Folic acid nonresponsive homocystinuria due to methylenetetrahydrofolate reductase deficiency.

Four siblings from a family with 11 children of Irish ancestry were observed to suffer from an essentially identical clinical illness, consisting of delayed psychomotor development in infancy and childhood, severe mental retardation, and upper motor neuron dysfunction. Death occurred at an early age in three siblings. In cases in which detailed physical examinations were performed, ectopia lentis, marfanoid features, and severe bony deformities were absent. Homocystinuria, homocystinemia, relatively normal concentrations of methionine and cystine in tissue fluids, and absence of methylmalonic aciduria were found. A deficiency of methylenetetrahydrofolate reductase was demonstrated in cultured skin fibroblasts from two siblings. Postmortem examination of two of the three patients who died showed extensive vascular thrombosis. No biochemical improvement was observed in the surviving child following treatment with large doses of folic acid.