Classic homocystinuria due to cystathionine β-synthase (CBS) deficiency presents with ectopia lentis (downward), Marfanoid habitus, intellectual disability, and thromboembolism. Pyridoxine (B6) at high doses reduces homocysteine levels in responsive patients. What is the biochemical basis of this pyridoxine responsiveness?

• A Pyridoxine increases MTHFR activity, diverting homocysteine toward remethylation
• B CBS requires pyridoxal phosphate (PLP) as a cofactor; high doses stabilise residual mutant enzyme by increasing cofactor saturation ✓
• C Pyridoxine directly activates methionine synthase to consume homocysteine
• D Pyridoxine activates betaine-homocysteine methyltransferase, converting homocysteine to methionine

Explanation

CBS is a PLP-dependent enzyme. Approximately 50% of CBS-deficient patients carry missense mutations that reduce the enzyme's affinity for PLP but retain some residual catalytic potential. Pharmacologic doses of pyridoxine (50–500 mg/day) raise PLP levels sufficiently to saturate these mutant enzymes, partially restoring transsulfuration of homocysteine to cystathionine. Pyridoxine does not activate MTHFR (which requires FAD/riboflavin) or methionine synthase (which requires B12/cobalamin); betaine supplementation is used for B6-non-responsive patients.

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

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