Genetic Disorders

Dr.CSBR.Prasad, M.D.

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

Normal karyotype

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

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

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

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

All enzyme deficiencies are transmitted as

recessive – AR / XR

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

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

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

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

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

PRESENTATION OF PRINCE NAPOLEON BY SECRETARY SEWARD TO THE PRESIDENT (Abraham Lincoln) --- August, 1861

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

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

A 28 year old man with skin hyperextensibility and multiple scars on the legs and arms was diagnosed with Ehlers-Danlos syndrome

This 8-year-old boy demonstrated his hyperextensible joints.

This 8-year-old boy demonstrated his hyperextensible joints

Knee hyperextensibility

Hyperextensibility of fingers

Familial Hypercholesterolemia

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

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

Eruptive XanthomasThe patient was found to

have a triglyceride level of 2,940 (Normal 70-150)

Collections of macrophages with a foamy cytoplasm were present in the dermis. A variable admixture of lymphocytes and neutrophiles were also be present.

Unilateral 3-4 mmpale yellow

papules.

Xanthalasma

Tendinous xanthomas

Tuberous xanthomas

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

Lysosomal Storage Diseases

Types Glycogenosis

• Pompe disease Sphingolipidosis

• Taysachs disease Sulfatidoses

• Gaucher, Niemann-pick disease Mucoploysaccharidosis

• Hurler, Hunter disease Mucolipidoses

When to suspect storage disorder?

Young patients Oraganomegaly (hepatosplenomegaly) lymphadenopathy Failure to thrive Cytopenias Recurrent infections / hosptial

admissions Hemorrhagic tendencies Skeletal abnormalities

Glycogen storage disorders

3 subgroups – based on pathophysiology Hepatic forms Myopathic forms Miscellaneous forms

Glycogen storage disorders

Hepatic forms Hepatomegaly Renomegaly Failure to thrive, stunted

growth Hypoglycemia – convulsion

Glycogen storage disorders

Myopathic forms Subsarcolemmal accumulation

of glycogen Painful cramps associated with

exercise Myoglobinuria – 50 % cases

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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