Methylenetetrahydrofolate reductase deficiency in four siblings: A clinical, biochemical, and molecular study of the family

A diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency was m ade in four sibs at different ages. The first three, including a pair of tw ins, had retarded psychomotor development, poor social contact, and seizure s. Biologically, hyperhomocysteinemia and hypomethioninemia were found asso ciated with low folate levels in serum and red cells, especially undetectab le methyltetrahydrofolate in red cells. In the fourth child, prenatal diagn osis was not conclusive because of moderate decrease of enzymatic activity in chorionic villi and trophoblast, The girl was also affected, as shown by hyperhomocysteinemia and low folate levels found several days after birth, A 677C-->T (Ala-->Val) mutation was found in a homozygous state in the fou r children and in the father, Additionally, a second homozygous mutation, 1 081C-->T, changing an arginine to cysteine also was identified in all of th e children, whereas the distantly consanguineous parents were heterozygous, This amino acid substitution affecting an arginine residue in a sequence l ocated at the end of catalytic domain seems critical for the function of th e enzyme, The difficulty of prenatal diagnosis is discussed given the varia bility found in enzymatic activity and in the clinical phenotypes, (C) 2000 Wiley-Liss, Inc.