Elevated homocysteine with pseudo-homozygosity for MTHFR677T as predisposing factors for transient ischemic attacks:...

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.