GENETIC DISEASES (M6)

• Genetic Disorders


  Diseases originating from the genes of the chromosomes
• Environmental Diseases


  Acquired diseases caused by the presence of infectious agents, foreign bodies in the environment, lifestyle practices or habits of the individual
• Multifactorial Diseases


  Several factors that are causing the diseases, not just one. Collaborative action of several factors.
• Late Onset Genetic Diseases


  Genetic diseases that appear in middle ages or adulthood, not in early stages of life
• Mutations


  Permanent changes in the DNA
• Causes of Mutations


  Radiation, exposure to environmental factors, bacteria, viruses, chemicals or toxic substances or mutagens
• Types of Mutations

  • Gene Mutation (single base error)
  • Chromosome Mutation (visible chromosome change)
  • Genome Mutation (whole chromosome problem)
• Gene Mutation


  Deletion, substitution or point mutation of a single base
• Chromosome Mutation


  Missing, extra or translocated segment of a chromosome
• Genome Mutation


  Missing or extra whole chromosome

  
• Nonsense Mutation


  Point mutation that changes an amino acid codon to a chain termination codon
• Nonsense Mediated Decay


  Rapid degradation of RNAs with nonsense mutations, resulting in little or no protein formation
• Frameshift Mutation


  Insertion or deletion of one or two base pairs that alters the reading frame of the DNA strand
• Tri-nucleotide Repeats


  Repeats of three nucleotides, e.g. CGG in Fragile X Syndrome, CAG in others
• Effects of Mutations

  • Interfere with protein synthesis
  • Suppress transcription
  • Produce abnormal mRNA
  • Defects carried over into translation
  • Abnormal proteins without impairing syntheses
• Sickle Cell Anemia


  • Point mutation in the beta-globin chain of hemoglobin changes the shape of red blood cells
• Types of Genetic Disorders

  • Single gene mutations
  • Multifactorial inheritance
  • Chromosomal disorders
  • Non-mendelian disorders
• Autosomal Dominant Inheritance


  Disease is in heterozygotes, can be a new mutation, reduced penetrance and variable expressivity, may have delayed onset, usually result in reduced or inactive protein
• Autosomal Recessive Inheritance


  Disease is in homozygotes, more uniform expression, often complete penetrance, onset usually early in life, new mutations rarely detected clinically, proteins show loss of function
• sex Linked

  Affects males only, father's sons are ok but all his daughters are carriers, heterozygous females have no phenotypic expression
• Types of Single Gene Disorders

  • Enzyme defect
  • Receptor/Transport Protein defect
  • Structural Protein defect
• Marfan Syndrome


  Fibrillin-1 defect, tall stature, dislocated lens, aortic arch aneurysms
• Ehlers-Danlos Syndromes


  Multiple types with different collagen defects, hyperelastic skin and hyperextensible joints
• Familial Hypercholesterolemia


  LDL receptor defect, impaired cholesterol transport across liver cell, cholesterol buildup in blood
• Enzyme Deficiency Disorders


  • Lysosomal storage diseases
  • Glycogen storage diseases
  • Sphingolipidoses
  • Sulfatidoses
  • Mucopolysaccharidoses
  • Mucolipidoses
  • Fucosidosis
  • Mannosidosis
  • Aspartylglycosaminuria
  • Wolman
  • Acid Phosphate Deficiency
• Glycogen Storage Diseases have many types (at least 13), including Pompe, von Gierke, and McArdle
• Microfibrils


  Composed of end-to-end polymers of fibrillin
• Familial Hypercholesterolemia


  LDL receptor defect
• LDL receptor defect


  Cholesterol transport across liver cell impaired
• Enzyme Deficiencies

  • Substrate buildup
  • Product lack
  • Substrate could be harmful
• Lysosomal Storage Diseases


  • Glycogen Storage Diseases
  • Sphingolipidoses (Gangliosides)
  • Sulfatidoses
  • Mucopolysaccharidoses
  • Mucolipidoses
  • Fucosidosis
  • Mannosidosis
  • Aspartylglycosaminuria
  • Wolman
  • Acid Phosphate Deficiency
• Glycogen Storage Diseases


  Type 2 Pompe, von Gierke, McArdle most studied and discussed
• Glycogen Storage Diseases

  Storage sites: Liver, Striated Muscle (Skel + Ht)
• Sphingolipidoses

  • Tay-Sachs most often referred to
  • Gangliosides are accumulated
  • Ashkenazi Jews (1/30 are carriers)
  • CNS neurons a site of accumulation
  • Cherry red spot in Macula
  • Usually fatal by age 4
• Sulfatidoses

  • Metachromatic leukodystrophies (CNS)
  • Krabbe
  • Fabry
  • Gaucher
  • Niemann-Pick (A and B)
• Niemann-Pick


  • Types A, B, C
  • Sphingomyelin buildup
  • Sphingomyelinase (ASM) is the missing enzyme
  • Massive splenomegaly
  • Also in Ashkanazi Jews
  • Often fatal in early life, CNS, organomegaly
• Gaucher Disease


  • Glucocerebroside buildup
  • 99% are type I, no CNS involvement
  • All macrophages, liv, spl, nodes, marrow
• Mucopolysaccharidoses


  • Hurler / Hunter, for I and II, respectively
  • Dermatan sulfate, Heparan sulfate buildup, respectively
  • Coarse facial features
  • Clouding of the cornea
  • Joint stiffness
  • Mental retardation
  • Urinary excretion of sulfates common
• Other Lysosomal Storage Diseases

  • Fucosidosis
  • Mannosidosis
  • Aspartvlglvcosaminuria
  • Wolman (cholesterol, triglycerides)
  • Acid phosphate deficiency (phosphate esters)
  • Alcaptonuria
• Alcaptonuria


  • Not a lysosomal enzyme disease
  • First one to be described
  • Homogentisic acid
  • Homogentisic acid oxidase
  • Black urine
  • Black nails (ochronosis), skin
  • Black joint cartilage (severe arthritis)