Genetic disorder

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Genetic Disorder:

Genetic Disorder DR Muhammad Sajid Khan Assistant Professor Department of Physiology

Genetic Disorder:

Genetic Disorder The genetic disorder is the disorder that occur due to abnormalities in genetic material ie genome. Genetic disorder are either hereditary disorder or defect in gene.

Genetic Disorder:

Genetic Disorder Genetic effect may be due to two causes Genetic variation Presence of different form of gene 2. Genetic mutation There is change in nature, form or quality of DNA.

Classification of genetic disorder:

Classification of genetic disorder Single gene disorder Multifactorial genetic disorder Chromosomal disorder Mitochondrial DNA disorder

Single gene disorder:

Single gene disorder Single gene disorder also called Mandelian or monogenic disorder, occur because of variation or mutation in one single gene. Eg ; Sickle cell anemia


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 proteins Mutations resulting in unusual reactions to drugs

Multifactorial genetic disorder:

Multifactorial genetic disorder Also called polygenic disorder caused by combination of environmental factor and mutation in multiple gene. Eg , Coronary heart disease and diabetes

Mutation :

Mutation Defined as permanent change in the DNA Point mutation Fram shift mutation Point mutation within coding system Mutations within noncoding sequences Deletion and insertion Tri nucleotide repeat mutations

Chromosomal disorder :

Chromosomal disorder Caused by abnormalities in chromosome. It involve physical and mental abnormalities. The chromosomal abnormalities are of two types, A) Chromosomal disorder caused by numerical abnormalities. B) Chromosomal disorder caused by structural abnormalities

Chromosomal disorder caused by numerical abnormalities:

Chromosomal disorder caused by numerical abnormalities The numerical abnormalities of chromosome are of two types. Monosomy : Chromosomal abnormalities is due to normal diploid number Eg ; Turner,s syndrom b) Trisomy: Chromosomal abnormalities is due to presence of one extra chromosome along with normal pair of chromosome in cells, eg Down syndrom

Autosomal disorders:

Autosomal disorders Trisomy 21 (Down syndrome) most frequent - 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)

Clinical symptoms:

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)

Turner syndrome (45, X0):

Turner syndrome ( 45, X0 ) 1:3000 females primary hypogonadism in phenotypic female growth retardation (short stature, webbing of the neck, low posterior hairline, broad chest, cubitus valgus) streak ovaries - infertility, amenorrhea, infantile genitalia, little pubic hair

Prenatal diagnostics:

Prenatal diagnostics amniocentesis - analysis of amniotic fluid cytogenetic analysis (karyotype - e.g. Down) biochemical activity of various enzymes (e.g. Tay-Sachs) analysis of various specific genes (CF gene - PCR) sex of the fetus (X-linked disorders - hemophilia)

Mitochondrial DNA disorder:

Mitochondrial DNA disorder Mitochondrial DNA disorder are genetic disorder caused by mutation in DNA of mitochondria, non chromosomal DNA. Eg : Keams sayre syndrome, neuromuscular disorder caused by loss of myopathy, cardiomyopathy and paralysis of ocular muscle

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

What is a metabolic disease?:

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

What is a metabolic disease?:

What is a metabolic disease? Small molecule disease Carbohydrate Protein Lipid Nucleic Acids Organelle disease Lysosomes Mitochondria Peroxisomes Cytoplasm


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


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


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


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


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

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