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83 Cards in this Set

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What is the most common form of genetic variation in the human genome?
SNP
What are the three categories of genetic change?
1. Genome mutation
2. Chromosome mutation
3. Gene mutation
What type of inheritance is a delayed onset of the disease seen in?
Autosomal dominant
What are the two major non-enzymatic categories of proteins that are affected by an autosomal dominant mode of inheritance.
1. Proteins involved in regulation of complex metabolic pathways subject to feedback
2. Key structural proteins
Name five characteristics of autosomal recessive inheritance.
1. Phenotype is more uniform
2. Early onset
3. Affects enzymes
4. 100% penetrance
5. New mutations are rare
Which is more affected by a sex-linked disorder: hemizygous male or a heterozygous female?
Hemizygous male
What are the three consequences of defects in enzymes?
1. Increased amount of substrate
2. Lack of essential end-product
3. Failure to inactivate tissue-damaging substrate
What is a common problem in substrate build-up and a lack of essential end-product?
Build-up of toxic metabolites
What is an example of a failure to inactivate tissue-damaging substrates?
Alpha Anti-trypsin deficiency
What is the prime example of a genetic enzyme deficiency that is unmasked when a certain drug is administered?
Glucose-6-phosphate dehydrogenase deficiency - hemolysis after sulfa drugs are administered
Marfan syndrome is a syndrome that mainly affects connective tissue of what areas?
1. CV systen
2. Skeleton
3. Eyes
What is the defective protein in Marfan syndrome?
Extracellular glycoprotein FBN-1
What is another way to describe the mutation of fibrillin-1?
Dominant negative
A defect in FBN-2 is called what and how is it inherited?
1. Congenital contractual arachnodactyly
2. AD
What is a hallmark sign of Marfan syndrome?
Bilateral subluxation (up and out) of the lens - ectopia lentis
What two major cardiovascular changes are seen in Marfan syndrome?
1. Mitral valve prolapse
2. Dilation of the ascending aorta
What type of inheritance is seen in Marfan?
AD
What is the best characterized form of EDS? What is the defect in this variant? What is the MOI?
1. Kyphoscoliosis
2. Lysyl hydroxylase
3. AR
The vascular variant of EDS involves what type of collagen?
Type III (COL3A1)
Three different mutations to COL3A1 can cause the vascular variant of EDS. How do the mutations function?
1. Decreased synthesis of pre-procollagen
2. Decreased secretion of procollagen
3. Defective type III collagen produced (dominant negative)
Dermatosparaxis EDS is caused by what? What is the MOI?
1. Defective procollagen-N-peptidase that cannot cleave Type I collagen (COL1A1 and COL1A2).
2. AR
Arthrochalasia EDS is caused by what? What is the MOI?
1. Cleavage resistant COL1A1 and COL1A2
2. AD
What is the defect in Classical EDS? What is the MOI?
1. The defect is in COL5A1 and COL5A2 (Type V collagen).
2. 30% to 50% AD
What is probably the most frequent Mendelian disorder? This results in the loss of what?
1. Familial hypercholesterolemia
2. Feedback
What is the major source of LDL?
IDL
Once cholesterol is taken into the cell, what are the three results?
1. Reduction in cholesterol synthesis - downregulation of HMG-CoA Reductase
2. Activation of cholesterol acetyltransferase - storage
3. Reduction in the production of LDL receptors
What are the five classes of mutations that can occur in familial hypercholestrolemia?
1. Null allele
2. Receptor cannot leave the ER
3. Receptor has poor LDL binding ability
4. Receptor doesn't migrate to the coated pits
5. The receptor is not properly recycled
What is the most effective treatment for familial hypercholesterolemia?
Use statins that inhibit HMG-CoA Reductase
What are two properties of enzymes used in lysosomes
1. They function in acidic enviroments
2. They are part of a special group of enzymes destined for the lysosome.
What is added to lysosomal enzymes that target them to the lysosome?
Terminal mannose-6-phosphate groups
What are six different ways a lysosomal storgae disorder can arise?
1. Synthesis of an inactive protein that cross reacts with active enzyme
2. No terminal mannose-6-phosphate
3. Lack of enzyme activator or protection protein
4. Lack of substrate activator
5. Lack of a way to remove material from the lysosome
6. Inactive enzyme
What is the defective enzyme in Tay-Sachs disease? What accumulates?
1. Hexosaminidase A - Alpha subunit
2. GM2 gangliosides
What do lysosomes look like histologically in Tay-Sachs?
Lysosomes look like they are filled with onion-skin layers of membrane.
What proliferates in Tay-Sachs?
Microglia
What actually causes a macular cherry spot?
