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Deficiencia de Ácido Fólico/genética , Síndromes de Malabsorción/genética , Consanguinidad , Femenino , Ácido Fólico/líquido cefalorraquídeo , Ácido Fólico/metabolismo , Ácido Fólico/uso terapéutico , Deficiencia de Ácido Fólico/diagnóstico , Humanos , Lactante , Imagen por Resonancia Magnética , Síndromes de Malabsorción/diagnóstico , Microcefalia/genética , Examen Neurológico , Transportador de Folato Acoplado a Protón/genética , Convulsiones/etiología , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that currently has no approved medical therapy to address core symptoms or underling pathophysiological processes. Several compounds are under development that address both underlying pathophysiological abnormalities and core ASD symptoms. This article reviews one of these treatments, d,l-leucovorin calcium (also known as folinic acid) for treatment of folate pathway abnormalities in children with ASD. Folate is a water-soluble B vitamin that is essential for normal neurodevelopment and abnormalities in the folate and related pathways have been identified in children with ASD. One of these abnormalities involves a partial blockage in the ability of folate to be transported into the brain utilizing the primary transport mechanism, the folate receptor alpha. Autoantibodies which interfere with the function of the folate receptor alpha called folate receptor alpha autoantibodies have been identified in 58%-76% of children with ASD and independent studies have demonstrated that blood titers of these autoantibodies correlate with folate levels in the cerebrospinal fluid. Most significantly, case-series, open-label, and single and double-blind placebo-controlled studies suggest that d,l-leucovorin, a reduced folate that can bypass the blockage at the folate receptor alpha by using the reduced folate carrier, an alternate pathway, can substantially improve particular symptoms in children with ASD, especially those positive for folate receptor alpha autoantibodies. This article reviews the current evidence for treating core and associated symptoms and underlying pathophysiological mechanisms in children with ASD with d,l-leucovorin.
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Trastorno del Espectro Autista , Receptor 1 de Folato/inmunología , Deficiencia de Ácido Fólico , Ácido Fólico , Leucovorina/farmacología , Complejo Vitamínico B/farmacología , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/inmunología , Trastorno del Espectro Autista/metabolismo , Autoanticuerpos , Niño , Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/tratamiento farmacológico , Humanos , Leucovorina/administración & dosificación , Complejo Vitamínico B/administración & dosificaciónRESUMEN
Intravenous and/or intrathecal administration of the anti-folate drug methotrexate is a common chemotherapeutic procedure in childhood leukemia. Therapeutic and prophylactic efficacy of these procedures notwithstanding, the occurrence of late adverse effects remains a cause of clinical concern in leukemia survivors. We propose an experimental mouse model to mimic the impact of methotrexate exposure on brain biochemistry and cell proliferation, as well as behavioral and neurocognitive functioning at adult age. Female C57Bl6/J mouse pups received saline or methotrexate injection (20â¯mg/kg, i.p.). CSF and serum concentrations of folate metabolites and toxicity makers were analyzed at 4â¯h, 24â¯h, and 1â¯week following injection. Behavioral test battery performance was assessed at adult age (3-4â¯months). We found acute changes in serum and CSF levels of folate in exposed pups that coincided with increases in CSF Tau, whereas homocysteine in serum and CSF, and CSF levels of pTau were unchanged or remained below detection. In addition, methotrexate injection coincided with diminished hippocampal cell proliferation 1â¯week after methotrexate injection. At adult age, exposed mice displayed hippocampus-dependent deficits in the Morris water maze, whereas exploration and anxiety-related behaviors were largely unaffected. Particularly during the reference memory (probe) trial after reversal learning, methotrexate-exposed animals were less precise than controls. These findings demonstrate adult neurocognitive sequelae in a mouse model that can be attributed to the biochemical and cellular impact of early-life methotrexate exposure.
