Skip to main content

The MTHFR C677T polymorphism modifies age at onset in Parkinson’s disease


Hyperhomocysteinemia is a risk factor for Parkinson’s disease (PD) and may result from genetic mutations or/and environmental factors. 5,10-methylenetetrahydrofolate reductase (MTHFR) is a folate-dependent enzyme that catalyzed remethylation of homocysteine (Hcy) and the MTHFR C677T polymorphism makes the MTHFR enzyme thermolabile causing hyperhomocysteinemia. In this study we analyzed whether two functional polymorphisms of MTHFR gene, A1298C and C677T, affect age of onset in PD. We enrolled 120 patients with sporadic PD. Patients were divided into three groups based on MTHFR C677T polymorphisms: (a) homozygotes wild type (CC) (b) heterozygotes (CT) and (c) homozygotes carriers of mutation (TT). MTHFR SNPs were analyzed using High-Resolution Melt analysis and ANOVA was performed to assess whether polymorphisms of MTHFR gene could influence age of onset. The MTHFR A1298C polymorphism had no effect on PD age at onset (p = 1.0) while there was a significant association with MTHFR C677T (p = 0.019 Bonferroni-adjusted post hoc) showing an earlier onset in CC as compared with TT. (p = 0.024). No differences were found for vascular load assessed with magnetic resonance imaging, pharmacological therapy and cognitive state for two MTHFR SNPs. Our results suggest a possible association of MTHFR C677T with age at onset of PD and may have important implications regarding the role of MTHFR.

This is a preview of subscription content, access via your institution.


  1. Wickremaratchi MM, Ben-Shlomo Y, Morris HR (2009) The effect of onset age on the clinical features of Parkinson’s disease. Eur J Neurol 16(4):450–456

    CAS  PubMed  Article  Google Scholar 

  2. Antonini A, Barone P, Marconi R, Morgante L, Zappulla S, Pontieri FE, Ramat S, Ceravolo MG, Meco G, Cicarelli G, Pederzoli M, Manfredi M, Ceravolo R, Mucchiut M, Volpe G, Abbruzzese G, Bottacchi E, Bartolomei L, Ciacci G, Cannas A, Randisi MG, Petrone A, Baratti M, Toni V, Cossu G, Del Dotto P, Bentivoglio AR, Abrignani M, Scala R, Pennisi F, Quatrale R, Gaglio RM, Nicoletti A, Perini M, Avarello T, Pisani A, Scaglioni A, Martinelli PE, Iemolo F, Ferigo L, Simone P, Soliveri P, Troianiello B, Consoli D, Mauro A, Lopiano L, Nastasi G, Colosimo C (2012) The progression of non-motor symptoms in Parkinson’s disease and their contribution to motor disability and quality of life. J Neurol 259(12):2621–2631

    PubMed  Article  Google Scholar 

  3. Valente EM, Arena G, Torosantuccia L, Gelmetti V (2012) Molecular pathways in sporadic PD. Parkinsonism and Relat Disord 18:S71–S73

    Article  Google Scholar 

  4. Sachdev PS (2005) Homocysteine and brain atrophy. Prog Neuropsychopharmacol Biol Psychiatry 29(7):1152–1161

    CAS  PubMed  Article  Google Scholar 

  5. Duan W, Ladenheim B, Cutler RG, Kruman II, Cadet JL, Mattson MP (2002) Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease. J Neurochem 80:101–110

    CAS  PubMed  Article  Google Scholar 

  6. Doshi SN, Goodfellow J, Lewis MJ, McDowell IF (1999) Homocysteine and endothelial function. Cardiovasc Res 42(3):578–582

    CAS  PubMed  Article  Google Scholar 

  7. Antonini A, Vitale C, Barone P, Cilia R, Righini A, Bonuccelli U, Abbruzzese G, Ramat S, Petrone A, Quatrale R, Marconi R, Ceravolo R, Stefani A, Lopiano L, Zappia M, Capus L, Morgante L, Tamma F, Tinazzi M, Colosimo C, Guerra UP (2012) The relationship between cerebral vascular disease and parkinsonism: the VADO study. Parkinsonism Relat Disord 18(6):775–780

    CAS  PubMed  Article  Google Scholar 

  8. de Lau LM, Koudstaal PJ, van Meurs JB, Uitterlinden AG, Hofman A, Breteler MM (2005) Methylenetetrahydrofolate reductase C677T genotype and PD. Ann Neurol 57(6):927–930

    PubMed  Article  Google Scholar 

  9. Wüllner U, Kölsch H, Linnebank M (2005) Methylenetetrahydrofolate reductase in Parkinson’s disease. Ann Neurol 58(6):972–973

    PubMed  Article  Google Scholar 

  10. Yasui K, Kowa H, Nakaso K, Takeshima T, Nakashima K (2000) Plasma homocysteine and MTHFR C677T genotype in levodopa patients with PD. Neurology 55(3):437–440

    CAS  PubMed  Article  Google Scholar 

  11. Lin JJ, Yueh KC, Liu CS, Liu JT, Lin SZ (2007) 5,10-Methylenetetrahydrofolate reductase C677T polymorphism can influence age at onset of Parkinson’s disease. Acta Neurol Taiwan 16(3):150–157

    PubMed  Google Scholar 

  12. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. McHugh PR. J Psychiatry Res 12(3):189–198

    CAS  Article  Google Scholar 

  13. Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJ, Vermersch P, Steinling M, Valk J (1993) A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 114(1):7–12

    CAS  PubMed  Article  Google Scholar 

  14. Butler Rob, Morris Andrew D, Struthers Allan D (2002) Polymorphism may protect endothelial function in young, normal subjects the T Allele of the C677T 5,10-Methylenetetrahydrofolate reductase (MTHFR) gene. Arterioscler Thromb Vasc Biol 22:193–194

    CAS  PubMed  Google Scholar 

  15. Spence MS, McGlinchey PG, Patterson CC, Belton C, Murphy G, McMaster D, Fogarty DG, Evans AE, McKeown PP (2002) Family-based investigation of the C677T polymorphism of the methylenetetrahydrofolate reductase gene in ischaemic heart disease. Atherosclerosis 165(2):293–299

    CAS  PubMed  Article  Google Scholar 

  16. Jacques PF, Bostom AG, Williams RR, Curtis Ellison R, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93:7–9

    CAS  PubMed  Article  Google Scholar 

  17. Kilarski LL, Pearson JP, Newsway V, Majounie E, Knipe MD, Misbahuddin A, Chinnery PF, Brucia DJ, Clarke CE, Marion MH, Lewthwaite AJ, Nicholl DJ, Legno NW, Morrison KE, Williams-Gray CH, Evans JR, Sawcer SJ, Barker RA, Wickremaratchi MM, Ben-Shlomo Y, Williams NM, Morris HR (2012) Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson’s disease. Mov Disord 12:1522–1529

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Annamaria Vallelunga.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vallelunga, A., Pegoraro, V., Pilleri, M. et al. The MTHFR C677T polymorphism modifies age at onset in Parkinson’s disease. Neurol Sci 35, 73–77 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Parkinson disease
  • MTHFR C677T
  • MTHFR A1298C
  • Homocysteine
  • Brain vascular load
  • Age at onset of PD