cystathionine beta-synthase

**Biochemistry / Pathway** - Methionine → SAM → SAH → homocysteine. Homocysteine has two fates: (1) remethylation to methionine (methionine synthase; requires B12 and N5-methyl-THF; or betaine-homocysteine methyltransferase in liver/kidney using betaine) or (2) transsulfuration: homocysteine + serine → cystathionine via CBS (cofactor: PLP/vitamin B6). Cystathionine is then cleaved by cystathionase (cystathionine gamma-lyase, also B6-dependent) to cysteine + alpha-ketobutyrate. - Cysteine becomes essential in CBS deficiency (it is normally synthesized from methionine via this pathway). - CBS is also regulated allosterically: activated by S-adenosylmethionine (SAM). It also uses heme as a cofactor and generates H2S.

**Classic homocystinuria (CBS deficiency)** - Autosomal recessive; gene on chromosome 21q22.3. - Labs: markedly elevated homocysteine (plasma and urine) and methionine; low cysteine. Urine cyanide-nitroprusside test is positive. - Clinical features (mnemonic: "HOMOCYSTINURIA" — Homocysteine in urine, Osteoporosis, Marfanoid habitus, Ocular changes (ectopia lentis), Cardiovascular (thrombosis), Kyphosis, Intellectual disability, Stroke): - Ectopia lentis: downward and inward (inferonasal) lens dislocation (vs. Marfan: upward and outward/superotemporal) - Marfanoid habitus, long limbs, arachnodactyly, pectus deformity, scoliosis - Intellectual disability / developmental delay, seizures, psychiatric disease - Thromboembolism (venous and arterial: stroke, MI, DVT, PE) — the major cause of morbidity/mortality; homocysteine damages endothelium and promotes a prothrombotic state - Premature atherosclerosis, osteoporosis - Fair skin, malar flush/livedo reticularis - Key differentiator from Marfan: homocystinuria has intellectual disability, thrombosis, and lens dislocation in a different direction; Marfan has aortic root dilation/dissection and mitral valve prolapse, and normal intelligence.

**Treatment** - Vitamin B6 (pyridoxine) — about 50% of patients are B6-responsive (mutations affecting cofactor binding) - Low-methionine diet with cysteine supplementation (cysteine becomes essential) - Betaine (trimethylglycine) — promotes remethylation of homocysteine to methionine, lowering homocysteine - Folate and B12 supplementation as adjuncts - Anticoagulation/perioperative hydration as needed to prevent thrombosis (avoid nitrous oxide anesthesia)

**Differential for hyperhomocysteinemia** - CBS deficiency: ↑ homocysteine, ↑ methionine, ↓ cysteine - Methionine synthase / B12 deficiency / MTHFR deficiency or folate deficiency: ↑ homocysteine, ↓ or normal methionine (± methylmalonic acid ↑ in B12 deficiency, which also causes megaloblastic anemia) - Homocysteine remethylation defects (e.g., cobalamin C disease): ↑ homocysteine, ↑ methylmalonic acid, low/normal methionine - Cystathionine gamma-lyase deficiency (cystathioninuria): benign

**High-yield associations** - Down syndrome: CBS is on chromosome 21 and is overexpressed (trisomy 21), leading to low homocysteine levels. - Newborn screening: elevated methionine (not always reliable for B6-responsive forms). - Elevated homocysteine is an independent risk factor for atherosclerosis/thrombosis; however, lowering it with B vitamins in the general population has not reduced cardiovascular events.