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Antimetabolitos Antineoplásicos/toxicidad , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/inducido químicamente , Ácido Fólico/líquido cefalorraquídeo , Metotrexato/toxicidad , Proteínas tau/líquido cefalorraquídeo , Animales , Animales Recién Nacidos , Antimetabolitos Antineoplásicos/administración & dosificación , Disfunción Cognitiva/patología , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Inyecciones Espinales , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Metotrexato/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Distribución AleatoriaRESUMEN
OBJECTIVE: To describe the phenotype and the response to folinic acid supplementation of cerebral folate deficiency (CFD) in adults, a disorder diagnosed on low 5-methyltetrahydro-folate (5MTHF) in cerebrospinal fluid (CSF), which can correspond to a inherited disorder of folate metabolism (IDFM) or to a metabolic consequence of various neurological diseases. METHODS: We conducted a retrospective study on 224 adult patients with neurological symptoms who had a 5MTHF CSF dosage, collecting their neurologic and neuroimaging data. RESULTS: 69 patients had CFD (CSF 5MTHF levelâ¯<â¯41â¯nmol/L), 25 of them had severe CFD (sCFD; ≤25â¯nmol/L) with adult onset neurological symptoms in 41%. 56% of sCFD patients had an underlying identified neurologic disorder, mainly mitochondrial diseases, hepatic encephalopathy and primary brain calcifications (no identified IDFM), the others were classified as undiagnosed. sCFD patients presented most frequently pyramidal syndrome (75%), movement disorders (56%), cerebellar syndrome (50%) and intellectual disability (46%). MRI findings mostly showed white matter abnormalities (WMA; 32%) and calcifications (12%), and were normal in 23%. The clinico-radiological phenotype of sCFD patients was not clearly different from non CFD patients in terms of manifestations frequency. However, their neurological picture was more complex with a higher number of combined neurological symptoms (4.7±1.6 vs 3.4±1.7, pâ¯=â¯.01). In Magnetic Resonance Spectroscopy (MRS), Choline/Creatine (Cho/Cr) ratio was lower in sCFD patients (nâ¯=â¯7) compared to non-CFD patients (nâ¯=â¯73) (pâ¯=â¯.005), with good sensitivity (71%) and excellent specificity (92%). Among twenty-one CFD patients treated with folinic acid, nine had a sustained improvement, all with sCFD but one (50% of sCFD patients improved). In two undiagnosed patients with extremely low 5MTHF CSF values, MRI WMA and low Cho/Cr ratios, folinic acid treatment leaded to a dramatic clinical and radiological improvement. CONCLUSION: CSF 5MTHF dosage should be considered in patients with mitochondrial diseases, primary brain calcifications and unexplained complex neurological disorders especially if associated with WMA, since folinic acid supplementation in patients with sCFD is frequently efficient.
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Enfermedades Cerebelosas/complicaciones , Deficiencia de Ácido Fólico/complicaciones , Deficiencia de Ácido Fólico/genética , Mutación/genética , Proteínas/genética , Adolescente , Adulto , Anciano , Calcinosis/diagnóstico por imagen , Calcinosis/etiología , Calcinosis/genética , Enfermedades Cerebelosas/líquido cefalorraquídeo , Enfermedades Cerebelosas/diagnóstico por imagen , Enfermedades Cerebelosas/genética , Niño , Preescolar , Femenino , Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/diagnóstico por imagen , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/etiología , Estudios Retrospectivos , Tetrahidrofolatos/líquido cefalorraquídeo , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
Hydrocephalus (HC) is an imbalance in cerebrospinal fluid (CSF) secretion/absorption resulting in fluid accumulation within the brain with consequential pathophysiology. Our research has identified a unique cerebral folate system in which depletion of CSF 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is associated with cortical progenitor cell-cycle arrest in hydrocephalic Texas (H-Tx) rats. We used tissue culture, immunohistochemistry, in-situ PCR and RT-PCR and found that the in-vitro proliferation of arachnoid cells is highly folate-dependent with exacerbated proliferation occurring in hydrocephalic CSF that has low FDH but high folate-receptor-alpha (FRα) and folate. Adding FDH to this CSF prevented aberrant proliferation indicating a regulatory function of FDH on CSF folate concentration. Arachnoid cells have no detectable mRNA for FRα or FDH, but FDH mRNA is found in the choroid plexus (CP) and CSF microvesicles. Co-localization of FDH, FRα and folate suggests important functions of FDH in cerebral folate transport, buffering and function. In conclusion, abnormal CSF levels of FDH, FRα and folate inhibit cortical cell proliferation but allow uncontrolled arachnoid cell division that should increase fluid absorption by increasing the arachnoid although this fails in the hydrocephalic brain. FDH appears to buffer available folate to control arachnoid proliferation and function.
