Diagnosis and management of cerebral folate deficiency. A form of folinic acid-responsive seizures

Neurosciences (Riyadh). 2014 Oct;19(4):312-6.


Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests.

Publication types

  • Case Reports

MeSH terms

  • Atrophy
  • Brain / pathology
  • Brain Diseases, Metabolic, Inborn / cerebrospinal fluid
  • Brain Diseases, Metabolic, Inborn / diagnosis
  • Brain Diseases, Metabolic, Inborn / drug therapy*
  • Brain Diseases, Metabolic, Inborn / genetics
  • Brain Diseases, Metabolic, Inborn / pathology
  • Child Development Disorders, Pervasive / genetics
  • Child, Preschool
  • Consanguinity
  • Developmental Disabilities / genetics
  • Early Diagnosis
  • Electroencephalography
  • Epilepsies, Myoclonic / cerebrospinal fluid
  • Epilepsies, Myoclonic / diagnosis
  • Epilepsies, Myoclonic / drug therapy*
  • Epilepsies, Myoclonic / genetics
  • Epilepsies, Myoclonic / pathology
  • Female
  • Folate Receptor 1 / deficiency
  • Folate Receptor 1 / genetics*
  • Folic Acid Deficiency / cerebrospinal fluid
  • Folic Acid Deficiency / diagnosis
  • Folic Acid Deficiency / drug therapy*
  • Folic Acid Deficiency / genetics
  • Humans
  • Leucovorin / therapeutic use*
  • Magnetic Resonance Imaging
  • Male
  • Mutation, Missense*
  • Point Mutation*
  • Pyridoxine / therapeutic use
  • Siblings
  • Tetrahydrofolates / cerebrospinal fluid


  • FOLR1 protein, human
  • Folate Receptor 1
  • Tetrahydrofolates
  • Pyridoxine
  • Leucovorin
  • 5-methyltetrahydrofolate