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Mendelian Disorders

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					                             Mendelian Disorders

                              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

            INACTIVATION OF TISSUE DAMAGING SUBSTRATE
    • Failure in inactivation of a tissue damaging substrate
       α1-ANTITRYPSIN DEFICIENCY → inability to inactivate neutrophil elastase in
the lung → destruction of elastin in the walls of alveoli → pulmonary emphysema

    DEFECTS IN MEMBRANE RECEPTORS IN TRANSPORT SYSTEMS
   • Receptor mediated endocytosis
   • Transport protein
   • FAMILIAL HYPERCHOLESTEROLEMIA
    Reduced synthesis or function of low density lipoproteins (LDL) receptors →
     defective transport of LDL into the cells → excessive cholesterol synthesis by
     complex intermediary mechanisms
     ALTERATION IN STRUCTURE, FUNCTION, OR QUANTITY OF NON
                                ENZYME PROTEINS
    • Sickle cell disease
      Defects in the structure of the globin molecule
    • Thalassemia
      Mutation in the globin gene → amount in the globin chain synthesized
    • Osteogenesis imperfecta
      Defects in collagen and spectrin
    • Muscular dystrophies
      Defect in dystrophin

        MUTATIONS RESULTING IN UNUSUAL REACTION TO DRUGS
    •   Genetically determined enzyme deficiencies are unmasked on exposure to certain
        drugs
    •   G6PD deficiency
        Antimalarial drug primaquine → severe hemolytic anemia

                                    CYSTIC FIBROSIS
       Defect in the transport system of chloride ions in
    •   Sweat ducts
    •   Lungs
    •   Pancreas → serious injury in the lungs and pancreas

    DISORDERS ASSOCIATED WITH DEFECTS IN STRUCTURAL PROTEIN

•   Fibrillin: Marfan Syndrome
•   Collagen: Ehler-Danlos Syndrome
•   Dystrophin: Duchene/ Becker
•   Spectrin/ Ankyrin/ Protein4,1: Spherocytosis

                                    MARFAN SYNDROME
•   Autosomal dominant inheritance
•   Inherited defect in fibrillin, an extra cellular glycoprotein
•   70-80% familial vs. 20-30% new mutations
•   Variable expression: genetically heterogeneous
•   Mutation
     – Negative dominant
     – Chromosome 15q21.1
     – FNB1 gene
                              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 can’t 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




                        EHLER DANLOS SYNDROME (EDS)
• Genetically heterogeneous
• At least 10 variant
• Clinical manifestations
   – Skin
       • Hyperextensible
       • Extremely fragile
   – Joints
       • Prone to dislocation
       • Hypermobile
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.
                       LYSOSOMAL STORAGE DISEASES
  Lack of any protein essential for the normal function of lysosomes




                               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




Ganglion cells with large lipid vacuolation
                                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

                      GLYCOGEN STORAGE DISEASES
Genetic disease with metabolic defect in synthesis or catabolism of glycogen.
   – Pompe (acid maltase, -glucosidase)
       • Lysosomal accumulation of glycogen
       • Predominantly heart involvement
       • Early death.

                      GLYCOGEN STORAGE DISEASES
• Hepatic type
   – Hepatomegaly
   – Hypoglycemia
   – Examples
      • Von Gierke: Glucose-6-phosphatase (I)
      • Liver phosphorylase (VI)
      • Debranching enzyme(III)
• Myopathic type
   – Muscle weakness
   – Cramps following exercise
   – Following exercise lactate does not increase
   – Examples
      • McArdle: muscle phosphorylase(V)
      • Muscle phosphofructokinase (VII)
GLYCOGEN STORAGE DISEASES




                          REFERENCES
PATHOLOGIC BASIS OF DISEASES
ROBBINS & COTRAN
8TH EDITION
CH. 5 GENETIC DISORDERS
Pgs # 140 -155

				
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posted:3/24/2012
language:English
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