Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects

Arch Neurol. 2011 May;68(5):615-21. doi: 10.1001/archneurol.2011.80.


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.

Design: 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.

Setting: Academic pediatric medical center.

Participants: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Biogenic Amines / cerebrospinal fluid
  • Brain / metabolism*
  • Child
  • Child, Preschool
  • Female
  • Folate Receptor 1 / genetics
  • Folic Acid / administration & dosage
  • Folic Acid / therapeutic use*
  • Folic Acid Deficiency / cerebrospinal fluid*
  • Folic Acid Deficiency / diagnosis*
  • Folic Acid Deficiency / drug therapy
  • Folic Acid Deficiency / metabolism
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Prospective Studies
  • Pterins / cerebrospinal fluid
  • Sequence Analysis, DNA
  • Spinal Puncture
  • Tetrahydrofolates / cerebrospinal fluid*
  • Tetrahydrofolates / deficiency*


  • Biogenic Amines
  • FOLR1 protein, human
  • Folate Receptor 1
  • Pterins
  • Tetrahydrofolates
  • Folic Acid
  • 5-methyltetrahydrofolate