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Ácido Fólico/metabolismo , Hidrocefalia/patología , Animales , Aracnoides/citología , Aracnoides/metabolismo , Aracnoides/patología , Proliferación Celular , Células Cultivadas , Femenino , Receptor 1 de Folato/líquido cefalorraquídeo , Receptor 1 de Folato/metabolismo , Ácido Fólico/líquido cefalorraquídeo , Hidrocefalia/líquido cefalorraquídeo , Hidrocefalia/metabolismo , Masculino , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/líquido cefalorraquídeo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
INTRODUCTION: Cerebral folate deficiency (CFD) syndromes are defined as neuro-psychiatric conditions with low CSF folate and attributed to different causes such as autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus, FOLR1 gene mutations or mitochondrial disorders. High-dose folinic acid treatment restores many neurologic deficits. STUDY AIMS AND METHODS: Among 36 patients from 33 families the infantile-onset CFD syndrome was diagnosed based on typical clinical features and low CSF folate. All parents were healthy. Three families had 2 affected siblings, while parents from 4 families were first cousins. We analysed serum FR autoantibodies and the FOLR1 and FOLR2 genes. Among three consanguineous families homozygosity mapping attempted to identify a monogenetic cause. Whole exome sequencing (WES) was performed in the fourth consanguineous family, where two siblings also suffered from polyneuropathy as an atypical finding. RESULTS: Boys (72%) outnumbered girls (28%). Most patients (89%) had serum FR autoantibodies fluctuating over 5-6â¯weeks. Two children had a genetic FOLR1 variant without pathological significance. Homozygosity mapping failed to detect a single autosomal recessive gene. WES revealed an autosomal recessive polynucleotide kinase 3´phosphatase (PNKP) gene abnormality in the siblings with polyneuropathy. DISCUSSION: Infantile-onset CFD was characterized by serum FR autoantibodies as its predominant pathology whereas pathogenic FOLR1 gene mutations were absent. Homozygosity mapping excluded autosomal recessive inheritance of any single responsible gene. WES in one consanguineous family identified a PNKP gene abnormality that explained the polyneuropathy and also its contribution to the infantile CFD syndrome because the PNKP gene plays a dual role in both neurodevelopment and immune-regulatory function. Further research for candidate genes predisposing to FRα-autoimmunity is suggested to include X-chromosomal and non-coding DNA regions.
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Autoanticuerpos/sangre , Encefalopatías Metabólicas Innatas/genética , Receptor 1 de Folato/inmunología , Deficiencia de Ácido Fólico/genética , Adolescente , Encefalopatías Metabólicas Innatas/líquido cefalorraquídeo , Encefalopatías Metabólicas Innatas/diagnóstico , Niño , Preescolar , Consanguinidad , Enzimas Reparadoras del ADN/genética , Diagnóstico Diferencial , Familia , Femenino , Receptor 1 de Folato/genética , Receptor 2 de Folato/genética , Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/diagnóstico , Humanos , Lactante , Masculino , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Polineuropatías/etiología , Secuenciación del Exoma , Adulto JovenRESUMEN
Apraxic agraphia can be caused by left hemispheric cerebral lesions in the area that contains the spatial representations of the movements required to write, from a lesion in, or connections to, the frontal premotor cortex that converts these spatial representations to motor programs (Exner's area). A right-handed woman with Marchiafava Bignami disease and lesions of the genu and splenium of her corpus callosum had apraxic agraphia without ideomotor apraxia of her left. A disconnection of Exner's area in the left hemisphere from the right hemisphere's premotor and motor areas may have led to her inability to write with her left hand.
