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Dihydrofolate reductase
25%
69/274
Inosine monophosphate (IMP) dehydrogenase
14%
37/274
Methionine synthase
9%
25/274
Pyruvate kinase
11%
29/274
Ribonucleotide reductase
38%
103/274
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The most likely diagnosis in this case is sickle cell anemia, which is caused by a mutation in the beta hemoglobin chain from glutamate to valine at the 6th position. It is often treated with hydroxyurea, an inhibitor of the enzyme ribonucleotide reductase. The family history and early age of onset suggest that the patient’s disease has a genetic component. The disorder itself should then be classified as an anemia as shown by the symptom of fatigue and the presence of a peripheral blood smear. The next step is to either recognize the presence of sickled red blood cells on the peripheral blood smear or to recognize the pain crises and acute chest syndrome as representative of sickle cell anemia, a diagnosis that is supported by the patient’s African American demographic. One pharmacologic treatment of sickle cell anemia is induction of fetal hemoglobin through the use of hydroxyurea. Hydroxyurea normally acts through inhibition of ribonucleotide reductase, though the mechanism of HbF induction is unclear and discussed below. Figure A is a peripheral blood smear that shows sickled red blood cells characteristically found in homozygous sickle cell anemia patients. Incorrect Answers: Answer 1: Dihydrofolate reductase is inhibited by the folinic acid analog methotrexate. Methotrexate is used in the treatment of rheumatoid arthritis (which can present with anemia of chronic disease), psoriasis, and inflammatory bowel disease, but has no role in the treatment of sickle cell anemia. Answer 2: IMP dehydrogenase is inhibited by mycophenolate mofetil. This drug acts by inhibiting development of immune cells and can be used as transplant rejection prophylaxis and treatment of lupus. Though IMP dehydrogenase is also in the nucleotide synthesis pathway, it is not targeted by any sickle cell anemia drugs. Answer 3: Methionine synthase requires both vitamin B12 and folate as cofactors in order to convert homocysteine to methionine. The administration of either vitamin will therefore affect the activity of this enzyme. Both folate deficiency and B12 deficiency would present with a megaloblastic anemia rather than sickle cell anemia. Answer 4: Pyruvate kinase deficiency is a possible inherited cause of an exercise induced intravascular hemolytic anemia similar to sickle cell anemia; however, it would not present with sickled cells on peripheral blood smear nor the pain crises seen in this case. There is also no drug currently available to target pyruvate kinase. Bullet Summary: Sickle cell anemia commonly presents with a constellation of pain symptoms due to occlusion of the microvasculature by abnormal red blood cells. One common treatment for sickle cell anemia is increasing the production of fetal hemoglobin (which does not contain the mutated beta chain) through administration of hydroxyurea.
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