Toxic Encephalopathy and Delayed MTX Clearance after High-dose Methotrexate Therapy in a Child Homozygous for the MTHFR C677T Polymorphism

Abstract

Background: High-dose methotrexate (HD-MTX) is one of the most important agents in the therapy of osteosarcoma (OSC). Acute and delayed toxicities still constitute clinical problems. Methylenetetrahydrofolate reductase (MTHFR) has a key role in the folate cycle. In case of homozygosity of the 677C →T polymorphism, treatment with antimetabolites, such as MTX, can cause additional toxicity. Case Report: In the present work, we describe the case of a 10-year-old boy with OSC. After the first HD-MTX infusion (12 g/m²/6 h) acute neurological disturbances were detected followed by severe hepatotoxicity. Plasma concentrations of MTX and 7-OH-MTX showed delayed clearance. Calcium folinate was administered to the patient until +186 hours. Tha patient was homozygous for the 677 polymorphism and wild-type for the 1298 polymorphism of the MTHFR gene. Conclusion: We hypothesize that MTX toxicity can be explained by the association between homozygosity of the MTHFR C677T polymorphism causing disturbances in the folate status and thus an enhanced vulnerability of the central nervous system to antimetabolites and to the prolonged MTX exposure due to delayed MTX clearance.