Metabolic Brain Disease

, Volume 31, Issue 5, pp 1205–1208 | Cite as

Elevated homocysteine with pseudo-homozygosity for MTHFR677T as predisposing factors for transient ischemic attacks: a case report

  • A. Sobczyńska-MaleforaEmail author
  • J. Cutler
  • Y. Rahman
Short Communication


A 21 year old male presented with a history of intermittent, transient neurological events. A brain MRI showed an area of restricted diffusion in keeping with an infarct, and an angiogram demonstrated an intracranial stenosis in the internal carotid artery, consistent with atherosclerosis. Laboratory investigations revealed a highly elevated plasma homocysteine, with low plasma folate and 5-methyltetrahydrofolate and methionine at the lower end of the normal ranges. The homocysteine normalized following treatment with folic acid. Molecular analysis found heterozygosity for the common MTHFR c.665C > T (aka 677C > T) variant and heterozygosity for a c.3G > C nucleotide substitution, which result in the lack of translation from this allele. It is proposed that the loss of p. Met1, coupled with folate deficiency, may be significant for the remethylation process, and may have contributed to the neurological events in this patient. If the two genetic variants are on alternate alleles, the patient would present with pseudo-homozygosity for MTHFR677T. It is probable that the combination of pronounced dietary folate deficiency, an MTHFR ‘null allele’ and the 677 T variant is sufficient to explain both the moderate hyperhomocysteinaemia and the clinical presentation in this patient. This case highlights the need to investigate other possible mutations in MTHFR, particularly in the absence of homozygous MTHFR 677C > T status in premature cardiovascular events.


Hyperhomocysteinaemia MTHFR Transient ischemic attacks Folate Intracranial stenosis 



Methylene tetrahydrofolate reductase


Methylmalonic acid; holoTC holotranscobalamin




Transient ischemic attacks



We would like to thank the patient for participating in this study.


  1. Critcher MS, Sobczynska-Malefora A (2015) The prevalence of low and very high vitamin B6 (Pyridoxal 5'-phosphate) concentrations in hospital patients. Biomedical Scientist:2–3Google Scholar
  2. Ganguly P, Alam SF (2015) Role of homocysteine in the development of cardiovascular disease. Nutr J 14:6CrossRefPubMedPubMedCentralGoogle Scholar
  3. Fu HJ, Zhao LB, Xue JJ, ZX W, Huang YP, Liu W, Gao Z (2015) Elevated Serum Homocysteine (Hcy) Levels May Contribute to the Pathogenesis of Cerebral Infarction. J Mol Neurosci 56:553–561CrossRefPubMedGoogle Scholar
  4. Kang SS, Wong PW, Malinow MR (1992) Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 12:279–298CrossRefPubMedGoogle Scholar
  5. Kim SJ, Lee BH, Kim YM, Kim GH, Yoo HW (2013) Congenital MTHFR deficiency causing early-onset cerebral stroke in a case homozygous for MTHFR thermolabile variant. Metab Brain Dis 28:519–522CrossRefPubMedGoogle Scholar
  6. Lai WK, Kan MY (2015) Homocysteine-Induced Endothelial Dysfunction. Ann Nutr Metab 67:1–12CrossRefPubMedGoogle Scholar
  7. Marrin C, Lewis S (2009) Recurrent dural venous sinus thrombosis in a 20-year-old man: nature or nurture? Br J Haematol 145:439CrossRefPubMedGoogle Scholar
  8. McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56:111–128PubMedPubMedCentralGoogle Scholar
  9. McCully KS, Olszewski AJ, Vezeridis MP (1990) Homocysteine and Lipid-Metabolism in Atherogenesis - Effect of the Homocysteine Thiolactonyl Derivatives, Thioretinaco and Thioretinamide. Atherosclerosis 83:197–206CrossRefPubMedGoogle Scholar
  10. Sobczynska-Malefora A, Harrington DJ, Lomer MCE, Pettitt C, Hamilton S, Rangarajan S, Shearer MJ (2009) Erythrocyte folate and 5-methyltetrahydrofolate levels decline during 6 months of oral anticoagulation with warfarin. Blood Coagulation & Fibrinolysis 20:297–302CrossRefGoogle Scholar
  11. Sobczynska-Malefora A, Harrington DJ, Voong K, Shearer MJ (2014) Plasma and red cell reference intervals of 5-methyltetrahydrofolate of healthy adults in whom biochemical functional deficiencies of folate and vitamin B12 had been excluded. Adv Hematol, 2014: 465623Google Scholar
  12. Whyte AF, Jones DL, Dreyer MD (2012) Vitamin B12 deficiency causing hyperhomocysteinaemia and cerebral venous sinus thrombosis. Intern Med J 42:601–603CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.The Nutristasis Unit, Haemostasis & ThrombosisViapath, St. Thomas’ HospitalLondonUK
  2. 2.Molecular Haemostasis Laboratory, Haemostasis & ThrombosisViapath, St. Thomas’ HospitalLondonUK
  3. 3.Inherited Metabolic Disease Unit, Guy’s and St. Thomas’ NHS Foundation TrustLondonUK

Personalised recommendations