A 16-year-old boy from rural Maharashtra presents with acute ischemic stroke. On examination, he is tall with long limbs, arachnodactyly, and bilateral downward lens dislocation. Serum homocysteine is markedly elevated (100 μmol/L) and urine shows homocysteine crystals. The structure marked **B** in the diagram is deficient due to an autosomal recessive mutation. Which of the following best explains the pathophysiology of his thromboembolic presentation?

Question

A 16-year-old boy from rural Maharashtra presents with acute ischemic stroke. On examination, he is tall with long limbs, arachnodactyly, and bilateral downward lens dislocation. Serum homocysteine is markedly elevated (>100 μmol/L) and urine shows homocysteine crystals. The structure marked **B** in the diagram is deficient due to an autosomal recessive mutation. Which of the following best explains the pathophysiology of his thromboembolic presentation?

Accepted Answer

A. Deficiency of the enzyme at **B** prevents conversion of homocysteine to cystathionine, causing homocysteine accumulation which is endothelium-toxic and prothrombotic. ## Why option 1 is correct

The structure marked **B** is cystathionine β-synthase (CBS), the enzyme that catalyzes the first committed step of the transsulfuration pathway: conversion of homocysteine + serine → cystathionine. In classical homocystinuria (autosomal recessive CBS deficiency), this enzyme is absent or severely reduced, preventing homocysteine metabolism. Homocysteine accumulates to toxic levels (>100 μmol/L) in blood and urine. Homocysteine is directly endothelium-toxic, activates coagulation factors, and promotes platelet aggregation, making it a potent prothrombotic agent. This explains the clinical tetrad of homocystinuria, including premature thromboembolic disease (strokes, MIs, DVTs in young patients). The downward lens dislocation (ectopia lentis downward and inward) is pathognomonic for homocystinuria and distinguishes it from Marfan syndrome (where lens dislocation is upward and outward). [Harper 32e Ch 29; Harrison 21e Ch 414]

## Why each distractor is wrong

- **Option 2**: While CBS deficiency does affect the transsulfuration pathway and may indirectly reduce SAM availability, the primary pathophysiology of thrombosis in homocystinuria is NOT reduced methylation but rather direct homocysteine toxicity and prothrombotic effects. SAM depletion is not the mechanism of the thromboembolic phenotype.
- **Option 3**: Although cysteine synthesis is reduced in CBS deficiency (cysteine is normally produced downstream of cystathionine), the clinical thrombotic complications are NOT primarily due to reduced glutathione. Glutathione deficiency would manifest as oxidative stress and hemolysis, not the specific prothrombotic phenotype seen in homocystinuria.
- **Option 4**: CBS deficiency does not cause secondary MTHFR inhibition. MTHFR (marked **D**) catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate. CBS deficiency affects the transsulfuration pathway, not folate metabolism. This is a conceptual confusion between two separate metabolic pathways.

**High-Yield:** Classical homocystinuria = CBS deficiency → homocysteine accumulation → endothelium toxicity + prothrombosis + Marfanoid features + DOWNWARD lens dislocation (not upward like Marfan). Always screen young stroke patients for homocysteine.

[cite: Harper 32e Ch 29; Harrison 21e Ch 414]

Answer

B. Deficiency of the enzyme at **B** impairs methylation reactions, reducing S-adenosylmethionine (SAM) production and increasing platelet aggregation

Answer

C. Deficiency of the enzyme at **B** prevents synthesis of cysteine, leading to reduced glutathione and loss of antioxidant protection

Answer

D. Deficiency of the enzyme at **B** causes secondary MTHFR inhibition, trapping folate as methyltetrahydrofolate and reducing DNA synthesis

Explanation

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