The accentuation of the normal color of the retina by the pale color of swollen ganglion cells.
When are signs and symptoms first seen in Tay-Sachs disease?
Six months
When is death in Tay-Sachs?
2-3 years of age
What enzyme is involved in Sandoff disease?
Beta sub-unit of hexosaminidase A
What is the defect in the Niemann-Pick diseases?
Defect in sphingomyelinase
Which type of Niemann-Pick disease is the infantile form?
Type A
Which type of Niemann Pick disease only has organomegally?
Type B
What type of mutation causes the defect in Niemann-Pick disease?
Missense mutation
The lysosomes of what kind of cells are affected in Niemann-Pick disease?
Mononuclear phagocyte system
What is the special term for a histological finding in Niemann-Pick disease?
Zebra bodies
How often is a macular cherry spot seen in Niemann-Pick disease?
1/3 to 1/2
What is the most common type of Niemann-Pick disease?
Type C
What is the defect in Niemann-Pick type C?
NPC-1 gene involved in cholesterol trafficking
What is the most common presentation of Niemann-Pick type C?
1. Ataxia
2. SNP
3. Psychomotor regression
4. Hepatosplenomegaly
5. Dysarthria
What is the most common lysosomal storage disorder? What is the defect in this disorder?
1. Gaucher
2. Glucocerebrocidase
What are the three clinical sub-types of Gaucher?
1. Type I - Chronic non-neuronopathic
2. Type II - Infantile - acute neuronopathic
3. Type III - intermediate
What types of symptoms are seen in Type I Gaucher?
Splenic and skeletal disease
What types of symptoms are seen in Type II Gaucher?
CNS involvement due to no activity of glucocerebrocidase.
What do Gaucher cells look like?
Cytoplasm has a fibrillary appearance - that of crushed tissue paper
Cytoplasm has a fibrillary appearance - that of crushed tissue paper
Guacher Cell
Why are there skeletal problems in Type I Gaucher?
They are due to the fact that Gaucher cells infiltrate the bone marrow causing bone erosion.
What is a Gaucher cell?
Phagocytic cell with lots of infiltrated glucocerebroside.
What is often seen in Type I Gaucher due to spleen involvement?
Cytopenias
What levels are elevated in macrophages in Gaucher disease?
Chitotriosidase
Mucopolysaccharidoses involve the accumulation of what?
1. Heparan sulfate
2. Dermatn sulfate
3. Karatan sulfate
4. Chondroitin sulfate
The enzymes in mucopolysaccharidoses are supposed to cleave what?
Terminal sugars
Hurler syndrome is due to a deficiency of what enzyme?
Alpha-1 iduronidase
When does one usually die of Hurler syndrome?
Age of 6
What is seen in Hurler syndrome but is not seen in Hunter syndrome?
Corneal clouding
Hunter syndrome is due to a deficiency of what enzyme?
Alpha-1 iduronidase - milder than Hurler
What are the most common symptoms seen in MPS?
1. Hepatosplenomegaly
2. Skeletal deformities
3. Valvular lesions
4. Subendothelial arterial deposits
What are the usual causes of death in MPSs?
MI and cardiac decompression
Balloon cells are associated with what type of diseases?
MPSs
How is Hunter syndrome inherited?
X-linked
What are the three major subtypes of glycogenoses?
1. Hepatic - von Gierke
2. Myopathic - McArdle or Type VII
3. Systemic - Pompe
What is the deficient enzyme in von Gierke disease?
Glucose-6-phosphotase
What dominates the clinical picture in von Gierke disease?
1. Heptatomegaly
2. Hypoglycemia
What is the deficient enzyme in McArdle's disease?
Muscle phosphorylase
What is the deficient enzyme in Type VII glycogenosis?
PFK
What dominates the clinical picture in McArdle and Type VII glycogenosis?
1. Muscle weakness
2. Muscle cramping
3. Lack of exercise induced lactic acid build-up
What is the deficient enzyme in Pompe disease?
Alpha-glucosidase (Acid maltase)
Pompe disease usually results in what?
Early death
What is the deficient enzyme in Alkaptonuria? What builds up?
1. Homogentisic oxidase
2. Homogentisic acid
What is a hallmark of Alkaptonuria?
Black urine
What is a major histological sign of Alkaptonuria?
Ochronosis
What is a consequence of ochronosis?
Degeneration of articular joints
What is the usual point of attack for ochronosis and when does it manifest?
1. Intervertebral disc
2. 30's
Leber hereditary optic neuropathy is passed on how?
Mitochondrial genes
What is the main outcome of Leber hereditary optic neuropathy?
Progressive bilateral loss of central vision between the ages of 15 to 35