Paulus S Rommer1, Johannes Zschocke2, Brian Fowler3, Manuela Födinger4, Vassiliki Konstantopoulou5, Dorothea Möslinger5, Elisabeth Stögmann6, Erhard Suess6, Matthias Baumgartner7, Eduard Auff6, Gere Sunder-Plassmann8. 1. Department of Neurology, Medical University of Vienna, Vienna, Austria. Electronic address: paulus.rommer@meduniwien.ac.at. 2. Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. 3. Metabolic Unit, University Children's Hospital, Basel, Switzerland. 4. Institute of Laboratory Diagnostics, Kaiser-Franz-Josef Spital der Stadt Wien, Vienna, Austria; Sigmund Freud University, Vienna, Austria. 5. Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. 6. Department of Neurology, Medical University of Vienna, Vienna, Austria. 7. Division of Metabolism, University Children's Hospital, Zürich, Switzerland. 8. Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
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 32years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135μmol/L and 231μmol/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.
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 32years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135μmol/L and 231μmol/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.
Authors: Jochen Weile; Nishka Kishore; Song Sun; Ranim Maaieh; Marta Verby; Roujia Li; Iosifina Fotiadou; Julia Kitaygorodsky; Yingzhou Wu; Alexander Holenstein; Céline Bürer; Linnea Blomgren; Shan Yang; Robert Nussbaum; Rima Rozen; David Watkins; Marinella Gebbia; Viktor Kozich; Michael Garton; D Sean Froese; Frederick P Roth Journal: Am J Hum Genet Date: 2021-07-01 Impact factor: 11.025