Methylenetetrahydrofolate reductase in Parkinson's disease

In a recent issue of Annals of Neurology, de Lau and colleagues report that the TT variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism was associated with an increased risk for Parkinson's disease, particularly in smokers.1 We performed a case–control association study including 342 Parkinson's disease (PD) patients (mean age, 59 ± 9 years; 100 female patients) with diagnosis of PD according to the UK PD brain bank criteria and 342 control subjects (58 ± 16 years, 171 female patients). The MTHFR C677T (A222V) polymorphism was analyzed in addition to a second MTHFR polymorphism, A1298C (E429A), according to published methods.2 Logistic regression analysis was used to examine effects of genotypes, sex, and age on the risk for PD. Kaplan–Meier survival analysis was used to compare the age at onset in accordance with the different genotypes as published.2 The TT genotype of MTHFR C677T was not associated with an increased risk of PD in our population, and also the MTHFR A1298C genotype did not contribute a significant risk (Table). Unfortunately, for our population, information on smoking status was not available; therefore, multiplicative effects could not be analyzed as done by de Lau and colleagues.1 Analysis of age of onset in the PD patients showed a significant effect of the A1298C polymorphism showing that the CC genotype was associated with the latest onset of disease in our population. Similarly, we did not find any significant association of MTHFR polymorphisms with an increased risk for Alzheimer's disease (AD) in a previous study, but the CC genotype of the of A1298C variant, which was proved to lead to decreased enzyme activity, was associated also with a later age of onset in AD.2 In general, decreased MTHFR activity may favor unimpaired nucleic acid synthesis as well as glutathione synthesis.3 Because folate deficiency has been reported to endanger dopaminergic neurons in models of Parkinson's disease,4 and reduced glutathione levels have been demonstrated in the substantia nigra of PD patients,5 MTHFR genotypes may plausibly influence the pathogenesis of neurodegenerative disorders such as AD and PD. Different biochemical and nutritive features may contribute to different effects of the two MTHFR polymorphisms in different populations,2, 3 as suggested in the Rotterdam Scan Study and by our data. Analysis of the underlying mechanisms is required for prophylactic and therapeutic strategies. This work was supported by grants from the Bundesministerium für Bildung und Forschung (Nationales Genomforschungsnetz, 01GS0115NVS02T09; Kompetenznetz Parkinson, 01GI9901, U.W.) and Universitätsklinikum Bonn (Bonfor, M.L.). Ullrich Wüllner MD, PhD*, Heike Kölsch PhD , Michael Linnebank MD*, * Department of Neurology, University Bonn, Bonn, Germany, Department of Psychiatry, University Bonn, Bonn, Germany.