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 journalArticle

41 Citations (Scopus)

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. 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
Pages (from-to)615-621
Number of pages7
JournalArchives of Neurology
Volume68
Issue number5
DOIs
Publication statusPublished - May 2011

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Folic Acid
Cerebrospinal Fluid
Central Nervous System Diseases
Acute Hemorrhagic Leukoencephalitis
Kearns-Sayre Syndrome
Pterins
Rett Syndrome
Childhood
Syndrome
Corpus Striatum
Central Nervous System Infections
Inborn Errors Metabolism
Mitochondrial Diseases
Biogenic Amines
Spinal Puncture
Asphyxia
Brain Diseases
Biotin
Neurologic Manifestations
Metabolic Networks and Pathways

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Pérez-Dueñas, B., Ormazábal, A., Toma, C., Torrico, B., Cormand, B., Serrano, M., ... Artuch, R. (2011). Cerebral folate deficiency syndromes in childhood: Clinical, analytical, and etiologic aspects. Archives of Neurology, 68(5), 615-621. https://doi.org/10.1001/archneurol.2011.80

Cerebral folate deficiency syndromes in childhood : Clinical, analytical, and etiologic aspects. / Pérez-Dueñas, Belén; Ormazábal, Aida; Toma, Claudio; Torrico, Barbara; Cormand, Bru; Serrano, Mercedes; Sierra, Cristina; De Grandis, Elisa; Marfa, Merce Pineda; García-Cazorla, Angels; Campistol, Jaime; Pascual, Juan M.; Artuch, Rafael.

In: Archives of Neurology, Vol. 68, No. 5, 05.2011, p. 615-621.

Research output: Contribution to journalArticle

Pérez-Dueñas, B, Ormazábal, A, Toma, C, Torrico, B, Cormand, B, Serrano, M, Sierra, C, De Grandis, E, Marfa, MP, García-Cazorla, A, Campistol, J, Pascual, JM & Artuch, R 2011, 'Cerebral folate deficiency syndromes in childhood: Clinical, analytical, and etiologic aspects', Archives of Neurology, vol. 68, no. 5, pp. 615-621. https://doi.org/10.1001/archneurol.2011.80
Pérez-Dueñas B, Ormazábal A, Toma C, Torrico B, Cormand B, Serrano M et al. Cerebral folate deficiency syndromes in childhood: Clinical, analytical, and etiologic aspects. Archives of Neurology. 2011 May;68(5):615-621. https://doi.org/10.1001/archneurol.2011.80
Pérez-Dueñas, Belén ; Ormazábal, Aida ; Toma, Claudio ; Torrico, Barbara ; Cormand, Bru ; Serrano, Mercedes ; Sierra, Cristina ; De Grandis, Elisa ; Marfa, Merce Pineda ; García-Cazorla, Angels ; Campistol, Jaime ; Pascual, Juan M. ; Artuch, Rafael. / Cerebral folate deficiency syndromes in childhood : Clinical, analytical, and etiologic aspects. In: Archives of Neurology. 2011 ; Vol. 68, No. 5. pp. 615-621.
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AU - Cormand, Bru

AU - Serrano, Mercedes

AU - Sierra, Cristina

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