RESUMEN
Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate homeostasis, as well as with speculations on a compromised DNA-methylation. Folinic acid is the stable form of folate. Its derived intermediate 5-MTHF supports the conversion of homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). This in turn donates its methyl group to various acceptors, including DNA, thereby being converted to S-adenosylhomocysteine (SAH). The SAM/SAH ratio reflects the methylation potential. The goal of our study was to influence DNA methylation processes and ameliorate the clinical symptoms in Rett syndrome. Therefore we examined the hypothesis that folinic acid supplementation, besides increasing cerebrospinal fluid (CSF) 5-MTHF (p = 0.003), influences SAM and SAH and their ratio. In our randomized, double-blind crossover study on folinic acid supplementation, ten female Rett patients received both folinic acid and placebo for 1 year each. It was shown that both SAM and SAH levels in the CSF remained unchanged following folinic acid administration (p = 0.202 and p = 0.097, respectively) in spite of a rise of plasma SAM and SAH (p = 0.007; p = 0.009). There was no significant change in the SAM/SAH ratio either in plasma or CSF. The apparent inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome. Our studies warrant further attempts to promote DNA methylation in the true region of interest, i.e. the brain.
Asunto(s)
Ácido Fólico/uso terapéutico , Síndrome de Rett/tratamiento farmacológico , S-Adenosilhomocisteína/sangre , S-Adenosilhomocisteína/líquido cefalorraquídeo , S-Adenosilmetionina/sangre , S-Adenosilmetionina/líquido cefalorraquídeo , Adolescente , Adulto , Niño , Preescolar , Suplementos Dietéticos , Femenino , Ácido Fólico/análogos & derivados , Ácido Fólico/líquido cefalorraquídeo , Ácido Fólico/farmacología , Humanos , Lactante , Síndrome de Rett/sangre , Síndrome de Rett/líquido cefalorraquídeo , Adulto JovenRESUMEN
OBJECTIVE: Interference of methotrexate (MTX) with the metabolism of homocysteine may contribute to MTX neurotoxicity. In this pilot study we measured the concentration of homocysteine and related metabolites in the cerebrospinal fluid (CSF) of patients with primary central nervous system lymphoma undergoing intensive treatment with MTX. MATERIAL AND METHODS: CSF samples from lymphoma patients (n = 4) were drawn at the end of high-dose MTX infusions (3-5 g/m2/24 h, HDMTX) and one day after intraventricular injections of MTX (3 mg, ICVMTX) or cytarabine (30 mg) and analyzed for homocysteine, cysteine, sulfur-containing excitatory amino acids (cysteine sulfinic acid, cysteic acid, homocysteine sulfinic acid and homocysteic acid), S-adenosylmethionine, 5-methyltetrahydrofolate and MTX. The concentration of homocysteine, cysteine and sulfur-containing excitatory amino acids were also measured in the CSF of a reference population not exposed to MTX. The Wilcoxon signed rank-test and the Friedman test were used to compare concentrations of homocysteine and its metabolites at various time-points during chemotherapy. Comparison of patient and control samples were performed using the Mann-Whitney U-test. Allelic variants of homocysteine metabolism previously shown to influence MTX neurotoxicity (MTHFR c.677C>T, MS c.2756A>G and Tc2 c.776C>G) were also analyzed. RESULTS: After application of HD- and ICVMTX, the CSF homocysteine concentrations in the lymphoma patients were markedly elevated and significantly higher than those in the control group (p < 0.05, Mann-Whitney U-test), whereas 5-methyltetrahydrofolate was depleted. A rapid elevation of homocysteine sulfinic acid, a sulfur-containg amino acid which was not detected in the CSF of the control group, was observed. One patient developed confluent white matter brain changes visible using MRI. This patient had the lowest concentration of S-adenosylmethionine in the CSF and carried two risk alleles for MTX neurotoxicity. CONCLUSIONS: In this pilot study, MTX administered either intravenously or intraventricularly, induced marked biochemical alterations in the CSF. Whether these changes can be used to predict MTX-induced neurotoxicity at an early stage in treatment needs to be elucidated in larger clinical trials.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Homocisteína/análogos & derivados , Homocisteína/líquido cefalorraquídeo , Linfoma/tratamiento farmacológico , Metotrexato/farmacología , Adulto , Anciano , Alelos , Antimetabolitos Antineoplásicos/efectos adversos , Química Encefálica/efectos de los fármacos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Citarabina , Aminoácidos Excitadores/líquido cefalorraquídeo , Femenino , Humanos , Inyecciones Intravenosas , Inyecciones Intraventriculares , Masculino , Metotrexato/efectos adversos , Persona de Mediana Edad , Síndromes de Neurotoxicidad , Proyectos Piloto , S-Adenosilmetionina/líquido cefalorraquídeo , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
