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Genetics > Lecture 6: Sickle Cell Disease and HH > Flashcards

Lecture 6: Sickle Cell Disease and HH Flashcards

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Biology 101 flashcards
1
Q

Sickle Cell Anemia (3)

A
  1. most frequent hemoglobinopathy
  2. mutation in Hb gene
  3. single amino acid change and hb polymerizes in low oxygen, deforms cells, stick in capillaries, are destroyed
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2
Q

Hemoglobinopathy

A
  1. Kind of genetic* defect that results in abnormal structure of one of the globin* chains of hb* molecule
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3
Q

Genetics of Sickle Cell Disease

A
  1. inherited in autosomal recessive pattern *
  2. when offspring inherit both defective genes (homozygous recessive) the result is sickle cell disease
  3. when offspring inherit one recessive allele and one normal (heterozygous) they are unaffected but are carrier
    - sickle cell trait
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4
Q

Sickle Cell Trait

A

When a person carries the recessive gene for sickle cell anemia

  • heterozygous expression
  • *recessive trait (sickle cell) covered up by dominant (normal)
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5
Q

Hemoglobin (3)

A
  1. tetramer
  2. each of the four globin chains binds a single heme molecule
    - 2 alpha (one from mom, one from dad)
    - 2 beta (one from mom, one from dad)
  3. four binging sites for O2
  4. function in O2 and CO2 transport
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6
Q

Sickle Cell Hb mutation (HbS) (2)

A
  1. point mutation resulting in glutamate to valine substitution at residue 6 or beta-globin chains
  2. missense mutaiton
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7
Q

HbS

Pathopysiology (4)

A
  1. presence of valine at position 6
    - promotes aggregation of HbS into larger polymers
  2. DeoxyHbS is more prone to aggregation than oxyHbS
    - low pH favors aggregation
  3. Aggregation of HbS into large polymers alters the shape of RBCs
    - sickled appearance
  4. Disease significantly changes the protein Hb A to HbS
    - DOES NOT ALTER HOW PROTEIN TRANSPORTS O2 IN BLOOD
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8
Q

Ethnic Variation of Allelic Frequency

A
  1. HbS is more common among persons whose ancestry is geographically connected to
    - sub-Saharan Africa
    - Cuba
    - South America
    - Central America
    - Saudi Arabia
    - India
    - Mediterranean Regions
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9
Q

Heterozygote Advantage (3)

A
  1. when a person inherits only one allele for HbS
    - they do not express the disease
  2. Heterozygous expression HbS is correcte with lower rates of mortality among carriers* who are of Afrian and Mediterranean descent
    - HbS allele decreased the risk of infection by malarial parasites endemic in those areas
  3. Theory: clearance of sickled cells by the spleen may explain the protection against P. falciparum.
    - parasites lower the pH which promotes sickling
    - clearance of infected cells disrupt the parasite’s life cycle
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10
Q

Phenotypic Features of Sickle cell disease (9)

A
  1. failure to thrive
  2. anemia
  3. multiple chronic infection
  4. jaundice
  5. steeling extremities
  6. painful joints
  7. priapism
  8. loss vision
  9. vas occlusive infarction to major organs
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11
Q

Clinical Diagnosis and Testing (6)

A
  1. family hx sickle cell disease of parents or proband to be known carriers
  2. newborn screening in all 50 states
  3. CBC
    - normocytic anemia with target cells
  4. hypoxia=sickle cells reported
  5. Hb solubility test
  6. Hb electrophoresis
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12
Q

Thalassemia

4 types

A
  1. collection of inherited blood d/o characterized by low Hb production

a. alpha thalassemia
b. beta thalassemia
c. beta-zero
d. beta-plus

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13
Q

Alpha-Thalassemia

A

one or more of the 4 genes for alpha-Hb are missing

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14
Q

Beta-thalassemia

A

one or two genes genes for beta-Hb are missing

*more severe than alpha

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15
Q

Beta-zero thalassemia

A

no beta chain is produced in Hb

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16
Q

Beta-plus

A

Less beta chain produced

17
Q

Other sickle cell d/o

3 types

A
  1. non-sickling beta Hb d/o such as thalassemia can interact with a sickle cell disease mutation to cause clinically significant disease
    - carrier for sickle cell procreates with thalassemia carrier?

a. sickle beta zero thalassemia
- present as sickle cell disease

b. sickle beta plus thalassemia
- sickle cell disease

c. sickle alpha thalassemia
- sickle cell trait

18
Q

Sickle beta zero thalassemia

A

clinically present as sickle cell disease

-more severe than sickle beta plus

19
Q

Sickle beta plus

A

clinically presents as sickle cell disease

20
Q

sickle alpha thalassemia

A

clinically present as sickle cell trait (NOT DISEASE)

21
Q

Hereditary Hemochromatosis (5)

A
  1. Common d/o iron metabolism
  2. too much Iron absorbed
    - toxic accumulation in parenychmal cells- particularly liver, heart, pancreas
  3. 20-40 g iron may accumulate
  4. excess iron in HH is only whithin body storage compartments
  5. Autosomal recessive inheritance*
22
Q

Clinical Hallmark advanced HH (4)

A
  1. cirrhosis
  2. diabetes
  3. skin pigmentation
  4. cardiac failure
23
Q

Phenotypic Features of HH (7)

A
  1. typically presents 40+ years old
  2. affected tissues
    - livers
    - pancreas
    - skin
    - heart
    - other organs
  3. hyper pigmented skin: bronzed diabetes
  4. fatigue
  5. joint aches
  6. male sexual dysfunction
  7. 10x more common in males than females
24
Q

Genetics HH (5)

A
  1. single mutation in HFE gene C282Y
  2. HFE protein involved in regulating the amount of dietary iron absorbed
  3. mutation causes increased amount iron absorption in intestines
    - increased iron storage in body tissues
  4. inherited autosomal recessive pattern
  5. mutations exhibit penetrance, variable expressivity, sex-influenced phenotype
25
Q

Diagnosis HH (2)

A
  1. clinical suspicion is based on
    - family hx
    - patient presentation at early or later stages of disease
  2. elevated transferrin saturation, serum ferritin concentrations and serum liver enzymes
26
Q

Early signs/symptoms HH (3)

A
  1. RUQ pain
  2. fatigue
  3. arthralgias
27
Q

Later signs/symptoms HH (8)

A
  1. hepatomegaly
  2. hepatic cirrhosis
  3. hepatocellular carcinoma
  4. diabetes mellitus
  5. cardiomyopathy
  6. hypogonadism
  7. arthritis
  8. hyper pigmented skin
28
Q

Transferrin

A

binds and transports iron in blood serum, and functions to deliver iron from absorption centers into the intestines to all tissues

29
Q

Ferritin

A

protein that stores iron inside cells

30
Q

Genetic Testing/counseling HH (3)

A
  1. routine labs
    - serum iron levels
    - serum ferritin levels
    - total iron binding capacity (TIBC)
    - transferrin saturation levels
  2. liver bx with hepatic iron index > 2
  3. PCR for HFE gene

Genetics (14 decks)

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