Spherocytosis and osmotic fragility
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Spherocytosis and osmotic fragility
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[post_date] => 2024-12-23 18:05:47
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[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Hereditary spherocytosis is a genetic disease characterized by the production of red blood cells with an abnormally spherical shape. The disease is inherited in an autosomal dominant fashion and is most prevalent in individuals of Northern European ancestry (frequency estimated at 1 in 2000 individuals in the population). Spherical erythrocytes are broken down in the systemic circulation (hemolysis), and thus patients with spherocytosis often show signs of jaundice (yellowing of skin and sclera) and anemia, which leads to shortness of breath with exertion.
Given that spherical erythrocytes are more susceptible to osmotic stress, the osmotic fragility test can be used to identify patients who have spherocytosis. When normal red blood cells are placed in a dilute saline solution, the biconcave disk stretches and assumes a spherical shape. With increasing osmotic stress, hemoglobin begins to appear in the surrounding solution. As Figure 1 illustrates, the erythrocyte membrane remains intact when placed in an isotonic 0.9% saline solution. With increasingly dilute saline solutions, hemoglobin starts to be detected in the surrounding solution. Eventually, erythrocytes burst from osmotic stress and all hemoglobin exits the cell.
Figure 1: Progressive cell membrane disruption seen in the erythrocyte osmotic fragility test
The amount of hemoglobin that has exited the cell and entered the solution can be measured with spectroscopy; in this method, the percent of hemolysis is calculated by dividing the measured absorbance by the absorbance at 100% hemolysis. Sample hemolysis curves are shown in Figure 2.
Figure 2: Hemolysis curves for the osmotic fragility experiment
Visual analysis of experimental test tubes can also be used to compare erythrocyte samples.
Figure 3: Graphical representation of test tube coloration from the osmotic fragility experiment
[post_title] => Spherocytosis and osmotic fragility
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[question] => What is the frequency of the spherocytosis disease-causing allele in the Northern European population?
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[answer] => 2
[description] => Reason for Correct Answer:
The passage says that the frequency of the disease hereditary spherocytosis is 1 in 2000 individuals.
So, frequency of disease itself = 1/2000 = 0.0005 = 5 x 10⁻⁴
If you have a hard time calculating that, try calculating 1/1000 (=0.001) first, then take half of that.
Now, the question is asking you for the frequency of the disease-causing allele. This is easier because it’s an autosomal dominant condition, as stated in the passage.
In an autosomal dominant condition, the frequency of the disease-causing allele is the same as the frequency of the disease, because every carrier has the disease. Therefore, the frequency of the disease allele is 5 x 10⁻⁴.
Note that if this were an autosomal recessive condition, where two copies of the allele were needed for the disease to occur, then the disease would have a frequency of q^2, where q is the frequency of the allele. In this case, you would use the square root of the disease frequency to determine the allele frequency.
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[answers] => Array
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[each_answer] => A. 5 x 10⁻³
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[each_answer] => B. 5 x 10⁻⁴
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[2] => Array
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[each_answer] => C. √(5 x 10⁻³)
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[each_answer] => D. √(5 x 10⁻⁴)
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => Which community is most likely to exhibit the highest prevalence of hereditary spherocytosis due to limited genetic variation?
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[answer] => 2
[description] => Reason for Correct Answer:
In small, isolated communities, limited genetic variation and a small population size can lead to a higher prevalence of hereditary spherocytosis.
This is especially the case in a community where a specific genetic variation is introduced and then passed down through generations.
In fact, the founder effect is a phenomenon in genetics that occurs when a small group of individuals separates from a larger population and establishes a new, isolated population. Due to the small number of individuals in the founding population, the genetic makeup of the new population is largely determined by the genes of the founders.
The best example of this is a remote fishing community of 1000 established by a family with hereditary spherocytosis. Although the passage suggests that spherocytosis is relatively common in the Northern European population, an isolated population such as that described in Choice B would be most likely to have a disproportionate number of disease cases if their founders had the disease, regardless of the prevalence in the broader North African population.
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[each_answer] => A. A Northern African mid-sized city of 100,000 with an established hereditary spherocytosis database with several enrolled patients
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[each_answer] => B. A Northern African remote fishing community of 1000 established by a family with hereditary spherocytosis
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[each_answer] => C. A Northern European large city of 1 million
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[3] => Array
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[each_answer] => D. A Northern European remote mining town of 250
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[quiz_unique_key] => 1403770772
[question] => Why do patients with hereditary spherocytosis develop shortness of breath with exertion?
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[answer] => 3
[description] => Reason for Correct Answer:
The normal shape of a red blood cell is a biconcave disc; the cell is concave on both sides, creating a dimpled, disc-like shape. In spherocytosis, red blood cells become more rounded.
The normal biconcave shape of a red blood cell allows it to have a larger surface area relative to its volume compared with a spherical cell. A larger surface area allows more molecules, such as oxygen and carbon dioxide, to be exchanged across the cell membrane, enhancing the efficiency of respiratory processes.
A spherical red blood cell, on the other hand, would have a lower surface area to volume ratio and less oxygen-carrying capacity.
The spleen plays a vital role in filtering the blood and removing abnormal or damaged red blood cells from circulation.
