Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency
Version of Record online: 11 FEB 2010
© 2010 John Wiley & Sons A/S
Volume 78, Issue 5, pages 441–448, November 2010
How to Cite
Urreizti, R., Moya-García, A., Pino-Ángeles, A., Cozar, M., Langkilde, A., Fanhoe, U., Esteves, C., Arribas, J., Vilaseca, M., Pérez-Dueñas, B., Pineda, M., González, V., Artuch, R., Baldellou, A., Vilarinho, L., Fowler, B., Ribes, A., Sánchez-Jiménez, F., Grinberg, D. and Balcells, S. (2010), Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency. Clinical Genetics, 78: 441–448. doi: 10.1111/j.1399-0004.2010.01391.x
- Issue online: 11 FEB 2010
- Version of Record online: 11 FEB 2010
- Received 20 October 2009, revised and accepted for publication 22 January 2010
- MTHFR deficiency;
- structure modelling;
- mefolinate treatment
Urreizti R, Moya-García AA, Pino- Ángeles A, Cozar M, Langkilde A, Fanhoe U, Esteves C, Arribas J, Vilaseca MA, Pérez-Dueñas B, Pineda M, González V, Artuch R, Baldellou, A, Vilarinho L, Fowler B, Ribes A, Sánchez-Jiménez F, Grinberg D, Balcells S. Molecular characterization of five patients with homocystinuria due to severe MTHFR deficiency.
Methylenetetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism. Disturbed function of the enzyme results in hyperhomocysteinemia and causes severe vascular and neurological disorders and developmental delay. Five patients suspected of having non-classical homocystinuria due to MTHFR deficiency were examined with respect to their symptoms, MTHFR enzyme activity and genotypes of the MTHFR gene. All patients presented symptoms of severe central nervous system disease. Two patients died, at the ages of 15 months and 14 years. One patient is currently 32 years old, and is being treated with betaine and folinic acid. The other two patients, with an early diagnosis and a severe course of the disease, are currently improving under treatment. MTHFR enzyme activity in the fibroblasts of four of the patients was practically undetectable. We found four novel mutations, three of which were missense changes c.664G> T (p.V218L), c.1316T> C (p.F435S) and c.1733T> G (p.V574G), and the fourth was the 1-bp deletion c.1780delC (p.L590CfsX72). We also found the previously reported nonsense mutation c.1420G> T (p.E470X). All the patients were homozygous. Molecular modelling of the double mutant allele (p.V218L; p.A222V) revealed that affinity for FAD was not affected in this mutant. For the p.E470X mutation, the evidence pointed to nonsense-mediated mRNA decay. In general, genotype–phenotype analysis predicts milder outcomes for patients with missense changes than for those in which mutations led to severe alterations of the MTHFR protein.