Methotrexate-induced subacute neurotoxicity in a child with acute lymphoblastic leukemia carrying genetic polymorphisms related to folate homeostasis.
Subacute methotrexate neurotoxicity (MTX-NT) may occur days to weeks after systemic or intrathecal (IT) MTX administration and is often manifest by stroke-like symptoms. The pathogenesis of MTX-NT has mainly been associated with cerebral folate homeostasis, but the specific mechanism leading to the development of this complication is mostly unknown and is likely to be multifactorial. Most of studies aimed to determine putative genetic determinants of this syndrome have been focused on the methylenetetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism (SNP). However, there are other functional polymorphisms that have also been identified in enzymes and transporters related to MTX and folate homeostasis. In this context, we carried out an extensive genetic analysis through the screening of 21 SNPs in 11 relevant genes in a five-year-old girl with acute lymphoblastic leukemia (ALL) who developed MTX-NT. The analysis revealed the presence of numerous genetic variants that may have accounted for the neurotoxicity observed. We discuss the putative role of MTX pharmacogenetics in the pathogenesis of MTX-NT.
Department of Pediatric Hematology, University Hospital Infanta Cristina, Badajoz, Spain.
Jose Manuel
JM
Vagace
Cristina
C
Caceres-Marzal
Mercedes
M
Jimenez
Maria Soledad
MS
Casado
Silvia Gonzalez
SG
de Murillo
Guillermo
G
Gervasini
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D002675:Child, Preschool; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D005492:Folic Acid; D008727:Methotrexate