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.

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.

• Authors: 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
• Journal: Archives of neurology (Arch Neurol) Vol. 68 Issue 5 Pg. 615-21 (May 2011) ISSN: 1538-3687 [Electronic] United States
• PMID: 21555636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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