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LEARNING OBJECTIVES
At The End Of Lecture The Student Should Be Able To Give:
Discuss the postulates of Mendelian Disorders
Explore the pattern of inheritance in Autosomal Dominant Disorders, Autosomal
Recessive Disorders, X-Linked Disorders
List the examples of autosomal and X-linked disorders
CLASSIFICATION OF MECHANISM
Enzyme defects and their consequences
Defects in membrane receptors in transport system
Alteration in the structure, function or quantity of non enzyme proteins
Mutations resulting in unusual reaction to drugs
ENZYME DEFECTS
Defective enzyme with reduced activity
Reduced amount of normal enzyme
The consequence is a metabolic block
DECREASED END PRODUCTS
End product is a feedback inhibitor of the enzyme involved in the early reactions
Deficiency of the end product overproduction of the intermediates and their
catabolic products
Some may be injurious at higher concentrations
ALBINISM
Deficiency of tyrosinase deficiency of melanin from its precursor tyrosine
FBN-1 Gene
Located on chromosome 15
Codes for the creation of protein Fibrillin1
Disease is caused by over 500 different mutations on FBN1
60% mutations are change in one protein building block.
40% mutations produce small protein that cant function.
SYMPTOMS
Skeleton
Disproportionately long appendages
Indented or protruding sternum
Overcrowded teeth
Eyes
Dislocated lenses
Nearsightedness
Development of cataracts
at a younger age: 30s to 50s
Retinal detachment
Heart
Mitral regurgitation
Aortic regurgitation
Tears in inner and
middle aortic layers
FAMILIAL HYPERCHOLESTROLEMIA
The most frequent mendelian disorder
Mutation in the gene encoding LDL receptor
Hypercholestrolemia
Premature atherosclerosis: MI
Xanthoma
Heterozygotes
1/500
2-3 times higher plasma cholestrol
Homozygotes
5-6 times higher plasma cholestrol
MI before 20 years of age
FAMILIAL HYPERCHOLESTROLEMIA
Pathogenesis
Decreased LDL clearance
Increased LDL production
More IDL coverts to LDL
In both heterozygotes and homozygotes
Increased LDL uptake by macrophage/ monocyte
Acetylated or oxidized LDL.
TAY-SACHS DISEASE
Most common form of GM2 gangliosidosis
All tissues lack hexosaminidase A
Including leukocytes and plasma
GM2 accumulation in many organs
Heart, liver, spleen, CNS, ANS, retina
NIEMANN-PICK DISEASE
Rare lysosomal storage disease
Lysosomal accumulation of sphingomyelin
Sphingomyelinase deficiency
Common in Ashkenazi jews
Types A & B
Previously type C
Defect in intracellular cholesterol esterification & transport.
DIAGNOSIS
Biochemical studies:
Sphingomyelinase activity in leukocytes and cultured fibroblasts
DNA probes:
Both patients and carriers.
GAUCHER DISEASE
Glucocerebrosidase gene mutation
Accumulation of glucocerebroside in phagocytes and sometimes CNS.
Most common lysosomal storage disease
Diagnosis
Homozygotes
Enzyme activity
Peripheral blood leukocytes
Cultured skin fibroblasts
Heterozygotes
Enzymatic methods not reliable
Detection of mutation
More than 30 different mutations
GAUCHER DISEASE
Types
I (chronic non-neuropathic): 99%
Decreased enzyme activity
Without CNS involvement
Predominantly spleen & skeleton
Pancytopenia or thrombocytopenia
Pathologic Fractures and bone pain
II (acute neuropathic)
No enzyme activity
No predilection for jews
Infantile
Progressive involvement of CNS & early death
Hepatosplenomegaly
REFERENCES
PATHOLOGIC BASIS OF DISEASES
ROBBINS & COTRAN
8TH EDITION
CH. 5 GENETIC DISORDERS
Pgs # 140 -155