Clinical Information

Hyperhomocysteinemia is an independent risk factor for coronary artery disease, acute myocardial infarction, peripheral arterial disease, stroke, and venous thromboembolism. Homocysteine is a sulfhydryl-containing amino acid formed as an intermediary during the conversion of methionine to cystathionine. Genetic or nutrition-related disturbances (eg, deficiency of vitamins B12, B6, and folic acid) may impair the transsulfuration or remethylation pathways of homocysteine metabolism and cause hyperhomocysteinemia. The enzyme MTHFR catalyzes reduction of 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate, the major form of folate in plasma; 5-methyl tetrahydrofolate serves as a methyl donor for remethylation of homocysteine to methionine. Patients with severe MTHFR deficiency (enzymatic activity 0%-20% of normal) develop homocysteinuria, a severe disorder with a wide range of associated clinical manifestations, including developmental delay, mental retardation, and premature vascular disease. Seven unique MTHFR mutations have been associated with homocysteinuria, all among patients who were either homozygous or compound heterozygotes for 1 or more of these mutations.

 

A milder deficiency of MTHFR, with approximately 50% residual enzyme activity and marked enzyme lability to heat inactivation, is associated with a cytosine to thymine mutation at nucleotide position 677, encoding for an alanine-223 to valine substitution (MTHFR C677T). A second mutation in MTHFR exon 7, A1298C, results in a conversion of a glutamic acid codon to an alanine codon. The MTHFR A1298C mutation reduces MTHFR activity to a lesser extent than C677T, but compound heterozygous MTHFR A1298C/C677T may develop hyperhomocysteinemia.  

For suspected hyperhomocysteinemia, we recommend that a basal plasma homocysteine level be measured. Vitamin B12, B6, and folic acid levels should be measured in patients with hyperhomocysteinemia.