MULTIPLE ALLELES IN METHYLENETRAHYDROFOLATE REDUCTASE DEFICIENCY

Abstract

Methyleuetetrahydrofolate reductase (MTHFR) catalyzes the formation of 5-methyltetrahydrofolate, the main tissue and serum form of folic acid, and methyl donor for conversion of homocysteine to methionine. Four patients, 2 of whom are sibs, have been identified. All 4 have neurologic abnormalities and one of the sisters has a folate-responsive, schizophrenia-like disorder (Freeman et al. N. Engl. J. Med. 292:491, 1975). MTHFR activity is present at comparable levels in normal skin fibroblasts, amniotic fluid cells and lymphoblasts. MTHFR activities in extracts of both normal and reductase-deficient fibroblasts were low and quite variable during log growth, and were therefore studied at confluency. MTHFR activity in the patients' fibroblasts was 14-20% of normal. Activities in the parents of a patient with 20% of normal activity were 40% and 35% of normal suggesting autosomal recessive inheritance. When extracts were incubated at 55°C, residual MTHFR activity in the sibs showed normal thermal stability, decreasing to 22% and 38% of the initial values in 30 min. In contrast MTHFR from a 3rd patient was exponentially inactivated in 20 min, while that from a 4th unrelated patient was also completely inactivated but somewhat less rapidly. These results suggest that the reductase deficiency in these unrelated families results from at least 3 distinct mutant alleles.