5-methyltetrahydrofolate and Nervous-System-Diseases

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.

Topics: Betaine; Cerebral Cortex; Folic Acid; Folic Acid Deficiency; Genetic Predisposition to Disease; Humans; Intestinal Absorption; Leucovorin; Nervous System Diseases; Tetrahydrofolates

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Anemia, Megaloblastic; Animals; Humans; Liver; Macaca fascicularis; Methionine; Methylmalonyl-CoA Mutase; Nervous System Diseases; Nitrous Oxide; Rats; S-Adenosylhomocysteine; S-Adenosylmethionine; Tetrahydrofolates; Vitamin B 12 Deficiency

Topics: Cells, Cultured; Cerebrum; Down-Regulation; Female; Folate Receptor 1; Folic Acid Deficiency; HEK293 Cells; Humans; Loss of Function Mutation; Male; Nervous System Diseases; Neuroaxonal Dystrophies; Pedigree; Repressor Proteins; Sequence Analysis, DNA; Tetrahydrofolates

Analysis of pyridoxal 5'-phosphate (PLP) concentration in 256 cerebrospinal fluid (CSF) samples from patients with neurological symptoms showed that the variance is greater than indicated by previous studies. The age-related lower reference limit has been revised to detect inborn errors of metabolism that lead to PLP depletion without a high false positive rate: < 30 days, 26 nmol/L; 30 days to 12 months, 14 nmol/L; 1-2 years, 11 nmol/L; > 3 years, 10 nmol/L. Inborn errors leading to PLP concentrations below these values include pyridoxine-dependent epilepsy due to antiquitin deficiency, and molybdenum cofactor deficiency that leads to the accumulation of sulfite, a nucleophile capable of reacting with PLP. Low PLP levels were also seen in a group of children with transiently elevated urinary excretion of sulfite and/or sulfocysteine, suggesting that there may be other situations in which sulfite accumulates and inactivates PLP. There was no evidence that seizures or the anticonvulsant drugs prescribed for patients in this study led to significant lowering of CSF PLP. A small proportion of patients receiving L-dopa therapy were found to have a CSF PLP concentration below the appropriate reference range. This may have implications for monitoring and treatment. A positive correlation was seen between the CSF PLP and 5-methyl-tetrahydrofolate (5-MTHF) and tetrahydrobiopterin (BH(4)) concentrations. All are susceptible to attack by nucleophiles and oxygen-derived free-radicals, and CSF has relatively low concentrations of other molecules that can react with these compounds. Further studies of CSF PLP levels in a wide range of neurological diseases might lead to improved understanding of pathogenesis and possibilities for treatment.

Topics: Adolescent; Adult; Biopterins; Child; Child, Preschool; Cysteine; Epilepsy; False Positive Reactions; Female; Free Radicals; Humans; Infant; Infant, Newborn; Levodopa; Male; Metabolism, Inborn Errors; Middle Aged; Nervous System Diseases; Oxygen; Pyridoxal Phosphate; Reference Values; Reproducibility of Results; Sulfites; Tetrahydrofolates

Topics: Base Sequence; Brain; Carrier Proteins; Child, Preschool; Disease Progression; DNA Mutational Analysis; Dose-Response Relationship, Drug; Folate Receptor 1; Folate Receptors, GPI-Anchored; Humans; Leucovorin; Male; Mutation; Nervous System Diseases; Receptors, Cell Surface; RNA; Tetrahydrofolates; Treatment Outcome

The diagnosis of pediatric neurologic disorders with a deficiency in the biosynthesis of either the neurotransmitters serotonin and dopamine, or the co-factor tetrahydrobiopterin or a cerebral 5-methyltetrahydrofolate (5-MTHF) deficiency, strongly relies on a robust analysis of neurotransmitter metabolites, pterins and 5-MTHF in the cerebrospinal fluid (CSF). The aim of this study was to investigate which technical and biochemical factors affect the CSF concentration of 5-MTHF, neopterin and biopterin in a pediatric population.. We studied effects of the ventriculo-spinal gradient, total protein concentration, pretreatment with ascorbic acid (in case of 5-MTHF analysis), pretreatment of CSF with trichloro acetic acid (TCA)/dithiotreitol (DTE) and oxidation with either iodine or manganese oxide (in case of pterin analysis), storage time and age of the patients. We included CSF samples from children until the age of 18 years and analysed 5-MTHF, neopterin, biopterin, homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and total protein.. The major findings of our study are: (1) CSF 5-MTHF, neopterin and biopterin concentrations are not affected by the ventriculo-spinal gradient; (2) pretreatment of CSF with ascorbic acid has negligible effects on 5-MTHF concentrations; (3) pretreatment of CSF with TCA/DTE and oxidation with iodine results in the most accurate determination of neopterin and biopterin; (4) when adjusted for age and total protein, CSF 5-MTHF correlated with 5-HIAA, but not with HVA; (5) the reference value of 5-MTHF in CSF in childhood is age-dependent (r=-0.634; p0.001); (6) we did not observe an age-dependency for neopterin and biopterin in CSF.. 5-MTHF, neopterin and biopterin can be analysed in any volume of CSF that is collected. For correct analysis of pterins, CSF will have to be pretreated to stabilize the concentrations and stored properly, whereas such pretreatment is not necessary for 5-MTHF.

Topics: Adolescent; Biopterins; Child; Child, Preschool; Female; Humans; Infant; Male; Neopterin; Nervous System Diseases; Specimen Handling; Tetrahydrofolates

Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.

Topics: Adolescent; Autistic Disorder; Autoantibodies; Carrier Proteins; Child; Child, Preschool; Female; Folate Receptors, GPI-Anchored; Folic Acid; Folic Acid Deficiency; Humans; Male; Nervous System Diseases; Receptors, Cell Surface; Tetrahydrofolates; Treatment Outcome

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