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Agrafia/etiología , Apraxias/etiología , Cuerpo Calloso/patología , Lateralidad Funcional , Enfermedad de Marchiafava-Bignami/complicaciones , Enfermedad de Marchiafava-Bignami/patología , Adulto , Agrafia/diagnóstico por imagen , Apraxias/diagnóstico por imagen , Femenino , Ácido Fólico/sangre , Ácido Fólico/líquido cefalorraquídeo , Homocisteína/sangre , Homocisteína/líquido cefalorraquídeo , Humanos , Imagen por Resonancia Magnética , Enfermedad de Marchiafava-Bignami/sangre , Enfermedad de Marchiafava-Bignami/líquido cefalorraquídeo , Vitamina B 12/sangre , Vitamina B 12/líquido cefalorraquídeoRESUMEN
OBJECTIVE: Treatment-refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. At least 15% of cases of major depressive disorder remain refractory to treatment. The authors previously identified a young adult with treatment-refractory depression and multiple suicide attempts with an associated severe deficiency of CSF tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis. Treatment with sapropterin, a tetrahydrobiopterin analogue, led to dramatic and long-lasting remission of depression. This sentinel case led the authors to hypothesize that the incidence of metabolic abnormalities contributing to treatment-refractory depression is underrecognized. METHOD: The authors conducted a case-control, targeted, metabolomic evaluation of 33 adolescent and young adult patients with well-characterized histories of treatment-refractory depression (at least three maximum-dose, adequate-duration medication treatments), and 16 healthy comparison subjects. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry and high-performance liquid chromatography electrospray ionization tandem mass spectrometry. RESULTS: CSF metabolite abnormalities were identified in 21 of the 33 participants with treatment-refractory depression. Cerebral folate deficiency (N=12) was most common, with normal serum folate levels and low CSF 5-methyltetrahydrofolate (5-MTHF) levels. All patients with cerebral folate deficiency, including one with low CSF levels of 5-MTHF and tetrahydrobiopterin intermediates, showed improvement in depression symptom inventories after treatment with folinic acid; the patient with low tetrahydrobiopterin also received sapropterin. None of the healthy comparison subjects had a metabolite abnormality. CONCLUSIONS: Examination of metabolic disorders in treatment-refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities remains to be determined.
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Trastorno Depresivo Resistente al Tratamiento/diagnóstico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Deficiencia de Ácido Fólico/diagnóstico , Deficiencia de Ácido Fólico/tratamiento farmacológico , Ácido Fólico/líquido cefalorraquídeo , Ácido Fólico/uso terapéutico , Intento de Suicidio/psicología , Adolescente , Trastorno Depresivo Resistente al Tratamiento/psicología , Quimioterapia Combinada , Deficiencia de Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/psicología , Humanos , Adulto JovenRESUMEN
Objective: This study aimed to investigate the clinical, biochemical and genetic features of two Chinese children with hereditary folate malabsorption. Method: Clinical features, laboratory examinations, treatment and SLC46A1 gene of two cases were studied. Reports on hereditary folate malabsorption utill September of 2016 were searched and the clinical and genetic characteristics of reported cases were summarized. Result: The two patients presented with megaloblastic anemia from their infant period and seizures, psychomotor retardation and regression. In case1, mean corpuscular volume (MCV) was 100 fl. Serum folate was 9.96 nmol/L. Folate and 5-methylenetetrahydrofolate in cerebrospinal fluid were 0 and 0.01 separately. In case 2, MCV was 93.9 fl. Serum folate was 4.49 nmol/L. The concentration of folate and 5-methylenetetrahydrofolate in cerebrospinal fluid were both zero. On their brain CT, progressive bilateral symmetrical calcification was observed. On their SLC46A1 gene, four mutations were identified. Case 1 had one novel mutation, c. 1238T>C (L413P) and c. 194-195insG (p.Cys66LeufsX99). From Case 2, two reported mutations, c. 1A>T (M1L) and c. 194-195insG (p.Cys66LeufsX99) were identified. The administration of folinic acid (60 to 120 mg per day) was initiated after diagnosis. Clinical improvement and normalized hematologic markers were observed after treatment. Totally 37 cases were reported in reviewed English literature, including 30 cases with mutations on SLC46A1 gene (only one Chinese patient). All the cases had the onset in infancy. The ratio of boys to girls was 1 to 1.5. Main manifestations were characterized by megaloblastic anemia (77%), failure to thrive (50%), diarrhea (27%), psychomotor retardation (63.6%), epilepsy (27%), and infection of respiratory system (45.5%). The concentration of folate in both serum and cerebrospinal fluid was decreased (72.7% and 63.6% respectively). Hypoimmunoglobulinemia accounted for 27.3%. Most of mutations in HFM were distributed between p. 65 and p. 68 (c.194-c.204), mainly due to insertion- or deletion-related frame shifts or generation of stop codons. Oral and parenteral folinic acid treatment was effective. Conclusion: Hereditary folate malabsorption often presented with megaloblastic anemia, abnormalities of digestive and nervous system, and hypoimmunoglobulinemia with recurrent infections. Low level of serum and CSF folate and screening SLC46A1 gene are keys to the etiologic study of the patients. Early supplement with folinic acid is beneficial to the prognosis.
