## Cystathionine β-Synthase Deficiency and Homocystinuria ### Transsulphuration Pathway Overview ```mermaid flowchart LR A[Methionine]:::outcome --> B[Homocysteine]:::outcome B --> C{CBS}:::decision C -->|Deficient| D[Homocysteine accumulation]:::urgent C -->|Normal| E[Cystathionine]:::outcome E --> F[Cystathionine γ-lyase]:::action F --> G[Cysteine]:::outcome G --> H[Taurine/Glutathione]:::action ``` **Key Point:** Cystathionine β-synthase (CBS) catalyzes the **first committed step** of the transsulphuration pathway: condensation of homocysteine with serine to form cystathionine. ### The Enzymatic Reaction **Homocysteine + Serine** → [CBS, pyridoxal-5'-phosphate] → **Cystathionine + H~2~O** Deficiency of CBS prevents this reaction, causing: - Accumulation of homocysteine (and its precursor methionine) - Depletion of cystathionine and downstream cysteine - Elevated plasma and urinary homocysteine (homocystinuria) ### Clinical Features of CBS Deficiency | Feature | Mechanism | |---------|----------| | Homocystinuria | Homocysteine accumulation exceeds renal threshold | | Ectopia lentis | Homocysteine cross-links lens proteins | | Marfanoid features | Connective tissue abnormalities | | Thrombosis | Homocysteine damages endothelium | | Intellectual disability | Neurological effects of homocysteine | | Seizures | CNS involvement | **High-Yield:** CBS is a **pyridoxal-5'-phosphate (B~6~)-dependent enzyme**. Some cases of homocystinuria respond to high-dose vitamin B~6~ supplementation (B~6~-responsive CBS deficiency). **Mnemonic:** **CBS = Cystathionine β-Synthase** — the enzyme that makes cystathionine from homocysteine. If CBS is deficient, homocysteine cannot be converted forward → accumulation. **Clinical Pearl:** Homocystinuria is one of the few inborn errors of amino acid metabolism that presents with thrombosis as a major feature, distinguishing it from other aminoacidopathies.
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