Congenital Methylmalonic Aciduria-Homocystinuria With Megaloblastic Anemia: Observations on Response to Hydroxocobalamin and on the Effect of Homocysteine and Methionine on the Deoxyuridine Suppression Test

Abstract

Congenital methylmalonic aciduria-homocystinuria, a disorder with an incompletely defined cobalamin abnormality, has not been accompanied by megaloblastosis in most of the initially described cases. This has raised questions about the exact role of cobalamin in relation to megaloblastic anemia. Therefore, we present our observations on a patient with this syndrome whose manifestations conformed to current concepts of cobalamin function and on her response to hydroxocobalamin. In addition to the megaloblastic anemia (and other hematologic abnormalities) she developed severe neurologic impairment shortly after birth. Hydroxocobalamin injections diminished her methylmalonic acid and homocys-tine excretion and corrected her megaloblastosis, though mild neutrophil nuclear hypersegmentation has persisted even after a year. Clinical status also improved, particularly physical growth and neurologic development. However, she remains neurologically impaired following an unexplained clinical catastrophe. We documented her megaloblastic process by demonstrating abnormal deoxyuridine suppression test results in her initial bone marrow aspirate and normal results after treatment. Furthermore, the abnormal deoxyuridine suppression was corrected in vitro by folic acid, but not by methyltetrahydrofolic acid, cyanocobalamin, adenosylcobalamin, methylcobalamin, or methionine. Homocysteine slightly worsened the deoxyuridine suppression pattern. Subsequent studies showed that, in contrast to previous reports, homocysteine had no beneficial effect in other normoblastic or megaloblastic marrows either. The findings in our patient are compatible with the “methyltetrahydrofolate trap” hypothesis. Why this syndrome presents such a wide spectrum of manifestations is not entirely clear, nor is it clear why it should differ so from other disorders of cobalamin. These aspects are reviewed. Severity of the defect, differences in tissue susceptibility, or possibly even other factors such as ability to retain cobalamin intracellularly may influence the manifestations of this metabolic disorder.