A 34-year-old previously healthy man comes to the emergency department due to a 3-hour history of chest pain, diaphoresis, and dyspnea. He does not smoke, exercises regularly, and eats a balanced diet. His father died at age 56 from a myocardial infarction. His blood pressure is 110/70 mm Hg and pulse is 110/min and regular. Physical examination is unremarkable. ECG shows ST elevation in the anterolateral leads. Coronary angiogram reveals proximal left anterior descending artery stenosis and thrombosis, which is treated with angioplasty and stent placement. Laboratory results are as follows: Further testing reveals a homozygous mutation in the methylene tetrahydrofolate reductase gene that leads to decreased enzymatic activity. Due to this defect, the patient most likely has impairment converting homocysteine to which of the following?

Question

A 34-year-old previously healthy man comes to the emergency department due to a 3-hour history of chest pain, diaphoresis, and dyspnea.  He does not smoke, exercises regularly, and eats a balanced diet.  His father died at age 56 from a myocardial infarction.  His blood pressure is 110/70 mm Hg and pulse is 110/min and regular.  Physical examination is unremarkable.  ECG shows ST elevation in the anterolateral leads.  Coronary angiogram reveals proximal left anterior descending artery stenosis and thrombosis, which is treated with angioplasty and stent placement.  Laboratory results are as follows:  Further testing reveals a homozygous mutation in the methylene tetrahydrofolate reductase gene that leads to decreased enzymatic activity.  Due to this defect, the patient most likely has impairment converting homocysteine to which of the following?

Quizplus · Accepted Answer

11ec160b_36a4_6f5e_9249_ad230ec31601_MD0001_00 Elevated levels of plasma homocysteine are an independent risk factor for thrombotic events, including venous thromboses, coronary artery disease, and ischemic stroke. The mechanism is thought to be due to direct and indirect induction of endothelial damage. Homocysteine can be metabolized to methionine via remethylation or to cystathionine via transsulfuration. Remethylation to methionine occurs with the donation of a methyl group from methyl-tetrahydrofolate via methionine synthase, with vitamin B₁₂ (cobalamin) as an important cofactor. Methyl-tetrahydrofolate is regenerated by the enzyme methylene tetrahydrofolate reductase (MTHFR), using FAD as a cofactor. Homocysteine can also undergo transsulfuration via cystathionine-β-synthase to cystathionine (Choice A) and subsequently to cysteine (Choice B) via the enzyme cystathionase, using vitamin B₆ as a cofactor. Elevations in plasma homocysteine can occur due to genetic mutations in critical enzymes and vitamin (cofactor) deficiencies. MTHFR deficiency is the most common genetic cause of hyperhomocysteinemia. Low levels of the B vitamins cobalamin, pyridoxine, and folate are associated with hyperhomocysteinemia. However, supplementation of B vitamins for patients with mildly to moderately elevated homocysteine levels has not demonstrated a decrease in cardiovascular risk or mortality. (Choices D and E) Vitamin B₁₂ is a cofactor for the enzyme methylmalonyl-CoA mutase in the conversion of methylmalonyl-CoA to succinyl-CoA, a reaction that occurs in the breakdown of odd-chain fatty acids and some amino acids. As a result, patients with vitamin B₁₂ deficiency have elevated methylmalonyl-CoA levels that subsequently result in buildup of neurotoxic methylmalonic acid. Symptomatic consequences include lethargy, seizures, paresthesias, and hypotonia. Homocysteine is elevated in both folate and vitamin B₁₂ deficiencies, but methylmalonyl-CoA is elevated in vitamin B₁₂ deficiency only. Educational objective: Elevated levels of plasma homocysteine are an independent risk factor for thrombotic events. Homocysteine can be metabolized to methionine via remethylation or to cystathionine via transsulfuration. Hyperhomocysteinemia is most commonly due to genetic mutations in critical enzymes or deficiencies of vitamin B₁₂, vitamin B₆, and folate. __________ References: Biochemistry of homocysteine in health and diseases. (http://www.ncbi.nlm.nih.gov/pubmed/17133733) Homocysteine-lowering interventions for preventing cardiovascular events. (http://www.ncbi.nlm.nih.gov/pubmed/25590290) Congenital MTHFR deficiency causing early-onset cerebral stroke in a case homozygous for MTHFR thermolabile variant. (http://www.ncbi.nlm.nih.gov/pubmed/23526309)

A 34-Year-Old Previously Healthy Man Comes to the Emergency Department