Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency

Authors

  • R Urreizti,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • AA Moya-García,

    1. Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Málaga, Spain
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  • A Pino-Ángeles,

    1. Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Málaga, Spain
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  • M Cozar,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • A Langkilde,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • U Fanhoe,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • C Esteves,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • J Arribas,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • MA Vilaseca,

    1. Servei de Bioquímica Clínica, Hospital Sant Joan de Déu
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  • B Pérez-Dueñas,

    1. Servei de Neurologia, Hospital Sant Joan de Déu, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • M Pineda,

    1. Servei de Neurologia, Hospital Sant Joan de Déu, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • V González,

    1. Servei de Neurologia, Hospital Sant Joan de Déu, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • R Artuch,

    1. Servei de Bioquímica Clínica, Hospital Sant Joan de Déu
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  • A Baldellou,

    1. Unidad de Enfermedades Metabólicas, Hospital Infantil Miguel Servet, Zaragoza, Spain
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  • L Vilarinho,

    1. Instituto de Genética Médica Jacinto Magalhaes, Porto, Portugal
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  • B Fowler,

    1. Metabolic Unit, University Children's Hospital, Basel, Switzerland
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  • A Ribes,

    1. Divisió d’Errors Congènits del Metabolisme (IBC), Departament de Bioquímica i Genètica Molecular, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • F Sánchez-Jiménez,

    1. Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Málaga, Spain
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  • D Grinberg,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
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  • S Balcells

    Corresponding author
    1. Departament de Genètica, Universitat de Barcelona, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
    • Dr Susana Balcells, Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Av. Diagonal 645, E-08028, Barcelona, Spain.
      Tel.: +34 93 403 5418;
      fax: +34 93 403 4420;
      e-mail: sbalcells@ub.edu

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Abstract

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.

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