DNA sequence; Rett syndrome; Biogenic Monoamines; Biological Markers; Blood-Brain Barrier; Carrier Proteins; Central Nervous System; Child, Preschool; Female; Folic Acid; Humans; Leucovorin; Protein Isoforms; Pterins; Receptors, Cell Surface; Sequence Analysis, DNA; Tetrahydrofolates
Abstract :
[en] Background: 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. Methods: 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. Results: 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. Conclusion: 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.
Disciplines :
Neurology Pediatrics
Author, co-author :
RAMAEKERS, Vincent ; University Hospital Aachen, Germany > Pediatrics > Pediatric Neurology
Hansen, Sylvain ; Department of Clinical Chemistry, Hillerød Sygehus, Hillerød, Denmark
Holm, J.; Department of Clinical Chemistry, Hillerød Sygehus, Hillerød, Denmark
Opladen, T.; Division of Pediatric Neurology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany
Senderek, J.; Division of Pediatric Neurology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany
Häusler, M.; Division of Pediatric Neurology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany
Heimann, G.; Division of Pediatric Neurology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany
Fowler, B.; Department of Clinical Chemistry, University Children's Hospital, Basel, Switzerland
Maiwald, R.; Inst. of Med. Genet./Molec. Medicine, Cologne, Germany
Blau, N.; Div. of Clin. Chem. and Biochemistry, University Children's Hospital, Zürich, Switzerland
Language :
English
Title :
Reduced folate transport to the CNS in female Rett patients
Publication date :
26 August 2003
Journal title :
Neurology
ISSN :
0028-3878
eISSN :
1526-632X
Publisher :
Lippincott Williams & Wilkins, United States - Maryland
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