A 22-year-old man presents with progressive fatigue, pallor, and bronze skin pigmentation. CBC shows microcytic hypochromic anemia (Hb 8.0 g/dL, MCV 72 fL) with basophilic stippling and dimorphic red cell population. Bone marrow Prussian blue stain reveals ringed sideroblasts (15% of erythroid precursors). Serum ferritin is markedly elevated at 1,800 ng/mL with transferrin saturation of 95%. Genetic testing reveals a hemizygous missense mutation in the gene located on the structure marked **A** in the diagram. Which of the following best describes the pathophysiologic consequence of this mutation?

Question

A 22-year-old man presents with progressive fatigue, pallor, and bronze skin pigmentation. CBC shows microcytic hypochromic anemia (Hb 8.0 g/dL, MCV 72 fL) with basophilic stippling and dimorphic red cell population. Bone marrow Prussian blue stain reveals ringed sideroblasts (>15% of erythroid precursors). Serum ferritin is markedly elevated at 1,800 ng/mL with transferrin saturation of 95%. Genetic testing reveals a hemizygous missense mutation in the gene located on the structure marked **A** in the diagram. Which of the following best describes the pathophysiologic consequence of this mutation?

Accepted Answer

D. Loss of ALAS2 activity prevents heme synthesis, causing iron accumulation in mitochondria and formation of ringed sideroblasts. ## Why option 1 is correct

The structure marked **A** is Chromosome X (ALAS2, Xp11.21). ALAS2 encodes erythroid 5-aminolevulinate synthase, the first and rate-limiting enzyme of heme biosynthesis. It catalyzes the condensation of glycine and succinyl-CoA to form δ-aminolevulinic acid using pyridoxal 5'-phosphate (vitamin B6) as a cofactor. Loss-of-function mutations in ALAS2 halt protoporphyrin IX synthesis, preventing iron incorporation into heme. Iron delivered to erythroid mitochondria therefore accumulates as ferritin within mitochondria surrounding the nucleus—the pathognomonic ringed sideroblast. This mechanism directly explains the patient's presentation: microcytic hypochromic anemia (iron cannot be used for hemoglobin), ringed sideroblasts on bone marrow examination, and secondary iron overload (high ferritin and transferrin saturation). X-linked sideroblastic anemia (XLSA) is the most common congenital sideroblastic anemia (Harrison 21e, Cazzola Blood 2015).

## Why each distractor is wrong

- **Option 2 (PKLR)**: PKLR encodes pyruvate kinase and is located on chromosome 1, not the anchor structure **A**. Pyruvate kinase deficiency causes hemolytic anemia with spherocytes, not ringed sideroblasts or iron accumulation. The clinical picture does not fit pyruvate kinase deficiency.

- **Option 3 (SPTB)**: SPTB encodes β-spectrin and is located on chromosome 14, not **A**. Spectrin mutations cause hereditary spherocytosis with membrane instability and hemolysis, not sideroblastic anemia or ringed sideroblasts. Iron overload is not a primary feature.

- **Option 4 (HBB)**: HBB encodes β-globin and is located on chromosome 11, not **A**. β-globin mutations cause sickle cell disease or thalassemia, not X-linked sideroblastic anemia. While thalassemia can cause secondary iron overload, it does not produce ringed sideroblasts or result from mutations on the X chromosome at Xp11.21.

**High-Yield:** X-linked sideroblastic anemia (ALAS2 mutations) = ringed sideroblasts + iron overload WITHOUT transfusion; pyridoxine-responsive in most cases; acquired sideroblastic anemias include MDS-RS, lead poisoning, copper deficiency, isoniazid, and alcohol.

[cite: Harrison 21e Ch 96; Cazzola Blood 2015 sideroblastic]

Answer

A. Abnormal SPTB causes membrane instability and spherocyte formation with compensatory iron uptake

Answer

B. Defective PKLR function reduces ATP production in erythroid cells, leading to premature hemolysis

Answer

C. Mutated HBB results in polymerization of hemoglobin chains, trapping iron in the cytoplasm

Explanation

Why option 1 is correct

Why each distractor is wrong

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