Journal of Inherited Metabolic Disease

, Volume 33, Issue 6, pp 795–802

Progressive ataxia and myoclonic epilepsy in a patient with a homozygous mutation in the FOLR1 gene

Authors

    • Departament of NeurologyHospital Sant Joan de Déu
    • Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII
  • Claudio Toma
    • Department of Genetics, Faculty of BiologyUniversity of Barcelona
    • Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII
  • Aida Ormazábal
    • Department of BiochemistryHospital Sant Joan de Déu
    • Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII
  • Jordi Muchart
    • Department of NeuroradiologyHospital Sant Joan de Déu
  • Francesc Sanmartí
    • Departament of NeurologyHospital Sant Joan de Déu
    • Epilepsy UnitHospital Sant Joan de Déu
  • Georgina Bombau
    • Department of Genetics, Faculty of BiologyUniversity of Barcelona
  • Mercedes Serrano
    • Departament of NeurologyHospital Sant Joan de Déu
    • Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII
  • Angels García-Cazorla
    • Departament of NeurologyHospital Sant Joan de Déu
    • Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII
  • Bru Cormand
    • Department of Genetics, Faculty of BiologyUniversity of Barcelona
    • Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII
    • Institute of Biomedicine of the University of Barcelona (IBUB)
  • Rafael Artuch
    • Department of BiochemistryHospital Sant Joan de Déu
    • Centre for Biomedical Research on Rare Diseases (CIBERER), ISCIII
Original Article

DOI: 10.1007/s10545-010-9196-1

Cite this article as:
Pérez-Dueñas, B., Toma, C., Ormazábal, A. et al. J Inherit Metab Dis (2010) 33: 795. doi:10.1007/s10545-010-9196-1

Abstract

Several unrelated disorders can lead to 5-methyltetrahydrofolate (5MTHF) depletion in the cerobrospinal fluid (CSF), including primary genetic disorders in folate-related pathways or those causing defective transport across the blood-CSF barrier. We report a case of cerebral folate transport deficiency due to a novel homozygous mutation in the FOLR1 gene, in an effort to clarify phenotype–genotype correlation in this newly identified neurometabolic disorder. A previously healthy infant developed an ataxic syndrome in the second year of life, followed by choreic movements and progressive myoclonic epilepsy. At the age of 26 months, we analyzed CSF 5MTHF by HPLC with fluorescence detection and conducted magnetic resonance (MR) imaging and spectroscopy studies. Finally, we performed mutational screening in the coding region of the FOLR1 gene. MR showed a diffuse abnormal signal of the cerebral white matter, cerebellar atrophy and a reduced peak of choline in spectroscopy. A profound deficiency of CSF 5MTHF (2 nmol/L; NV 48-127) with reduced CSF/plasma folate ratio (0.4; NV 1.5-3.5) was highly suggestive of defective brain folate-specific transport across the blood-CSF/brain barrier. Mutation screening of FOLR1 revealed a new homozygous missense mutation (p.Cys105Arg) that is predicted to abolish a disulfide bond, probably necessary for the correct folding of the protein. Both parents were heterozygous carriers of the same variant. Mutation screening in the FOLR1 gene is advisable in children with profound 5MTHF deficiency and decreased CSF/serum folate ratio. Progressive ataxia and myoclonic epilepsy, together with impaired brain myelination, are clinical hallmarks of the disease.

Supplementary material

10545_2010_9196_MOESM1_ESM.doc (32 kb)
Supplementary Table 1 Primer sequences used for the PCR amplification of the FOLR1 gene coding region (exons 4 to 7). The length of the PCR products (bp) and the annealing temperatures (°C) are shown for each amplicon (DOC 32 kb)

Copyright information

© SSIEM and Springer 2010