Homocystinuria due to cystathionine beta-synthase (CBS) deficiency causes intellectual disability, ectopia lentis (downward), marfanoid habitus, and thromboembolic events. Pyridoxine (B6) supplementation helps ~50% of patients. What is the biochemical rationale?

• A Pyridoxine promotes alternative transsulfuration via betaine-homocysteine methyltransferase
• B PLP activates methionine adenosyltransferase to consume methionine before it forms homocysteine
• C Pyridoxine induces MTHFR expression, increasing 5-methylTHF for remethylation of homocysteine
• D CBS requires pyridoxal phosphate (PLP) as cofactor; responsive mutations retain partial enzyme activity that is normalized by PLP excess — a cofactor-responsive enzyme defect ✓

Explanation

CBS condenses homocysteine + serine → cystathionine (transsulfuration pathway), requiring pyridoxal phosphate (PLP, derived from B6). In pyridoxine-responsive CBS deficiency, missense mutations reduce the enzyme's affinity for PLP but do not eliminate activity. Supraphysiological PLP (from high-dose B6) restores sufficient catalytic activity to normalize homocysteine levels. Pyridoxine-non-responsive patients require dietary methionine restriction and betaine supplementation (betaine donates a methyl group to remethylate homocysteine → methionine via BHMT). Lens dislocation is downward (vs. upward in Marfan syndrome).

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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