levoleucovorin and 5-11-methenyltetrahydrohomofolate

Rett disorder (RD) is a progressive neurodevelopmental entity caused by mutations in the MECP2 gene. It has been postulated that there are alterations in the levels of certain neurotransmitters and folate in the pathogenesis of this disease. Here we re-evaluated this hypothesis.. We evaluated CSF folate, biogenic amines and pterines in 25 RD patients. Treatment with oral folinic acid was started in those cases with low folate. Patients were clinically evaluated and videotaped up to 6 months after therapy.. CSF folate was below the reference values in 32% of the patients. Six months after treatment no clinical improvement was observed. Three of the four patients with the R294X mutation had increased levels of a dopamine metabolite associated to a particular phenotype. Three patients had low levels of a serotonin metabolite. Two of them were treated with fluoxetine and one showed clinical improvement. No association was observed between CSF folate and these metabolites, after adjusting for the patients age and neopterin levels.. Our results support that folinic acid supplementation has no significant effects on the course of the disease. We report discrete and novel neurotransmitter abnormalities that may contribute to the pathogenesis of RD highlighting the need for further studies on CSF neurotransmitters in clinically and genetically well characterized patients.

Topics: Administration, Oral; Child; Child, Preschool; DNA Mutational Analysis; Female; Fluoxetine; Folic Acid; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Leucovorin; Methyl-CpG-Binding Protein 2; Mutation; Neurotransmitter Agents; Polymerase Chain Reaction; Rett Syndrome; Seizures; Selective Serotonin Reuptake Inhibitors; Stereotyped Behavior; Treatment Outcome; Vitamin B Complex

Previous studies in Rett syndrome (RS) patients suggested various abnormalities in biogenic amines, pterins, and folate values in cerebrospinal fluid (CSF). Our aim was to analyse these metabolites in CSF of 16 RS patients (age range: 2 - 23 years). Biogenic amines, pterins, and 5-methyltetrahydrofolate were measured by HPLC with electrochemical and fluorescence detection.. CSF values of 5-methyltetrahydrofolate were decreased in 8 out of 16 RS patients (average: 53.6 nmol/L; range: 19 - 92) when compared with our reference values (average: 74.6 nmol/L; range: 45 - 127). These eight patients had epilepsy, while 4 out of 16 RS patients who did not have epilepsy showed normal CSF 5-methyltetrahydrofolate concentrations. Values of biogenic amines or pterins were decreased in four of the patients with low values of 5-methyltetrahydrofolate. No correlation was observed between CSF values of 5-methyltetrahydrofolate and pterins, biogenic amines, or age. Supplementation with folinic acid was applied in six out of the eight patients with CSF 5-methyltetrahydrofolate deficiency. An improvement was noticed in all cases.. An important percentage of RS patients showed 5-methyltetrahydrofolate concentrations under the reference values. Therefore, analysis of CSF 5-methyltetrahydrofolate seems advisable in RS, especially in patients with epilepsy and those resistant to antiepileptic drugs.

Topics: Adolescent; Biogenic Amines; Child; Child, Preschool; DNA Mutational Analysis; Dose-Response Relationship, Drug; Female; Folic Acid; Humans; Leucovorin; Methyl-CpG-Binding Protein 2; Pteroylpolyglutamic Acids; Rett Syndrome; Statistics, Nonparametric; Vitamin B Complex

To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD

Topics: Binding Sites; Crystallization; Enzyme Inhibitors; Folic Acid; Humans; Leucovorin; Methenyltetrahydrofolate Cyclohydrolase; Methylenetetrahydrofolate Dehydrogenase (NADP); Minor Histocompatibility Antigens; Mitochondria; NAD; Protein Multimerization

Auto-antibodies against folate receptor alpha (FRα) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide.. Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated.. Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (χ(2)=21.6; p<0.0001). FRα antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean±SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p=0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement.. Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process.

Topics: Adolescent; Adult; Autoantibodies; Biopterins; Child; Female; Folate Receptor 1; Folic Acid; Homocysteine; Humans; Leucovorin; Male; Middle Aged; Schizophrenia; Young Adult

Topics: Antidotes; Colonic Neoplasms; Folic Acid; Humans; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Oxidoreductases Acting on CH-NH Group Donors

The formyl-methenyl-methylenetetrahydrofolate synthetase from chicken liver catalyzes the formation of the 10-formyl- and 5,10-methenyltetrahydrofolate cofactors via three enzymatic activities. In this report we define the kinetic relationships between the activities of this trifunctional protein. An investigation of the time course for 10-formyl cofactor synthesis by computer modeling indicates that commencing with tetrahydropteroyltriglutamate, the activities of the synthetase/cyclohydrolase couple act as separate enzymic species. In contrast, 10-formyl cofactor formation from the 5,10-methylene cofactor utilizing the dehydrogenase/cyclohydrolase couple is described by a single or interactive site model that partitions the 5,10-methenyl intermediate primarily (85%) to the 10-formyl product. An unusual characteristic of the latter coupled activities is the negligible cyclohydrolase activity toward exogenous 5,10-methenyl cofactor, which serves as substrate in the individual activity assay. This is based on (1) competitive inhibition by 5,11-methenyltetrahydrohomofolate against the 5,10-methenyl derivative in the cyclohydrolase-catalyzed hydrolysis but the absence of such inhibition in the dehydrogenase/cyclohydrolase couple and (2) a pulse-chase experiment showing the failure of chase 5,10-methenyl cofactor to dilute the 10-formyl product derived from the coupled activities. The result of this coupling is to minimize the concentration of the 5,10-methenyl species, consistent with its noninvolvement in de novo purine biosynthesis.

Topics: Aminohydrolases; Animals; Chickens; Folic Acid; Formate-Tetrahydrofolate Ligase; Kinetics; Leucovorin; Ligases; Liver; Mathematics; Methenyltetrahydrofolate Cyclohydrolase; Methylenetetrahydrofolate Dehydrogenase (NADP); Multienzyme Complexes; Oxidoreductases; Tetrahydrofolates; Time Factors