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Am J Hum Genet. 1988 Oct;43(4):414-21.

Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase.

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Department of Pediatrics, Rush Medical College, Chicago, IL 60612.


A "newly detected" variant of methylenetetrahydrofolate (MTHF) reductase (E.C. deficiency associated with an 8-15-fold increase in plasma total homocysteine was discovered in two unrelated patients who had subnormal serum folate. However, the homocysteinemia was corrected by oral folic acid supplement. When MTHF reductase activities in lymphocyte extracts before and after heat treatment at 46 C for 5 min were compared, there was a consistent difference in heat stability between the enzyme from the controls and that from the patients. The mean residual activities after heat treatment were 37.0% (34.1%-42.6%) in the controls and 15.2% and 15.1% in the two patients, respectively. Two obligate heterozygotes for severe MTHF reductase deficiency had residual activities of 39.6% and 37.7%. A similar difference in thermostability was demonstrated in cultured skin fibroblasts and lymphoblasts. Studies with a mixture of lymphoblast extracts from a control and a patient and with partially purified enzyme suggested that the thermostability was an independent characteristic of MTHF reductase. These observations provided evidence of a hitherto undescribed mutant MTHF reductase in our two patients with intermediate homocysteinemia. Unlike previously reported patients with MTHF reductase deficiency, there was no apparent clinical problem related to the abnormal folate or homocysteine metabolism during infancy or childhood in these two subjects, but one of them had vascular disorders in adulthood. The observations in these two subjects suggested that a moderate deficiency of MTHF reductase might be associated with vascular disorders in adult life.

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