Over a four-year period, we collected clinical and biochemical data from five Amish children who were homozygous for missense mutations in 5,10-methylenetetrahydrofolate reductase (MTHFR c.1129C>T). The four oldest patients had irreversible brain damage prior to diagnosis. The youngest child, diagnosed and started on betaine therapy as a newborn, is healthy at her present age of three years. We compared biochemical data among four groups: 16 control subjects, eight heterozygous parents, and five affected children (for the latter group, both before and during treatment with betaine anhydrous). Plasma amino acid concentrations were used to estimate changes in cerebral methionine uptake resulting from betaine therapy. In all affected children, treatment with betaine (534+/-222 mg/kg/day) increased plasma S-adenosylmethionine, improved markers of tissue methyltransferase activity, and resulted in a threefold increase of calculated brain methionine uptake. Betaine therapy did not normalize plasma total homocysteine, nor did it correct cerebral 5-methyltetrahydrofolate deficiency. We conclude that when the 5-methyltetrahydrofolate content of brain tissue is low, dietary betaine sufficient to increase brain methionine uptake may compensate for impaired cerebral methionine recycling. To effectively support the metabolic requirements of rapid brain growth, a large dose of betaine should be started early in life.
Asunto(s)
Betaína/uso terapéutico , Encefalopatías/prevención & control , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Adolescente , Adulto , Encéfalo/metabolismo , Encefalopatías/líquido cefalorraquídeo , Encefalopatías/metabolismo , Niño , Preescolar , Humanos , Recién Nacido , Metionina/líquido cefalorraquídeo , Metionina/metabolismo , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metiltransferasas/metabolismo , Mutación Missense , Tamizaje Neonatal , S-Adenosilmetionina/sangre , S-Adenosilmetionina/líquido cefalorraquídeoRESUMEN
BACKGROUND: The prognosis of patients with acute lymphoblastic leukemia (ALL) in childhood has improved with intensive chemotherapy. In particular, central nervous system (CNS) leukemia has been well controlled by the presymptomatic administration of intrathecal methotrexate (MTX), high dose systemic MTX, and irradiation. However, the prolonged intrathecal administration and/or the administration of high doses of systemic MTX, especially when combined with irradiation, can lead to leukoencephalopathy (LE), a serious CNS complication of such prophylaxis. Because the mechanisms by which MTX causes this complication have not been elucidated, the authors investigated the transmethylation status of the cerebrospinal fluid (CSF) in two children with ALL and LE to investigate the pathophysiology of that disorder. METHODS: The levels of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were measured in the CSF of 2 children with ALL and LE, 7 children with ALL only who were undergoing presymptomatic administration of MTX, and 18 reference children in whom diagnostic lumbar puncture was indicated for other reasons. A sensitive, high performance liquid chromatography (HPLC) method was used with fluorescence detection. RESULTS: The concentrations of SAM in the CSF were lower in the patients with ALL during treatment with MTX compared with the reference children. The SAM levels in the 2 patients with both ALL and LE were slightly lower than the levels in the 7 patients with ALL only. The SAH concentrations in the CSF were higher in the patients with ALL and LE compared with the patients with ALL only and the reference children. The mean concentration of SAH in the CSF was similar in the reference children to that found in the 7 patients with ALL only. The SAM-to-SAH ratios were lower in the 2 patients with ALL and LE and in the 7 patients with ALL only compared with the reference children. The ratios in the patients with ALL and LE were still lower than in those with ALL only, thus providing supporting evidence of hypomethylation in the 2 patients with ALL and LE. CONCLUSIONS: The data suggest that the treatment of children with ALL using MTX causes subclinical hypomethylation and that progressive hypomethylation in the CNS, as evidenced in the 2 patients with ALL and LE, may be responsible for the demyelination in the LE induced by MTX.
Asunto(s)
Metilación de ADN , Demencia Vascular/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Niño , Cromatografía Líquida de Alta Presión , Demencia Vascular/complicaciones , Demencia Vascular/metabolismo , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , S-Adenosilhomocisteína/líquido cefalorraquídeo , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/líquido cefalorraquídeo , S-Adenosilmetionina/metabolismoRESUMEN
PURPOSE: To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.