Cerebral folate transporter deficiency syndrome in three siblings: Why genetic testing for developmental and epileptic encephalopathies should be performed early and include the FOLR1 gene

Am J Med Genet A. 2021 Aug;185(8):2526-2531. doi: 10.1002/ajmg.a.62345. Epub 2021 May 19.


Cerebral folate transporter deficiency syndrome, caused by FOLR-1 mutations is characterized by late infantile onset, severe developmental regression, epilepsy, and leukodystrophy. An extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid provides a crucial clue to its diagnosis and is a treatment target. Oral or intravenous folinic acid (5-formyltetrahydrofolate) administration improves clinical symptoms and brain magnetic resonance imaging (MRI) findings. We describe three siblings carrying a novel homozygous FOLR1 nonsense mutation, that were referred due to intractable epilepsy and progressive neurological decline. Brain MRI showed hypomyelination and cerebellar atrophy. Folinic acid (oral and intravenous) supplementation, initiated after over 15 years illness, has failed to result in any sizeable clinical or neurophysiological improvement. Cerebral folate transport deficiency bears overlapping clinical features with many severe developmental encephalopathies. It is crucial to recognize FOLR1 signs and establish an early clinical and molecular diagnosis in order to provide timely folinic acid treatment and improve outcome.

Keywords: FOLR1 gene mutation; cerebral folate transport deficiency; developmental delay; epilepsy; folinic acid therapy; leukoencephalopathy.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Alleles
  • Brain / diagnostic imaging
  • Brain / drug effects
  • Brain / pathology
  • Consanguinity
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / genetics
  • Disease Management
  • Epilepsy / diagnosis
  • Epilepsy / genetics
  • Female
  • Folate Receptor 1 / deficiency*
  • Folate Receptor 1 / genetics
  • Folic Acid / administration & dosage
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Genotype
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mutation
  • Neuroaxonal Dystrophies / diagnosis*
  • Neuroaxonal Dystrophies / genetics*
  • Neuroaxonal Dystrophies / therapy
  • Phenotype
  • Siblings*
  • Syndrome
  • Treatment Outcome


  • FOLR1 protein, human
  • Folate Receptor 1
  • Folic Acid

Supplementary concepts

  • Neurodegeneration Due To Cerebral Folate Transport Deficiency