Manifestations of neurological symptoms and thromboembolism in adults with MTHFR-deficiency

Abstract Background Methylenetetrahydrofolate-reductase (MTHFR) deficiency is a rare autosomal recessive disorder affecting intracellular folate metabolism with affection of different organ systems and clinical manifestation usually in childhood. Objective We report on four adult members of a family with MTHFR deficiency presenting with neurological and thromboembolic complications in adulthood. Methods Extensive diagnostic work-up including genetic testing was performed in four adult members. Results The male siblings aged 42 and 32 years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135 μmol/L and 231 μmol/L. and compound heterozygosity for two novel MTHFR gene mutations in exon 2 (c.202C > G, p.Arg68Gly) and intron 10 (c.1632 + 2T > G), and the known polymorphic variant MTHFR c.665C > T (p.Ala222Val, MTHFR 677C > T). Their mother was heterozygous for MTHFR c.1632 + 2T > G and c.665C > T, and a paternal relative was heterozygous for MTHFR c.202.C > G and MTHFR c.665C > T mutation. Both brothers showed partial response to therapy with betaine and multivitamins with clinical improvement. MTHFR activity was determined in fibroblast extracts and was around 4% of the mean control. Cell culture analysis indicated a re-methylation defect due to MTHFR deficiency. Conclusion Severe hyperhomocysteinemia due to two mutations of the MTHFR gene resulted in severe neurological symptoms in adulthood. Vitamin and methionine supplementation stabilize tHcy plasma levels. Severity of clinical manifestation varied greatly between the siblings. Damages to the nervous system may be present for years before becoming clinically manifest.