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Anemia Megaloblástica/etiología , Encéfalo/patología , Calcinosis , Deficiencia de Ácido Fólico/diagnóstico , Leucovorina/administración & dosificación , Síndromes de Malabsorción/diagnóstico , Pueblo Asiatico , Niño , Discapacidades del Desarrollo/etiología , Diarrea , Femenino , Ácido Fólico/sangre , Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/tratamiento farmacológico , Deficiencia de Ácido Fólico/genética , Humanos , Lactante , Síndromes de Malabsorción/tratamiento farmacológico , Síndromes de Malabsorción/genética , Masculino , Mutación , Transportador de Folato Acoplado a Protón , Convulsiones/etiología , Eliminación de SecuenciaRESUMEN
Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPα, soluble APPß, and amyloid ß1-42 (Aß1-42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys-CSF), 5-methyltetrahydrofolate (5-MTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Aß1-42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5-MTHF CSF levels. Higher CSF concentrations of sAPPα and sAPPß were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aß1-42, and may contribute to the accumulation of amyloid pathology in the brain. Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. We found associations between CSF levels of soluble APP forms and Aß1-42, and markers of the homocysteine metabolism in both plasma and CSF in adults with normal cognition. Disturbed homocysteine metabolism may represent a target for preventive and early disease-modifying interventions in Alzheimer's disease.
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Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Homocisteína/metabolismo , Fragmentos de Péptidos/líquido cefalorraquídeo , Adulto , Albúminas/metabolismo , Apolipoproteína E4/genética , Femenino , Ácido Fólico/líquido cefalorraquídeo , Voluntarios Sanos , Homocisteína/sangre , Homocisteína/líquido cefalorraquídeo , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Valores de Referencia , S-Adenosilmetionina/líquido cefalorraquídeo , Tetrahidrofolatos/líquido cefalorraquídeo , Vitamina B 12/líquido cefalorraquídeoRESUMEN
OBJECTIVE: To evaluate the relationship between folate, cobalamin (Cbl), and homocysteine (Hcy), and markers of inflammation and oxidative stress within the periphery and central nervous system (CNS) of a healthy human cohort. METHODS: Thirty-five matched cerebrospinal fluid (CSF) and plasma samples were collected from consenting participants who required a spinal tap for the administration of anaesthetic. Plasma concentrations of Hcy and both plasma and CSF levels of folate, Cbl, nicotinamide adenine dinucleotide (NAD(H)) and markers of inflammation (interleukin-6, IL-6), and oxidative stress (F2-isoprostanes, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and total antioxidant capacity (TAC)) were quantified. RESULTS: In the peripheral circulation, positive associations were observed between plasma folate and Cbl, and plasma TAC (P ≤ 0.01; P ≤ 0.01) and plasma NAD(H) (P ≤ 0.05; P ≤ 0.05) levels, respectively. Plasma folate was inversely associated with plasma Hcy concentrations (P ≤ 0.05); however, no statistically significant relationships were observed between plasma Hcy and plasma markers of inflammation, oxidative stress, or [NAD(H)]. Within the CNS plasma Hcy correlated positively with CSF IL-6 (P ≤ 0.01) and negatively with CSF NAD(H) (P ≤ 0.05) concentrations. An inverse association was observed between CSF folate and CSF levels of IL-6 (P ≤ 0.05). Unexpectedly, a positive association between CSF Cbl and CSF 8-OHdG levels was also found (P ≤ 0.01). DISCUSSION: These results indicate that folate and Cbl concentrations may influence the levels of oxidative damage, inflammation, and NAD(H), both systemically and within the CNS.
