genetics 3-csbrp
TRANSCRIPT
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Genetic Disorders
Dr.CSBR.Prasad, M.D.
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Mandelian Disorder
Disorders related to Single mutant genes of large effect
Transmission patterns Autosomal Dominant inheritance –
Dominant gene produces its effect whether combined with similar dominant or recessive gene
Autosomal Recessive inheritance – Recessive genes are effective only if both genes are similar
X- Linked inheritance
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Normal karyotype
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Autosomal Dominant Disorder Manifested in Heterozygous state One parent of an index case is
affected It affects both male and female &
both can transmit the condition Every child has one chance in two of
having disease Some patients may get the disease by
new mutation involving sperm/ ovum
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Autosomal Dominant Disorder Nervous – Huntington disease
NeurofibromatosisMyotonic dystrophyTuberous sclerosis
Urinary – Polycystic kidney disease GIT – Familial polyposis coli Haematopoietic – Hereditary spherocytosis
VWD
Skeletal – Marfan’s syndromeEhrler- Danlos syndromeOstogenesis imperfecta
Metabolic – Familial hypercholestremia
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Autosomal Recessive Disorder It occur only when both alleles at a
given gene locus are mutant Trait doesn't usually affect parents
but sibling may show disease Sibling have one chance in four
being affected Complete penetrance is common Onset is frequently early in life
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Autosomal Recessive Disorder Metabolic-
• Cystic Fibrosis• Phenylketonuria• Galactosemia• Homocystinuria• Lysosomal storage disease• Wilson’s disease• Hemochromatosis• Glycogen storage disease
Hematopoietic• Sickle cell anemia• Thalassemia
Endocrine • Cong. Adrenal hyperplasia
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All enzyme deficiencies are transmitted as
recessive – AR / XR
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X- Linked Disorders
All sex linked disorders are X- linked and almost all X- linked are recessive
An affected male does not transmit the disorder to his sons, but all daughters are carriers
Sons of heterozygous women have one chance in two of receiving the mutant gene
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X- Linked Disorders Musculoskeletal –
• Duchenne Muscular Dystrophy Blood
• Hemophilia A & B• G6PD deficiency
Immune – • Agammaglobulinemia• Wiskott- Aldrich Syndrome
Metabolic- • Diabetes Insipidus
Nervous – • Fragile – X Syndrome
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Marfan’s syndrome
Disorder of the connective tissue Inherited defect in extracellular
glycoprotein - Fibrillin Changes in skeleton, eyes and cvs Fibrillin 1 – gene – 15q21 1 in 10,000 to 1 in 20,000
individuals 70 – 85% are familial & AD
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Marfan’s syndrome
Skeletal abnormality Tall body with long extremities and long
tapering fingers and toes Lower segment longer than upper
segment Lax joints Long headed with bossing of frontal
eminences and prominent supraorbital ridges
Kyphosis, scoliosis, pectus excavatum
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Marfan’s syndrome
Occular changes Bilateral subluxation/ dislocation of lens
CVS changes Mitral valve prolapse(Floppy valve) Dilatation of ascending aorta due to
Medionecrosis- Aortic incompetance Aortic dissection due to weakening of
media and intimal tear High mortality
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PRESENTATION OF PRINCE NAPOLEON BY SECRETARY SEWARD TO THE PRESIDENT (Abraham Lincoln) --- August, 1861
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Ehlers – Danlos Syndrome
Clinically & Genetically heterogenous group of disorder that result from defect in collagen – 10 variants
Skin, ligaments and joints Hyperextensible skin- Delayed
wound healing Hypermobile joints
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Ehlers – Danlos Syndrome
Rupture of colon / large arteries (IV)
Rupture of cornea / retinal detachment (VI)
Diaphragmatic hernia ( I ) Type VI - ↓ Lysyl hydroxylase
↓ Hydroxylysine – cross linking of collagen fibres
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A 28 year old man with skin hyperextensibility and multiple scars on the legs and arms was diagnosed with Ehlers-Danlos syndrome
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This 8-year-old boy demonstrated his hyperextensible joints.
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This 8-year-old boy demonstrated his hyperextensible joints
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Knee hyperextensibility
Hyperextensibility of fingers
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Familial Hypercholesterolemia
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Familial Hypercholesterolemia Receptor Disease Mutation in the gene encoding for LDL
receptor which is involved in the transport & metabolism of Cholesterol
LDL receptor gene located on ch 19 Most common Mendelian disorder – 1 in 500 individuals ↑ Plasma cholesterol level (5-6 fold) Xanthoma and Premature atherosclerosis resulting in MI,
Stroke etc
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Familial Hypercholesterolemia Increased scavenger receptor
mediated clearance of LDL cholesterol
Accumulation of cholesterol in the Mononuclear phagocytic cells and vascular walls
Result in Xanthomas and Premature atherosclerosis
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Eruptive XanthomasThe patient was found to
have a triglyceride level of 2,940 (Normal 70-150)
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Collections of macrophages with a foamy cytoplasm were present in the dermis. A variable admixture of lymphocytes and neutrophiles were also be present.
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Unilateral 3-4 mmpale yellow
papules.
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Xanthalasma
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Tendinous xanthomas
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Tuberous xanthomas
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Lysosomal Storage Diseases
Lysosomes – Intracellular digestive tract
Bag of hydrolytic enzymes Active in acidic conditions Secreted into intracellular
organelles Lysosomal acid hydrolases –
breakdown of complex macromolecules
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Lysosomal Storage Diseases
Types Glycogenosis
• Pompe disease Sphingolipidosis
• Taysachs disease Sulfatidoses
• Gaucher, Niemann-pick disease Mucoploysaccharidosis
• Hurler, Hunter disease Mucolipidoses
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When to suspect storage disorder?
Young patients Oraganomegaly (hepatosplenomegaly) lymphadenopathy Failure to thrive Cytopenias Recurrent infections / hosptial
admissions Hemorrhagic tendencies Skeletal abnormalities
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Glycogen storage disorders
3 subgroups – based on pathophysiology Hepatic forms Myopathic forms Miscellaneous forms
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Glycogen storage disorders
Hepatic forms Hepatomegaly Renomegaly Failure to thrive, stunted
growth Hypoglycemia – convulsion
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Glycogen storage disorders
Myopathic forms Subsarcolemmal accumulation
of glycogen Painful cramps associated with
exercise Myoglobinuria – 50 % cases
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DIAGNOSIS OF GENETIC DISEASES
CYTOGENETIC ANALYSIS ( KARYOTYPING) = ABNORMALITIES OF WHOLE CHROMOSOMES AND ARRANGEMENT OF INDIVIDUAL CHROMOSOMES
MOLECULAR ANALYSISMOLECULAR ANALYSIS ( MOLECULAR ( MOLECULAR HYBRIDISATION TECHNIQUES),HYBRIDISATION TECHNIQUES),
= GENE DIAGNOSIS = GENE DIAGNOSIS POINT MUTATIONSPOINT MUTATIONS
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