Cerebral Folate Deficiency Syndromes in Childhood

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, Author Affiliations are listed at the end of this article.

Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism

“…For instance, because the growing descriptions for a GLUT-1 deficiency include cases with normal or near-normal CSF glucose values, the patients under suspicion of this syndrome were selected based on their clinical phenotype [ 26 , 27 ]. In the analysis of biogenic amines, impaired CSF HVA concentrations are associated with a large amount of neurological conditions, as previously reported [ 28 ], or cerebral folate deficiency syndrome, encompassing a large group of neurological conditions in which partial deficiencies unrelated to the primary defects in folate transport and metabolism are frequently encountered [ 29 ]. Despite the fact that epileptic encephalopathies are a frequent phenotype observed in neurometabolic disorders, IEM are not the most frequent etiology causing this neurological disruption.…”

Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism

“…For instance, because the growing descriptions for a GLUT-1 deficiency include cases with normal or near-normal CSF glucose values, the patients under suspicion of this syndrome were selected based on their clinical phenotype [ 26 , 27 ]. In the analysis of biogenic amines, impaired CSF HVA concentrations are associated with a large amount of neurological conditions, as previously reported [ 28 ], or cerebral folate deficiency syndrome, encompassing a large group of neurological conditions in which partial deficiencies unrelated to the primary defects in folate transport and metabolism are frequently encountered [ 29 ]. Despite the fact that epileptic encephalopathies are a frequent phenotype observed in neurometabolic disorders, IEM are not the most frequent etiology causing this neurological disruption.…”

Epilepsy in KCNH1‐related syndromes

“…Folate depletion could also result from secondary inhibition of sodium currents with mechanisms comparable to the action of a sodium blocker, such as phenytoin (Kortüm et al ., ). A third hypothesis could be based on the role of 5‐methyltetrahydrofolate as a non‐specific biomarker of cerebral dysfunction (Pérez‐Dueñas et al ., ).…”

The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption

“…The major challenge is achieving adequate CSF folate and this requires careful monitoring of CSF levels until a satisfactory concentration is reached. Of importance is that normal CSF folate blood levels during infancy and early childhood are much higher than previously appreciated: ~100–150 nM over the first year decreasing to ~50–90 by five years, falling further to >60 nM during puberty (Ormazabal et al, 2011; Perez-Duenas et al, 2011; Verbeek et al, 2008). These levels are difficult to achieve in subjects with HFM even with extraordinarily high doses of parenteral folate (Torres et al, 2015).…”

Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism

“…For instance, because the growing descriptions for a GLUT-1 deficiency include cases with normal or near-normal CSF glucose values, the patients under suspicion of this syndrome were selected based on their clinical phenotype [ 26 , 27 ]. In the analysis of biogenic amines, impaired CSF HVA concentrations are associated with a large amount of neurological conditions, as previously reported [ 28 ], or cerebral folate deficiency syndrome, encompassing a large group of neurological conditions in which partial deficiencies unrelated to the primary defects in folate transport and metabolism are frequently encountered [ 29 ]. Despite the fact that epileptic encephalopathies are a frequent phenotype observed in neurometabolic disorders, IEM are not the most frequent etiology causing this neurological disruption.…”

Epilepsy in KCNH1‐related syndromes

“…Folate depletion could also result from secondary inhibition of sodium currents with mechanisms comparable to the action of a sodium blocker, such as phenytoin (Kortüm et al ., ). A third hypothesis could be based on the role of 5‐methyltetrahydrofolate as a non‐specific biomarker of cerebral dysfunction (Pérez‐Dueñas et al ., ).…”

The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption

“…The major challenge is achieving adequate CSF folate and this requires careful monitoring of CSF levels until a satisfactory concentration is reached. Of importance is that normal CSF folate blood levels during infancy and early childhood are much higher than previously appreciated: ~100–150 nM over the first year decreasing to ~50–90 by five years, falling further to >60 nM during puberty (Ormazabal et al, 2011; Perez-Duenas et al, 2011; Verbeek et al, 2008). These levels are difficult to achieve in subjects with HFM even with extraordinarily high doses of parenteral folate (Torres et al, 2015).…”

Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism

“…For instance, because the growing descriptions for a GLUT-1 deficiency include cases with normal or near-normal CSF glucose values, the patients under suspicion of this syndrome were selected based on their clinical phenotype [ 26 , 27 ]. In the analysis of biogenic amines, impaired CSF HVA concentrations are associated with a large amount of neurological conditions, as previously reported [ 28 ], or cerebral folate deficiency syndrome, encompassing a large group of neurological conditions in which partial deficiencies unrelated to the primary defects in folate transport and metabolism are frequently encountered [ 29 ]. Despite the fact that epileptic encephalopathies are a frequent phenotype observed in neurometabolic disorders, IEM are not the most frequent etiology causing this neurological disruption.…”

Epilepsy in KCNH1‐related syndromes

“…Folate depletion could also result from secondary inhibition of sodium currents with mechanisms comparable to the action of a sodium blocker, such as phenytoin (Kortüm et al ., ). A third hypothesis could be based on the role of 5‐methyltetrahydrofolate as a non‐specific biomarker of cerebral dysfunction (Pérez‐Dueñas et al ., ).…”

The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption

“…The major challenge is achieving adequate CSF folate and this requires careful monitoring of CSF levels until a satisfactory concentration is reached. Of importance is that normal CSF folate blood levels during infancy and early childhood are much higher than previously appreciated: ~100–150 nM over the first year decreasing to ~50–90 by five years, falling further to >60 nM during puberty (Ormazabal et al, 2011; Perez-Duenas et al, 2011; Verbeek et al, 2008). These levels are difficult to achieve in subjects with HFM even with extraordinarily high doses of parenteral folate (Torres et al, 2015).…”