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Sistema Nervioso Central/efectos de los fármacos , Ácido Fólico/administración & dosificación , Inflamación/sangre , NAD/sangre , NAD/líquido cefalorraquídeo , Estrés Oxidativo , Vitamina B 12/administración & dosificación , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Anciano , Antioxidantes/metabolismo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Sistema Nervioso Central/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangre , Desoxiguanosina/líquido cefalorraquídeo , F2-Isoprostanos/sangre , F2-Isoprostanos/líquido cefalorraquídeo , Femenino , Ácido Fólico/sangre , Ácido Fólico/líquido cefalorraquídeo , Homocisteína/sangre , Homocisteína/líquido cefalorraquídeo , Humanos , Interleucina-6/sangre , Interleucina-6/líquido cefalorraquídeo , Modelos Lineales , Masculino , Persona de Mediana Edad , Vitamina B 12/sangre , Vitamina B 12/líquido cefalorraquídeoRESUMEN
BACKGROUND: Cerebral folate deficiency (CFD) may be underdiagnosed, as it manifests with various non-specific neurological symptoms. The diagnosis of CFD requires a determination of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF), which is available in a limited number of specialized laboratories. In clinical biochemistry laboratories, total folate (TF) determination in serum or plasma is routinely performed by automated analyzers. The aim of this study is to determine whether the automated assay of CSF TF is a helpful screening tool for CFD. METHODS: We analyzed CSF samples collected from 73 pediatric patients. We measured CSF TF, serum TF, and CSF 5MTHF in 73, 70, and 48 patients, respectively. The assay of 5MTHF was conducted by a newly developed system utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS). We investigated the correlation between TF and 5MTHF in the CSF. RESULTS: There was a strong positive correlation between CSF TF and 5MTHF (ρ=0.930, p<0.0001, n=48). Age was negatively correlated with CSF TF (ρ=-0.557, p<0.0001, n=51), serum TF (ρ=-0.457, p=0.0008, n=51), and CSF 5MTHF (ρ=-0.387, p=0.0263, n=33), but not with the CSF/serum TF ratio. CONCLUSIONS: The automated assay of CSF TF is helpful to estimate CSF 5MTHF. The CSF TF assay may have a significant impact on the early diagnosis of CFD, because clinicians have better access to it than the 5MTHF assay.
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Deficiencia de Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/diagnóstico , Ácido Fólico/líquido cefalorraquídeo , Tetrahidrofolatos/líquido cefalorraquídeo , Adolescente , Enfermedades Cerebelosas/líquido cefalorraquídeo , Enfermedades Cerebelosas/diagnóstico , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Diagnóstico Precoz , Humanos , Lactante , Valores de Referencia , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Asunto(s)
Autoanticuerpos/sangre , Receptor 1 de Folato/inmunología , Leucovorina/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/inmunología , Adolescente , Adulto , Biopterinas/líquido cefalorraquídeo , Niño , Femenino , Ácido Fólico/análogos & derivados , Ácido Fólico/sangre , Ácido Fólico/líquido cefalorraquídeo , Homocisteína , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE: The methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms, which are associated with hyperhomocysteinemia and nitric oxide (NO) deficiency (which is related to atherothrombosis and cerebral ischemia), have not been studied in moyamoya disease. A case-control study was performed to investigate whether the MTHFR 677C>T and 1298A>C polymorphisms contribute to moyamoya disease (MMD). METHODS: One hundred and seven Korean patients with MMD (mean age, 20.85 ± 15.89 years; 66.4 % female) and 232 healthy control subjects (mean age, 23.99 ± 16.16 years; 56.8 % female) were included. Genotyping for the MTHFR 677C>T and 1298A>C polymorphisms and measurements of homocysteine, folate, vitamin B12, and NO in the cerebrospinal fluid (CSF) were performed. The statistical analysis was performed by multivariate linear regression and logistic regression. RESULT: The MTHFR 677CT+TT genotype frequency was significantly increased with early-onset MMD (<10 years) compared with late-onset MMD (≥10 years) (adjusted odds ratio, 3.392; 95 % confidence interval, 1.294-8.893, P = 0.013). The MTHFR 677C-1298C/677T-1298A diplotype (1.71 ± 1.23 arbitrary units) presented significantly lower NO levels in the CSF compared with the 677C-1298A/677C-1298A diplotype (11.40 ± 12.24 arbitrary units). CONCLUSION: The MTHFR 677C>T and 1298A>C polymorphisms have restricted roles in the Korean MMD population. Therefore, further studies involving larger and more heterogeneous cohorts are needed to extend our understanding of the influence of polymorphisms in MTHFR and other thrombophilic genes on MMD.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Enfermedad de Moyamoya/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Ácido Fólico/líquido cefalorraquídeo , Genotipo , Homocisteína/líquido cefalorraquídeo , Humanos , Modelos Lineales , Masculino , Enfermedad de Moyamoya/líquido cefalorraquídeo , Óxido Nítrico/líquido cefalorraquídeo , República de Corea , Vitamina B 12/líquido cefalorraquídeo , Adulto JovenRESUMEN
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
BACKGROUND: Disturbances in the levels of one-carbon (1C) metabolism metabolites have been associated with a wide variety of neuropsychiatric diseases. Cerebrospinal fluid (CSF) levels of homocysteine (Hcy) and the other 1C metabolites, nor their interrelatedness and putative determinants, have been studied extensively in a healthy population. METHODS: Plasma and CSF samples from 100 individuals free from neuropsychiatric diseases were analyzed (55 male, 45 female; age 50±17 years). In blood, we measured plasma Hcy, serum folate and serum vitamin B12. In CSF, we measured total Hcy, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and 5-methyltetrahydrofolate (5-methylTHF). Highly selective analytical methods like liquid chromatography combined with either mass spectrometry or fluorescence detection were used. RESULTS: CSF Hcy was inversely correlated with CSF 5-methylTHF and positively with plasma Hcy, independent of serum folate status. CSF SAH correlated with age, lower CSF 5-methylTHF and higher CSF Hcy. CSF 5-methylTHF showed independent negative correlations with age and positive correlations with serum folate. CSF SAM did not correlate with any of the 1C metabolites. CONCLUSIONS: Aging is characterized by a reduction in CSF 5-methylTHF levels and increased CSF levels of the potentially neurotoxic transmethylation inhibitor SAH. CSF 5-methylTHF, which is itself determined in part by systemic folate status, is a powerful independent determinant of CSF levels of Hcy and SAH.
Asunto(s)
Ácido Fólico/líquido cefalorraquídeo , Homocisteína/líquido cefalorraquídeo , S-Adenosilhomocisteína/líquido cefalorraquídeo , S-Adenosilmetionina/líquido cefalorraquídeo , Adulto , Anciano , Envejecimiento , Cromatografía Líquida de Alta Presión , Femenino , Ácido Fólico/sangre , Humanos , Inmunoensayo , Masculino , Persona de Mediana Edad , Espectrometría de Masas en Tándem , Vitamina B 12/sangreRESUMEN
Over the past decade, a syndrome consisting of low folate values in the cerebrospinal fluid (CSF) has been described. The syndrome has been associated with both genetic and acquired conditions that affect folate transport and metabolism and can result in severe neurological disorders. There is a wide range of underlying pathophysiological mechanisms, but a common feature in most patients is a good clinical response to folate therapy, especially when the syndrome is diagnosed early. In this review, we focus our attention on the genetic diseases leading to profound cerebral folate deficiency (CFD) and review current clinical, metabolic and therapeutic approaches.
