Folate Receptor Autoantibodies and Spinal Fluid 5-Methyltetrahydrofolate Deficiency in Rett Syndrome

Abstract

Rett syndrome was associated with low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) in 42-50% of European patients whereas approximately 93% of the patients from North-America had a normal CSF 5MTHF status. We determined the CSF folate status in Rett patients living in North- and South-Western Europe and measured serum folate receptor (FR) autoantibodies of the blocking type to explain the reduced folate transport across the choroid plexus. Irrespective of their MECP2 genotype and despite normal plasma folate values, 14 of 33 Rett patients (42%) had low CSF folate levels. Blocking FR autoantibodies were found in 8 of the Rett patients (24%), 6 of whom had low CSF folate levels. FR autoimmunity was primarily found within the group of Rett patients with low CSF folate status with a higher incidence in North-Western Europe. In Rett patients from North-America 74 of 76 girls had higher folate values in both serum and CSF than European patients. The food folate fortification in North-America may account for the higher folate levels and may prevent CFD in these Rett patients. FR autoimmunity occurred predominantly in Rett patients from North-Western Europe and may contribute to cerebral folate deficiency (CFD).

Key words

Rett Syndrome - folate metabolism - folate receptor antibodies

References

• 1 Ramaekers VT, Hansen SI, Holm J. et al . Reduced folate transport to the CNS in female Rett patients.  Neurology. 2003;  61 506-515
• 2 Ramaekers VT, Blau N. Cerebral folate deficiency.  Dev Med Child Neurol. 2004;  46 843-851
• 3 Ormazabal A, Artuch R, Vilaseca MA, Aracil A, Pineda M. Cerebrospinal fluid concentrations of folate, biogenic amines and pterins in Rett Syndrome: Treatment with folinic acid.  Neuropediatrics. 2005;  36 ((6)) 380-385
• 4 Neul JL, Maricich SM, Islam M. et al . Spinal fluid 5-methyltetrahydrofolate levels are normal in Rett syndrome.  Neurology. 2005;  64 2151-2152
• 5 Ramaekers VT, Rothenberg SP, Sequeira JM. et al . Autoantibodies to folate receptors in the cerebral folate deficiency syndrome.  New Engl J Med. 2005;  352 1985-1991
• 6 Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett syndrome.  Eur J Paediatr Neurol. 2002;  6 293-297
• 7 Ormazabal A, Garcia-Cazorla A, Perez-Duenas B, Gonzalez V, Fernandez-Alvarez E, Pineda M, Campistol J, Artuch R. Determination of 5-methyltetrahydrofolate in cerebrospinal fluid of paediatric patients: Reference values for a paediatric population.  Clin Chim Acta. 2006;  371 159-462
• 8 Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000.  Am J Clin Nutr. 2005;  82 442-450
• 9 Svendsen I, Hansen SI, Holm J, Lyngbye J. Amino acid sequence homology between human and bovine low molecular weight folate binding protein isolated from milk.  Carlsberg Res Commun. 1982;  47 371-376
• 10 Suh JR, Herbig AK, Stover PJ. New perspectives on folate catabolism.  Ann Rev Nutr. 2001;  21 255-282

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