5-methyltetrahydrofolate and Demyelinating-Diseases

To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL).. Twenty-four patients treated on the Medical Research Council United Kingdom ALL trial no. 11 (MRC UKALL XI) were studied. The trial randomized patients at the presymptomatic CNS treatment (PCNS) phase to receive (1) intrathecal methotrexate and cranial radiotherapy (CRTX); (2) high-dose intravenous methotrexate with folinic acid rescue and continuing intrathecal methotrexate (HDMTX); and (3) continuing intrathecal methotrexate alone (ITMTX). Serial CSF samples were collected throughout treatment and concentrations of 5-methyltetrahydrofolate (MTF), methionine (MET), SAM, and myelin basic protein (MBP) were measured. The results were grouped into treatment milestones and compared with an age-matched reference population.. There was a highly significant effect of both treatment milestones and trial arm on the metabolite and MBP concentrations. CSF MTF reached a nadir during the induction phase of treatment, while SAM and MET reached their nadir during the consolidation phase. CSF MBP mirrored SAM concentration and there was a significant inverse relationship between the two. MTF, SAM, and MBP returned to normal values by the end of treatment, while MET was increased significantly. The effect of treatment was decremental across the ITMTX, HDMTX, and CRTX groups.. Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical demyelination. Methotrexate is one cause of this. Whether these abnormalities contribute to the late cognitive deficits requires further study.

Topics: Antidotes; Antimetabolites, Antineoplastic; Central Nervous System; Child; Child, Preschool; Combined Modality Therapy; Demyelinating Diseases; Drug Interactions; Humans; Infant; Leucovorin; Methionine; Methotrexate; Myelin Basic Protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma; S-Adenosylmethionine; Tetrahydrofolates

Topics: Antiparkinson Agents; Atrophy; Basal Ganglia; Brain Diseases, Metabolic; Carbidopa; Cerebellum; Demyelinating Diseases; Dystonia; Female; Folic Acid Deficiency; Humans; Leucovorin; Levodopa; Male; Syndrome; Tetrahydrofolates; Treatment Outcome; Vitamin B Complex

Four pairs of monkeys were maintained in an atmosphere of nitrous oxide under conditions which had previously been shown to produce subacute combined degeneration (SCD) of the spinal cord. The diet of one of each pair was supplemented with methionine. In every case the monkey with the unsupplemented diet became ataxic at around 10 weeks and the disorder progressed over a period of 2-3 weeks until the animal was moribund. During this period there was no detectable clinical change in the monkeys receiving methionine supplementation. Microscopical examination of the spinal cord and peripheral nerves of the unsupplemented monkeys showed the classical changes of SCD. The histological changes correlated with the clinical observations. Sections form the methionine-supplemented monkeys showed no change or only slight changes. These results suggest that, in these animals, inability to resynthesise methionine from homocysteine leads to SCD. It seems probable that the primary lesion producing SCD in human beings with pernicious anaemia is also inability to maintain methionine biosynthesis.

Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Humans; Macaca fascicularis; Methionine; Nitrous Oxide; Spinal Cord; Spinal Cord Diseases; Tetrahydrofolates; Vitamin B 12