agammaglobulinemia Becker muscular dystrophy Color blindness Chronic granulomatous disease Duchenne muscular dystrophy Diabetes insipidus Fragile X syndrome Fabry’s disease www.drarjunpatho.hpage.com

X-linked disorders:

X-linked disorders G6PD deficiency Hemophilia A Hemophilia B Hypophosphatemic rickets Lesch-Nyhan syndrome Ocular albinism Testicular feminization Wiskott-aldrich syndrome www.drarjunpatho.hpage.com

X-linked disorders :

X-linked disorders General features Males are affected as they have only X Females variably affected Oblique inheritance male cousins and maternal uncles suffers www.drarjunpatho.hpage.com

Pedigree:

Pedigree A carrier female 50 % male offspring affected Affected male No male to male transmission All female offspring will be carrier Affected female occurs Affected male mates with carrier female www.drarjunpatho.hpage.com X Y X XX XY X O XX O X O Y

Inborn Errors of Metabolism:

Inborn Errors of Metabolism An inherited enzyme deficiency leading to the disruption of normal bodily metabolism Accumulation of a toxic substrate (compound acted upon by an enzyme in a chemical reaction) Impaired formation of a product normally produced by the deficient enzyme www.drarjunpatho.hpage.com

What is a metabolic disease?:

What is a metabolic disease? Garrod’s hypothesis product deficiency substrate excess toxic metabolite A D B C www.drarjunpatho.hpage.com

What is a metabolic disease?:

What is a metabolic disease? Small molecule disease Carbohydrate Protein Lipid Nucleic Acids Organelle disease Lysosomes Mitochondria Peroxisomes Cytoplasm www.drarjunpatho.hpage.com

PowerPoint Presentation:

Categories of IEMs are as follows: Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, and urea cycle defects) Disorders of carbohydrate metabolism (eg, carbohydrate intolerance disorders, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) Lysosomal storage disorders Fatty acid oxidation defects Mitochondrial disorders Peroxisomal disorders www.drarjunpatho.hpage.com

PowerPoint Presentation:

Most common lysosomal storage disease Autosomal recessive disease Mutation in the gene encoding glucocebrosidase leads to accumulation of glucocerebroside in macrophage in brain, spleen, lymphnodes , payerpatches Three types Type 1 chronic non neuropathic forms Types 2 intermediate forms Types 3 Acute neuropathic forms in infantile forms Gaucher disease www.drarjunpatho.hpage.com

PowerPoint Presentation:

Distended phagocytic cells called Gaucher cells Present in spleen, liver, bone marrow, lymph nodes, tonsils, thymus and payer patches Cells are vacuolated appearance with fibrillary types of cytoplasm called Crumpled tissue paper appearance In CNS Gaucher cells are present in Virchow robins spaces Gaucher disease www.drarjunpatho.hpage.com

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Gaucher disease www.drarjunpatho.hpage.com

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Gaucher disease www.drarjunpatho.hpage.com

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Lysosomal accumulation of sphingomyelin due to inherited deficiency of the enzyme sphingomyelinase Type A:- Severe infantile forms death occure within 3 years of life Type B:- Adulthood with organomegaly and CNS involvement Type C:- Due to mutation in NPC1 and NPC2 gene leads to cholesterol and gangliosidase accumulation Niemann Pick disease www.drarjunpatho.hpage.com

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Lipid laden macrophages in spleen, liver, lymph nodes, bone marrow, tonsil and GIT Fat stain positive e.g. Oil red O Lysosome in electron microscopy appears as concentric laminated myelin figure called “ Zebra ” bodies Vacuolation and ballooning degeneration of neuron Niemann Pick disease www.drarjunpatho.hpage.com

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Niemann Pick disease www.drarjunpatho.hpage.com

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Niemann Pick disease www.drarjunpatho.hpage.com

Alkaptonuria (Ochronosis):

Alkaptonuria (Ochronosis) First disease discovered error of amino acids metabolism Autosomal recessive disorder Lack of homogenistic oxidase enzymes which convert homogenistic acids to methylacetoacetic acid in the tyrosine degradation pathways Urine become dark black after some times www.drarjunpatho.hpage.com

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No acute clinical symptoms Untreated leads to mental retardation Homogenestic acid binds to collagen in connective tissue leads to blue black pigmentation ( Ochronosis ) affect joint, vertebrae disc etc Associated complications: behavior disorders, cataracts, skin disorders, and movement disorders Treatment: phenylalaine restricted diet (specialized formulas available) Alkaptonuria ( Ochronosis ) www.drarjunpatho.hpage.com

Glycogen storage diseases :

Glycogen storage diseases Autosomal recessive Metabolic disorder Anabolism or catabolism affect Hypoglycemia Lactic acidosis Accumulation in macrophages Liver spleen kidney bone marrow Crumpled tissue paper cytoplasm www.drarjunpatho.hpage.com

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Summary :

Summary Introduction of genetics Mendelian Disorder Inborn of Metabolic Disease Gaucher Disease Niemann-Pick Disease Alkaptonuria www.drarjunpatho.hpage.com

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Thank You www.drarjunpatho.hpage.com

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