title: Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects.
abstract: BACKGROUND
  Cerebral folate deficiency may be amenable to therapeutic supplementation. Diverse metabolic pathways and unrelated processes can lead to cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) depletion, the hallmark of cerebral folate deficiency.
  
  
  OBJECTIVE
  To analyze cerebral folate abundance in a large prospective series of children diagnosed with any neurologic disorder for which a diagnostic lumbar puncture was indicated.
  
  
  METHODS
  We studied the spectrum and frequency of disorders associated with cerebral folate deficiency by measuring cerebrospinal fluid 5-MTHF, biogenic amines, and pterins. Direct sequencing of the FOLR1 transporter gene was also performed in some patients.
  
  
  METHODS
  Academic pediatric medical center.
  
  
  METHODS
  We studied 134 individuals free of neurometabolic disease and 584 patients with any of several diseases of the central nervous system.
  
  
  RESULTS
  Of 584 patients, 71 (12%) exhibited 5-MTHF deficiency. Mild to moderate deficiency (n = 63; range, 19-63 nmol/L) was associated with perinatal asphyxia, central nervous system infection, or diseases of probable genetic origin (inborn errors of metabolism, white matter disorders, Rett syndrome, or epileptic encephalopathies). Severe 5-MTHF depletion (n = 8; range, 0.6-13 nmol/L) was detected in severe MTHF reductase deficiency, Kearns-Sayre syndrome, biotin-responsive striatal necrosis, acute necrotizing encephalitis of Hurst, and FOLR1 defect. A strong correlation was observed between cerebrospinal fluid and plasma folate levels in cerebral folate deficiency.
  
  
  CONCLUSIONS
  Of the 2 main forms of cerebral folate deficiency identified, mild to moderate 5-MTHF deficiency was most commonly associated with disorders bearing no primary relation to folate metabolism, whereas profound 5-MTHF depletion was associated with specific mitochondrial disorders, metabolic and transporter defects, or cerebral degenerations. The results suggest that 5-MTHF can serve either as the hallmark of inborn disorders of folate transport and metabolism or, more frequently, as an indicator of neurologic dysfunction.
authors.affiliation: Department of Neurology, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu 2, Esplugues, Barcelona, Spain. bperez@hsjdbcn.org
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez-Dueñas
authors.forename: Aida
authors.initials: A
authors.lastname: Ormazábal
authors.forename: Claudio
authors.initials: C
authors.lastname: Toma
authors.forename: Barbara
authors.initials: B
authors.lastname: Torrico
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.forename: Mercedes
authors.initials: M
authors.lastname: Serrano
authors.forename: Cristina
authors.initials: C
authors.lastname: Sierra
authors.forename: Elisa
authors.initials: E
authors.lastname: De Grandis
authors.forename: Merce Pineda
authors.initials: MP
authors.lastname: Marfa
authors.forename: Angels
authors.initials: A
authors.lastname: García-Cazorla
authors.forename: Jaime
authors.initials: J
authors.lastname: Campistol
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pascual
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
mesh_terms: D000293:Adolescent; D001679:Biogenic Amines / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D058975:Folate Receptor 1 / Q000235:genetics; D005492:Folic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D005494:Folic Acid Deficiency / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011446:Prospective Studies; D011622:Pterins / Q000134:cerebrospinal fluid; D017422:Sequence Analysis, DNA; D013129:Spinal Puncture; D013763:Tetrahydrofolates / Q000134:cerebrospinal fluid* / Q000172:deficiency*
chemical_list: D001679:Biogenic Amines; C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D011622:Pterins; D013763:Tetrahydrofolates; D005492:Folic Acid; C005984:5-methyltetrahydrofolate