Abstract
S-adenosyl methionine, which is formed from methionine, is an essential methyl donor within the central nervous system. Methionine is formed by the enzyme methionine synthase for which 5-methyltetrahydrofolate (5-MTHF) and homocysteine are substrates. Patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency cannot make 5-MTHF and have extremely low levels in the CSF. As a consequence, methylation reactions in the CNS are compromised, and this is likely to play an important role in the neurological abnormalities that occur in MTHFR deficiency. Although treatment with oral betaine can remethylate homocysteine to methionine in the liver, betaine crosses the blood-brain barrier poorly, and CSF levels of methionine remain low. We report three patients with severe MTHFR deficiency (enzyme activity ≤1% of controls) who had undetectable levels of CSF 5-MTHF at diagnosis and while on treatment with either folic acid or calcium folinate. Only treatment with oral 5-MTHF given as calcium mefolinate at doses of 15–60 mg/kg/day resulted in an increase in CSF 5-MTHF.
Competing interests: None declared
An erratum to this chapter is available at 10.1007/8904_2016_574
An erratum to this chapter can be found at http://dx.doi.org/10.1007/8904_2016_574
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References
Burda P, Schafer A, Suormala T et al (2015) Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients. Hum Mutat 36:611–621
Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ (1986) Subacute combined degeneration of the cord, dementia and parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry 49:920–927
Diekman EF, de Koning TJ, Verhoeven-Duif NM, Rovers MM, van Hasselt PM (2014) Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. JAMA Neurol 71:188–194
El-Gharbawy AH, Smith EC, Bottiglieri T, Hyland K, Young SP, Koeberl D (2011) Why 5-methyltetrahydrofolate may be preferred to folinic acid in severe MTHFR deficiency complicated by cerebral folate deficiency. Results of an “n-1-clinical trial”. Mol Genet Metab 102:278–279
Huemer M, Mulder-Bleile R, Burda P et al (2015) Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency. J Inherit Metab Dis 39:115–124
Jadavji NM, Deng L, Leclerc D et al (2012) Severe methylenetetrahydrofolate reductase deficiency in mice results in behavioral anomalies with morphological and biochemical changes in hippocampus. Mol Genet Metab 106:149–159
Kempson SA, Zhou Y, Danbolt NC (2014) The betaine/GABA transporter and betaine: roles in brain, kidney, and liver. Front Physiol 5:159
Levitt M, Nixon PF, Pincus JH, Bertino JR (1971) Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5-formyltetrahydrofolate. J Clin Invest 50:1301–1308
Li D, Karp N, Wu Q et al (2008) Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in an animal model of severe methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis 31:403–411
Schiff M, Benoist JF, Tilea B, Royer N, Giraudier S, Ogier de Baulny H (2011) Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 34:137–145
Strauss KA, Morton DH, Puffenberger EG et al (2007) Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 91:165–175
Torres A, Newton SA, Crompton B et al (2015) CSF 5-methyltetrahydrofolate serial monitoring to guide treatment of congenital folate malabsorption due to proton-coupled folate transporter (PCFT) deficiency. JIMD Rep 24:91–96
Watkins D, Rosenblatt D, Fowler B (2012) Disorders of cobalamin and folate transport and metabolism. In: Saudubray J-M, van den Berghe G, Walter J (eds) Inborn metabolic diseases. Springer, Berlin/Heidelberg, pp 385–402
Acknowledgments
Prof. Simon Heales, London, for measurement of CSF5-MTHF.
Prof. Matthias Baumgartner and Prof. Brian Fowler, Zurich, for MTHFR enzyme assay and MTHFR mutation analysis.
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Communicated by: Viktor Kožich
Appendices
Take-Home Message
In severe methylenetetrahydrofolate reductase deficiency, measurable 5-methyltetrahydrofolate in cerebrospinal fluid is only achieved with mefolinate (5-methyltetrahydrofolate) supplements and not with either folic acid or folinic acid.
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Dr. Linzi Knowles, Dr. Andrew Morris and Prof. John Walter declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
This manuscript details the results of investigations and treatment that were undertaken as part of routine clinical care and not as part of a research study. Consent for treatment and routine investigations was obtained from the parents of all patients reported in this article.
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All authors contributed equally to the planning, conduct and reporting of the work described in the article.
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Knowles, L., Morris, A.A.M., Walter, J.H. (2016). Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 29. JIMD Reports, vol 29. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_529
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DOI: https://doi.org/10.1007/8904_2016_529
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