Cerebrospinal Fluid Concentrations of Folate, Biogenic Amines and Pterins in Rett Syndrome: Treatment with Folinic Acid

Abstract

Background: Previous studies in Rett syndrome (RS) patients suggested various abnormalities in biogenic amines, pterins, and folate values in cerebrospinal fluid (CSF). Our aim was to analyse these metabolites in CSF of 16 RS patients (age range: 2 - 23 years). Biogenic amines, pterins, and 5-methyltetrahydrofolate were measured by HPLC with electrochemical and fluorescence detection. Results: CSF values of 5-methyltetrahydrofolate were decreased in 8 out of 16 RS patients (average: 53.6 nmol/L; range: 19 - 92) when compared with our reference values (average: 74.6 nmol/L; range: 45 - 127). These eight patients had epilepsy, while 4 out of 16 RS patients who did not have epilepsy showed normal CSF 5-methyltetrahydrofolate concentrations. Values of biogenic amines or pterins were decreased in four of the patients with low values of 5-methyltetrahydrofolate. No correlation was observed between CSF values of 5-methyltetrahydrofolate and pterins, biogenic amines, or age. Supplementation with folinic acid was applied in six out of the eight patients with CSF 5-methyltetrahydrofolate deficiency. An improvement was noticed in all cases. Conclusions: An important percentage of RS patients showed 5-methyltetrahydrofolate concentrations under the reference values. Therefore, analysis of CSF 5-methyltetrahydrofolate seems advisable in RS, especially in patients with epilepsy and those resistant to antiepileptic drugs.

Key words

Rett Syndrome - 5-methyltetrahydrofolate - biogenic amines - folinic acid

References

• 1 Armstrong J, Pineda M, Aibar E, Gean E, Monros E. Classic Rett syndrome in a boy as a result of somatic mosaicism for a MECP2 mutation.  Ann Neurol. 2001;  50 692
• 2 Belz S, Frickel C, Wolfrom C, Nau H, Henze G. High-performance liquid chromatographic determination of methotrexate, 7-hydroxymethotrexate, 5-methyltetrahydrofolic acid and folinic acid in serum and cerebrospinal fluid.  J Chromatog B. 1994;  661 109-118
• 3 Blau N, Kierat L, Heizmann C W, Endres W, Giudici T, Wang M. Screening for tetrahydrobiopterin deficiency in newborns using dried urine on filter paper.  J Inherit Metab Dis. 1992;  15 402-404
• 4 Blau N, Thöny B, Cotton R, Hyland K. Disorders of tetrahydrobiopterin and related biogenic amines. Scriver C, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease. New York; McGraw-Hill 2001: 1725-1776
• 5 Botez M I, Young S N. Effects of anticonvulsant treatment and low levels of folate and thiamine on amine metabolites in cerebrospinal fluid.  Brain. 1991;  114 333-348
• 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 Moyano D, Vilaseca M A, Artuch R, Lambruschini N. Plasma amino acids in anorexia nervosa.  Eur J Clin Nutr. 1998;  52 684-689
• 8 Neul J L, Maricich S M, Islam M, Barrish J, O'Brian Smith E, Bottiglieri T. et al . Spinal fluid 5-methyltetrahydrofolate levels are normal in Rett syndrome.  Neurology. 2005;  64 2151-2152
• 9 Ormazabal A, García-Cazorla A, Fernández Y, Fernández-Álvarez E, Campistol J, Artuch R. HPLC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins.  J Neurosci Meth. 2005;  142 153-158
• 10 Ramaekers V T, Hansen S I, Holm J, Opladen T, Senderek J, Häusler M. et al . Reduced folate transport to the CNS in female Rett patients.  Neurology. 2003;  61 506-515
• 11 Ramaekers V T, Blau N. Cerebral folate deficiency.  Develop Med Child Neurol. 2004;  46 843-851
• 12 Ramaekers V T, Rothenberg S P, Sequeira J M, Opladen T, Blau N, Quadros E V. et al . Autoantibodies to folate receptors in the cerebral folate deficiency syndrome.  N Engl J Med. 2005;  352 1985-1991
• 13 Surtees R, Heales S, Bowron A. Association of cerebrospinal fluid deficiency of 5-methyltetrahydrofolate, but not S-adenosylmethionine, with reduced concentrations of the acid metabolites of 5-hydroxytryptamine and dopamine.  Clin Sci. 1994;  86 697-702
• 14 Vilaseca M A, Moyano D, Ferrer I, Artuch R. Total homocysteine in pediatric patients.  Clin Chem. 1997;  43 690-692
• 15 Zoghbi H Y, Milstien S, Butler I J, Smith E O, Kaufman S, Glaze D G. et al . Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome.  Ann Neurol. 1989;  25 56-60