In the case of hereditary spherocytosis, where red blood cells have a spherical shape instead of the normal biconcave disc shape, these abnormal cells are more prone to getting trapped and broken down in the spleen.
There is therefore increased splenic activity and splenic removal of red blood cells, as well as lower surface area to volume ratio and lower oxygen-carrying capacity in cases of spherocytosis. These both contribute to low oxygen levels and a feeling of shortness of breath, particularly in conditions requiring increased oxygen consumption.
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[each_answer] => A. Increased erythrocyte surface area to volume ratio and increased splenic activity
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[each_answer] => B. Increased erythrocyte surface area to volume ratio and decreased splenic activity
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[each_answer] => C. Decreased erythrocyte surface area to volume ratio and increased splenic activity
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[each_answer] => D. Decreased erythrocyte surface area to volume ratio and decreased splenic activity
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[quiz_unique_key] => 1403770772
[question] => What key interaction forms the basis of the osmotic stress in the osmotic fragility experiment?
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[answer] => 4
[description] => Reason for Correct Answer:
In the osmotic fragility experiment, the cells swell and eventually burst when the salt concentration is lowered below normal saline concentration (0.9%).
This means that the osmotic fragility experiment is based on the extracellular environment being hypotonic relative to the inside of the cell.
The key process underlying the bursting of the red blood cells is the sudden influx of water via osmosis in an attempt to equilibrate the dilute (outside) and concentrated (inside) solutions across the erythrocyte membrane.
The movement of water via osmosis driven by the osmotic pressure gradient between the inside of the cell and the extracellular hypotonic environment forms the basis of the osmotic stress demonstrated in the osmotic fragility experiment.
Eventually, the red blood cells swell up so much that they burst. When this happens, the hemoglobin exits the cell via the natural disruption of the cellular membrane and not via membrane channels.
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[answers] => Array
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[0] => Array
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[each_answer] => A. The movement of hemoglobin through membrane channels driven by the pressure gradient between the inside of the cell and the extracellular hypotonic environment
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[each_answer] => B. The movement of water via osmosis driven by the pressure gradient between the inside of the cell and the extracellular hypertonic environment
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[each_answer] => C. The movement of hemoglobin through membrane channels driven by the pressure gradient between the inside of the cell and the extracellular hypertonic environment
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[each_answer] => D. The movement of water via osmosis driven by the pressure gradient between the inside of the cell and the extracellular hypotonic environment
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[question] => In Figures 2 and 3, respectively, which curve and sample do you expect to represent behavior demonstrated by red blood cells taken from a patient with hereditary spherocytosis?
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[answer] => 4
[description] => Reason for Correct Answer:
Hereditary spherocytosis erythrocytes are more susceptible to osmotic stress, so they begin to hemolyze even when the solution is fairly close to isotonic (0.9%) concentration.
In Figure 3, a greater degree of hemoglobin exiting the erythrocytes should lead to darker coloration in the test tubes, as the solution becomes more hypotonic.
This is seen in Sample B.
Figure 2 is the same concept, but represented differently. The passage explains how absorbance is proportional to the percent hemolysis. This means that if you’re looking for the most fragile red blood cells, you’re looking for samples that show higher absorbance even in more concentrated solutions – in other words, the blood cells are bursting faster as the concentration of the surrounding solution is lowered.
This is shown in Curve Z. This curve shows that the sample starts absorbing when the concentration of the solution is lowered to only 0.8 % NaCl. Unlike the other samples, these red blood cells must be more fragile and burst in a less hypotonic/more hypertonic solution.
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[each_answer] => A. Curve Y and Sample A
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[each_answer] => B. Curve Z and Sample A
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[each_answer] => C. Curve Y and Sample B
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[each_answer] => D. Curve Z and Sample B
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[quiz_unique_key] => 1325138223
[question] => Red blood cells were treated with either a 0.05 M (0.3%) solution of NaCl or a 0.05 M solution of compound X. The hemolysis of the cells was greater in the NaCl solution than solution X. What is the most likely identity of compound X?
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[answer] => 3
[description] => Reason for Correct Answer:
Because the hemolysis was greater in NaCl than solution X, you are looking for a solution that would apply less osmotic stress to red blood cells when used at an equivalent molar concentration.
This means that solution X must be hypertonic relative to an equally concentrated solution of NaCl.
Therefore, you are looking for a solution that has more dissolved particles than NaCl even though it is at the same molar concentration.
The only compound that fulfills this criterion is MgCl2. When dissolved, it dissociates into three particles (one Mg2+ ion and two Cl— ions), whereas NaCl only dissociates into two particles (one Na+ ion and one Cl— ion).
Because MgCl2 has the most ions, you can answer this without doing any calculations. However, the math would go like this: a 0.05 M solution of MgCl2 will have 0.15 M of dissolved ions (0.05 x 3), and a 0.05 M solution of NaCl will have 0.1 M of dissolved ions (0.05 x 2). Therefore, the MgCl2 solution has a higher osmolarity.
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[each_answer] => A. NaI
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[each_answer] => B. Glucose
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[each_answer] => C. MgCl2
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[each_answer] => D. KCl
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Figure 1:
Figure 2:
Figure 3:
