5-methyltetrahydrofolate and Rett-Syndrome

Rett syndrome is a neurodevelopmental disorder in girls, related to mutations in MECP2 gene. It has been postulated that low 5-methyltetrahydrofolate (5-MTHF) levels are present in cerebrospinal fluid. Folinic acid demonstrated clinical improvement. However, because studies have produced conflicting results, we performed a randomized, double-blind crossover, long-term, follow-up study on folinic acid. Eight Rett syndrome patients received both folinic acid and placebo, for 1 year each. Measurements included plasma folate, 5-MTHF, and clinical outcome scores like Rett Syndrome Motor Behavioral Assessment, Hand Apraxia Scale, and the parental Overall Well-Being Index. In 2 patients, low 5-MTHF levels were present. Folinic acid supplementation increased cerebrospinal fluid 5-MTHF levels, but with no objective evidence of clinical improvement. The Overall Well-Being Index showed a significant difference in favor of folinic acid, not confirmed objectively. In our double-blind randomized study, folinic acid supplementation resulted in increased 5-MTHF levels, but with no objective signs of clinical improvement.

Topics: Adolescent; Adult; Child; Child, Preschool; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Female; Folic Acid; Humans; Leucovorin; Linear Models; Longitudinal Studies; Methyl-CpG-Binding Protein 2; Mutation; Neurologic Examination; Rett Syndrome; Tetrahydrofolates; Time Factors; Treatment Outcome; Young Adult

Cerebral folate deficiency (CFD) has been described as a neurological syndrome associated with low 5-methyltetrahydrofolate (5-MTHF) values in cerebrospinal fluid (CSF) with normal folate concentrations in plasma. Our aim was to analyse CSF 5-MTHF concentrations in a paediatric control population and in patients with various neurological disorders.. We studied plasma and CSF samples from 63 paediatric controls (age range: 2 days to 18 years, average: 3.8 years) and from 165 patients (age range: 1 day to 22 years, average: 5.0 years) with severe epileptic encephalopathies of unknown origin, movement disorders, Rett syndrome and mitochondrial diseases. CSF 5-methyltetrahydrofolate was analysed by reverse phase HPLC with fluorescence detection (excitation: 295 nm and emission: 355 nm).. A negative correlation between 5-MTHF values and age of controls was observed (r=-0.468; p<0.0001) and reference values were therefore stratified into 3 age groups. Regarding patients, 122 out of 165 showed normal CSF 5-MTHF values while 43 showed decreased values ranging from profound to mild deficiencies. Increased CSF total protein values were associated with the presence of low 5-MTHF concentrations (chi(2)=7.796; p=0.005).. The application of this method has been useful for the establishment of reference values and for diagnosis of CFD in paediatric patients. Furthermore, increased CSF total protein concentrations should be considered as a marker of a possible CFD.

Topics: Adolescent; Child; Child, Preschool; Chromatography, High Pressure Liquid; Epilepsy; Fluorescence; Humans; Mitochondrial Diseases; Movement Disorders; Nervous System Diseases; Reference Values; Rett Syndrome; Tetrahydrofolates

Topics: Adolescent; Adult; Biomarkers; Blood-Brain Barrier; Brain; Cerebrospinal Fluid; Child; Child, Preschool; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Predictive Value of Tests; Reference Values; Rett Syndrome; Tetrahydrofolates; Treatment Outcome

Topics: Autoantibodies; Autoimmune Diseases; Biological Transport; Diagnosis, Differential; Folic Acid; Folic Acid Deficiency; Humans; Infant; Receptors, Cell Surface; Rett Syndrome; Tetrahydrofolates

Previous CSF studies in Rett syndrome suggest reduced turnover of the biogenic monoamines serotonin and dopamine. Because diminished turnover may result from CNS folate depletion, the authors studied transport of folate across the blood-brain barrier.. In four patients with Rett syndrome, the authors measured CSF values of 5-methyltetrahydrofolate (5MTHF), biogenic monoamine end-metabolites, and pterins together with serum and red blood cell folate. In CSF, the overall folate binding capacity by the two soluble folate-binding proteins FBP1 and FBP2 (sFBP) was measured using a radioligand binding method for H3-labeled folate. A specific immunoreactive test (ELISA) detected sFBP1, which normally contributes to 30 to 35% of the total folate binding capacity. Genetic analysis included DNA sequencing of the MECP2, FBP1, and FBP2 genes. Empirical treatment with oral folinic acid was evaluated.. Two patients without and two with mutations of the MECP2 gene had normal values for red blood cell folate, serum folate, homocysteine, and methionine. In CSF, all patients had low values for 5MTHF, neopterin, and the serotonin end-metabolite 5-hydroxyindoleacetic acid (5-HIAA). Genetic analysis of FBP1 and FBP2 genes had normal results. Compared to controls, patients with Rett syndrome had normal immunoreactive sFBP1 in CSF, whereas the total folate binding capacity was disproportionately lowered. Empirical treatment with oral folinic acid normalized 5-MHTF and 5-HIAA levels in CSF, and led to partial clinical improvement.. Irrespective of the MECP2 genotype, 5MTHF transfer to the CNS is reduced in Rett syndrome. Folinic acid supplementation restores 5MTHF levels and serotoninergic turnover. The lowered folate binding capacity of FBP is not explained by a defect of the FBP1 or FBP2 gene, but most likely occurs as a secondary phenomenon in Rett syndrome.

Topics: Biogenic Monoamines; Biomarkers; Blood-Brain Barrier; Carrier Proteins; Central Nervous System; Child, Preschool; Female; Folate Receptors, GPI-Anchored; Folic Acid; Humans; Leucovorin; Protein Isoforms; Pterins; Receptors, Cell Surface; Rett Syndrome; Sequence Analysis, DNA; Tetrahydrofolates