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Corteza Cerebral/metabolismo , Deficiencia de Ácido Fólico/tratamiento farmacológico , Deficiencia de Ácido Fólico/genética , Predisposición Genética a la Enfermedad , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/genética , Betaína/administración & dosificación , Betaína/uso terapéutico , Corteza Cerebral/efectos de los fármacos , Ácido Fólico/líquido cefalorraquídeo , Ácido Fólico/metabolismo , Ácido Fólico/farmacocinética , Ácido Fólico/uso terapéutico , Deficiencia de Ácido Fólico/líquido cefalorraquídeo , Humanos , Absorción Intestinal/genética , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Tetrahidrofolatos/administración & dosificación , Tetrahidrofolatos/uso terapéuticoAsunto(s)
Encéfalo/metabolismo , Deficiencia de Ácido Fólico/diagnóstico , Deficiencia de Ácido Fólico/tratamiento farmacológico , Ácido Fólico/líquido cefalorraquídeo , Leucovorina/uso terapéutico , Tetrahidrofolatos/líquido cefalorraquídeo , Encéfalo/patología , Preescolar , Cromatografía Líquida de Alta Presión , Diagnóstico Diferencial , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Ácido Fólico/sangre , Ácido Fólico/metabolismo , Deficiencia de Ácido Fólico/etiología , Humanos , Lactante , Desnutrición/complicaciones , Desnutrición/diagnóstico , Tetrahidrofolatos/metabolismoRESUMEN
For patients with acute lymphoblastic leukemia or non-Hodgkin lymphoma, intrathecal (IT) methotrexate (MTX) significantly reduces the risk of relapse within the central nervous system, but is associated with neurotoxic sequelae. We established a rat model of MTX-induced cognitive deficits to further investigate the underlying pathophysiology and to develop protective therapeutic interventions. IT MTX 0.5 mg/kg was administered to 10-week old male Long Evans rats. Cerebrospinal fluid (CSF) was collected for measurement of folate, homocysteine, and excitotoxic glutamate analogs. Recognition and spatial memory were tested in the novel object recognition (NOR) task and the object placement (OP) task, respectively. Four doses of IT MTX in a two-week period induced cognitive deficits persisting at least three months after the final injection. CSF concentrations of the excitotoxic glutamate analogs homocysteic acid and homocysteine sulfinic acid were increased relative to baseline for the same three-month period. Dextromethorphan, a noncompetitive antagonist at the N-methyl-D-aspartate receptor, administered at a dose of 2 mg/kg intraperitoneally twice daily for a total of four doses, improved cognitive function among the MTX-treated rats, with no effect on control rats. Although this improvement was transient, each repeated treatment with dextromethorphan was followed by normalization of cognitive function. In conclusion, IT MTX induces persistent alterations in glutaminergic tone that may contribute to persistent cognitive deficits. Treatment with a glutamate receptor antagonist such as dextromethorphan may ameliorate the negative cognitive outcomes observed among patients with leukemia or lymphoma treated with repeated doses of prophylactic IT MTX.
Asunto(s)
Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos del Conocimiento/tratamiento farmacológico , Dextrometorfano/uso terapéutico , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ácido Glutámico/líquido cefalorraquídeo , Metotrexato/administración & dosificación , Animales , Trastornos del Conocimiento/inducido químicamente , Dextrometorfano/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Fólico/líquido cefalorraquídeo , Ácido Glutámico/análogos & derivados , Homocisteína/análogos & derivados , Homocisteína/líquido cefalorraquídeo , Humanos , Inyecciones Espinales , Masculino , Trastornos de la Memoria/líquido cefalorraquídeo , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Ratas , Ratas Long-Evans , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
BACKGROUND: Amyloid deposition in the brain is an early event in Alzheimer's disease (AD), but a dysfunction of the blood-brain barrier or a disturbance in the metabolism of folate and homocysteine (Hcy) may affect the development of dementia. We investigated if the concentrations of folate and Hcy would be modified in cerebrospinal fluid (CSF) of clinically diagnosed AD patients. METHODS: We included 70 AD patients, 33 patients with another type of dementia (nAD) and 30 age-matched control subjects. Plasma Hcy was assayed as well as Hcy, folate, Aß1-42 and T-tau in CSF. We used ANOVAs for comparison between groups, and then pairwise comparisons by Wilcoxon tests with Bonferroni-corrected p values. Correlations were tested with the Spearman's rank test. RESULTS: Levels of Aß1-42, T-tau and folates in CSF were significantly different between groups, but not Hcy. In addition, the average folate in CSF was lower in AD patients compared with controls (18.7 ± 2.4 vs. 20.3 ± 1.7 nmol/l, Bonferroni-corrected p value < 0.02). There was no correlation between Aß1-42 or T-tau and folate or Hcy in CSF, regardless of the group. In the AD group, there was a significant inverse correlation between Hcy and folate in CSF (ρ = -0.63, p < 0.0001), whereas in the nAD group, a significant correlation was found for Hcy between plasma and CSF (ρ = 0.59, p < 0.0005). CONCLUSION: The concentration of folate in CSF was found to be decreased in AD patients. These findings support the hypothesis of a possible role of folate in the onset or worsening of AD.