A 23-year-old Italian American man comes to the clinic for a follow-up visit. He was found to have mild anemia during a routine checkup 3 weeks ago and was started on iron supplementation. He has been taking the supplements as prescribed. The patient has otherwise been well. He feels that his energy levels are normal, and he has run several half-marathons in the last 2 years. The patient's initial hemoglobin level was 12.3 g/dL. Laboratory results obtained during today's visit are as follows: The patient's blood smear is shown in the image below. Which of the following processes is the initial step in the pathogenesis of this patient's disorder?

Question

A 23-year-old Italian American man comes to the clinic for a follow-up visit.  He was found to have mild anemia during a routine checkup 3 weeks ago and was started on iron supplementation.  He has been taking the supplements as prescribed.  The patient has otherwise been well.  He feels that his energy levels are normal, and he has run several half-marathons in the last 2 years.  The patient's initial hemoglobin level was 12.3 g/dL.  Laboratory results obtained during today's visit are as follows:  The patient's blood smear is shown in the image below.  Which of the following processes is the initial step in the pathogenesis of this patient's disorder?

Quizplus · Accepted Answer

11ec160b_3af9_4a66_9249_ddfe2fa15276_MD0001_00 This patient has a microcytic (mean corpuscular volume [MCV] <75 µm³) anemia and increased hemoglobin A2 (α2δ2) concentration. His peripheral blood smear shows hypochromia and poikilocytes, including spherocytes and target cells (arrows). This constellation of findings in an asymptomatic adult of Mediterranean heritage suggests beta-thalassemia minor. Beta-thalassemia is the most common thalassemia in patients of Mediterranean descent; alpha-thalassemia is more common in individuals from Southeast Asia. The microcytic anemia is often incorrectly attributed to iron deficiency, but iron supplements do not benefit these patients as they are not iron deficient. Normal adult hemoglobin (hemoglobin A) contains 2 alpha chains and 2 beta chains (α2β2) in combination with heme. Beta-thalassemia affects beta-chain production and can be caused by a variety of DNA mutations affecting the transcription, processing, and translation of beta-globin mRNA. Most commonly, these mutations cause aberrant precursor mRNA splicing or premature chain termination during mRNA translation. In some cases, point mutations prevent RNA polymerase from binding to the promoter region. The resulting beta-globin deficiency occurs in the setting of normal heme and alpha-chain synthesis, leading to increased formation of hemoglobin A2 and (in some patients) hemoglobin F (α2γ2). (Choices A and G) Decreased beta-chain synthesis in beta-thalassemia results in the formation of insoluble alpha-chain tetramers that precipitate within red blood cells. This can affect the membrane cytoskeleton and reduce membrane stability. However, the initial pathogenic abnormality in beta-thalassemia is a deficiency in beta-chain synthesis. (Choice B) In patients with beta-thalassemia, the DNA replicates normally despite the mutations in the beta-globin gene. It is not until the DNA is transcribed into mRNA that hemoglobin production becomes abnormal. Anemias due to DNA synthesis defects include the megaloblastic anemias (vitamin B₁₂ or folic acid deficiency), which are characterized by an elevated MCV (>100 µm³). (Choice C) Heme is an iron-containing porphyrin that is incorporated into globin proteins to form hemoglobin. Globin synthesis, not heme synthesis, is abnormal in thalassemia syndromes. Porphyrias are disorders of heme synthesis. (Choice D) Impaired intracellular oxidant detoxification occurs with glucose-6-phosphate dehydrogenase deficiency, a cause of hemolytic anemia. (Choice F) An example of a protein folding defect is that caused by the Z mutation in the gene coding for alpha-1 antitrypsin. Educational objective: Beta-thalassemia is caused by mutations that result in defective transcription, processing, and translation of beta-globin mRNA. This leads to deficiency of the beta-globin chains required for normal hemoglobin synthesis. __________ References: Control of human beta-globin mRNA stability and its impact on beta-thalassemia phenotype. (http://www.ncbi.nlm.nih.gov/pubmed/21357703) Update on fetal hemoglobin gene regulation in hemoglobinopathies. (http://www.ncbi.nlm.nih.gov/pubmed/21157349)

A 23-Year-Old Italian American Man Comes to the Clinic for a Follow-Up