Hagebeuk EEO et al. S-adenosylmethionine and S-adenosyl homocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation.
J Inherited Metab Dis (2013) 36:967-972
Rett syndrome, a devastating disorder characterised by neuroregression after an initial period of normalcy, is caused by mutations in the MECP2 gene encoding the methyl CpG-binding protein; much research on the syndrome has, therefore, focused on compromised DNA methylation. Some patients with Rett syndrome have been found to have low CSF 5-MTHF levels; this has suggested folinic acid as a possible treatment, aiming to optimise cerebral methylation processes.
In this randomised, double-blind crossover study, Hagebeuk et al assess the biochemical effect of oral folinic acid treatment (in combination with cyanocobalamin) versus placebo in 10 female patients with Rett syndrome, each of whom received both arms of the study for one year each. During both folinic acid and placebo therapy, plasma folate, methionine, homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and SAM/SAH ratio were measured, as were 5-MTHF, SAM, SAH and SAM/SAH in the cerebrospinal fluid. Clinical outcomes were not assessed.
The authors found that while, as expected, SAM and SAH rose in the plasma (with no change in the SAM/SAH ratio), these changes were not seen in the cerebrospinal fluid despite a rise in 5-MTHF.
The authors speculate, therefore, that “the inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome and may play a role in its pathophysiology.” Unfortunately, this hypothesis is difficult to confirm in the absence of a control group showing an upregulation of SAM and SAH in response to folinic acid therapy in normal children. Nevertheless, it suggests an interesting new avenue for the study of DNA methylation and the dynamics of folate metabolism in Rett syndrome.
Posted by Alina Levtova, MD