title: Neurological improvement following intravenous high-dose folinic acid for cerebral folate transporter deficiency caused by FOLR-1 mutation.
abstract: BACKGROUND
  Cerebral folate transporter deficiency caused by FOLR-1 mutations has been described in 2009. This condition is characterized by a 5MTHF level <5 nmol/l in the CSF, along with regression of acquisition in the second year of life, ataxia, and refractory myoclonic epilepsy. Oral or intravenous folinic acid (5-formyltetrahydrofolate) treatment has been shown to improve clinical status.
  
  
  METHODS
  We present the cases of two sisters with cerebral folate transport deficiency caused by mutation in the folate receptor 1 (FOLR1) gene (MIM *136430). Following recommendations, we administered oral folinic acid at 5 mg/kg/day, resulting in some initial clinical improvement, yet severe epilepsy persisted. During treatment, cerebrospinal fluid (CSF) analysis revealed normal 5-methyltetrahydrofolate (5MTHF) levels (60.1 nmol/l; normal range: 53-182 nmol/l). Epilepsy proved difficult to control and the younger patient exhibited neurological regression. We then administered high-dose folinic acid intravenously over 3 days (6 mg/kg/day for 24 h, then 12 mg/kg/day for 48 h), which significantly improved clinical status and epilepsy. CSF analysis revealed high 5MTHF levels following intravenous infusion (180 nmol/l). Treatment continued with monthly intravenous administrations of 20-25 mg/kg folinic acid. At 2 years post-treatment, clinical improvement was confirmed.
  
  
  CONCLUSIONS
  This report illustrates that cerebral folate transporter deficiency caused by FOLR-1 mutations is a treatable condition and can potentially be cured by folinic acid treatment. As already reported, early effective treatment is known to improve outcomes in affected children. In our study, intravenous high-dose folinic acid infusions appeared to optimize clinical response.
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Delmelle
authors.affiliation: Division of Metabolism, University Children's Hospital, Zürich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Thöny
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Clapuyt
authors.affiliation: University Children's Hospital, Division of Inborn Metabolic Diseases, Department of General Pediatrics, Heidelberg, Germany.
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium. Electronic address: marie-cecile.nassogne@uclouvain.be.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Nassogne
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D058975:Folate Receptor 1 / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage*; D009154:Mutation; D019150:Neuroaxonal Dystrophies / Q000188:drug therapy* / Q000235:genetics; D035781:Siblings; D013763:Tetrahydrofolates / Q000134:cerebrospinal fluid
chemical_list: C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D013763:Tetrahydrofolates; D002955:Leucovorin; C005984:5-methyltetrahydrofolate
keywords: Cerebral folate deficiency; Hypomyelination; Inborn error of metabolism; Neurological regression; Treatable disorder