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

Belén Pérez-Dueñas, Aida Ormazábal, Claudio Toma, Barbara Torrico, Bru Cormand, Mercedes Serrano, Cristina Sierra, Elisa De Grandis, Merce Pineda Marfa, Angels García-Cazorla, Jaime Campistol, Juan M. Pascual, Rafael Artuch

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)615-621
Number of pages7
JournalArchives of neurology
Issue number5
StatePublished - May 2011

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology


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