Correct Answer: C. Cysteine
Cystathionine β-synthase (CBS) deficiency causes homocystinuria, a classic inborn error of amino acid metabolism. The enzyme catalyzes the condensation of homocysteine and serine to form cystathionine, the first committed step in the transsulfuration pathway that converts methionine-derived homocysteine into cysteine. When CBS is deficient, homocysteine accumulates (causing vascular thrombosis, lens dislocation, and skeletal abnormalities), while cysteine becomes deficient because it cannot be synthesized from homocysteine. The clinical triad of tall stature, lens dislocation (ectopia lentis), and intellectual disability (if untreated) is pathognomonic. Since the patient cannot produce cysteine endogenously, it becomes a conditionally essential amino acid and must be supplemented. Cysteine supplementation bypasses the enzymatic block, provides the sulfur-containing amino acid needed for protein synthesis and glutathione formation, and reduces the metabolic drive to produce more homocysteine. Additionally, vitamin B6 (pyridoxine) is given to enhance residual CBS activity, and dietary methionine restriction reduces substrate flux into the pathway. This is the standard management in Indian pediatric centers following Harrison and biochemistry textbooks.
Why the other options are wrong
A. Tyrosine — Tyrosine is a nonessential amino acid synthesized from phenylalanine via tyrosine hydroxylase. It is not involved in the transsulfuration pathway and does not address the cysteine deficiency caused by CBS deficiency. This is a distractor that tests whether students confuse different amino acid metabolic pathways. B. Serine — Serine is a substrate for the CBS enzyme (it condenses with homocysteine to form cystathionine). Supplementing serine would only increase substrate availability and worsen homocysteine accumulation without providing the missing cysteine. This is an NBE trap for students who recognize serine's role in the pathway but miss that the block prevents cysteine synthesis. D. Methionine — Methionine is the precursor amino acid that is metabolized to homocysteine. In CBS deficiency, methionine is actually restricted in the diet to reduce homocysteine accumulation and prevent thrombotic complications. Supplementing methionine would be harmful, making this a critical distractor testing understanding of management strategy.
High-Yield Facts
- Cystathionine β-synthase deficiency causes homocystinuria with the triad of ectopia lentis, tall stature, and intellectual disability (if untreated).
- Cysteine becomes conditionally essential in CBS deficiency because the transsulfuration pathway is blocked and endogenous synthesis is impossible.
- Homocysteine accumulation (not cysteine deficiency) causes the vascular and skeletal manifestations; cysteine supplementation indirectly reduces homocysteine by decreasing metabolic drive.
- Management triad: cysteine supplementation + pyridoxine (B6) to enhance residual enzyme activity + methionine restriction to reduce substrate.
- Serine and methionine are contraindicated as supplements because serine increases substrate flux and methionine increases homocysteine production.
Mnemonics
CBS Deficiency → Cysteine Needed (C→C rule) Cystathionine β-synthase deficiency → Cysteine supplement. The enzyme is blocked, so cysteine (the product) becomes deficient and must be given. Methionine (the substrate) must be restricted, not supplemented. Homocystinuria Triad: ELI Ectopia lentis, Long stature (tall), Intellectual disability. This is the classic presentation of untreated homocystinuria from CBS deficiency.
NBE Trap
NBE pairs CBS deficiency with serine (a substrate in the pathway) to trap students who recognize serine's biochemical role but fail to understand that supplementing substrate worsens the problem. The correct answer requires knowing that the product (cysteine) is deficient, not the substrate.
Clinical Pearl
In Indian pediatric practice, early diagnosis of homocystinuria via newborn screening (where available) and prompt cysteine supplementation can prevent lens dislocation and intellectual disability. A tall, thin child with ectopia lentis should raise suspicion for CBS deficiency, and plasma homocysteine and methionine levels confirm the diagnosis.
_Reference: Harrison Ch. 370 (Disorders of Amino Acid Metabolism); KD Tripathi Ch. 32 (Amino Acid Metabolism)_