[Early neurotoxicity of high-dose of methotrexate and tetrahydrobiopterin deficiency].

Transient neurologic dysfunction associated with high-dose methotrexate and citrovorum factor rescue (MTX-CF) has been previously reported. At the biochemical level, there are at least two important pathways in central nervous system metabolism which might be disturbed by MTX: MTX may deplete the cell of the de novo synthesis of purine nucleotides and thymidylate through its action on dihydrofolate reductase (DHFR), and also inhibit dihydropteridine reductase (DHPR), an enzyme maintaining the cofactor of phenylalanine-hydroxylase in its active tetrahydrogenated form (tetrahydrobiopterin), and hence interfere with the supply of the neurotransmitters derived from tyrosine and tryptophan. We describe such a neurologic disease in a patient with acute lymphoblastic leukemia (ALL) receiving chemotherapy. Significant increase in cerebrospinal fluid biopterins supports the hypothesis of an inhibition of dihydropteridine reductase by MTX, and provides additional suggestions in terms of etiology, diagnosis and treatment.