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Neurological improvement following intravenous high-dose folinic acid for cerebral folate transporter deficiency caused by FOLR-1 mutation


Delmelle, Françoise; Thöny, Beat; Clapuyt, Philippe; Blau, Nenad; Nassogne, Marie-Cécile (2016). Neurological improvement following intravenous high-dose folinic acid for cerebral folate transporter deficiency caused by FOLR-1 mutation. European Journal of Paediatric Neurology, 20(5):709-713.

Abstract

BACKGROUND: Cerebral folate transporter deficiency caused by FOLR-1 mutations has been described in 2009. This condition is characterized by a 5MTHF level <5 nmol/l in the CSF, along with regression of acquisition in the second year of life, ataxia, and refractory myoclonic epilepsy. Oral or intravenous folinic acid (5-formyltetrahydrofolate) treatment has been shown to improve clinical status.
CASE PRESENTATION: We present the cases of two sisters with cerebral folate transport deficiency caused by mutation in the folate receptor 1 (FOLR1) gene (MIM *136430). Following recommendations, we administered oral folinic acid at 5 mg/kg/day, resulting in some initial clinical improvement, yet severe epilepsy persisted. During treatment, cerebrospinal fluid (CSF) analysis revealed normal 5-methyltetrahydrofolate (5MTHF) levels (60.1 nmol/l; normal range: 53-182 nmol/l). Epilepsy proved difficult to control and the younger patient exhibited neurological regression. We then administered high-dose folinic acid intravenously over 3 days (6 mg/kg/day for 24 h, then 12 mg/kg/day for 48 h), which significantly improved clinical status and epilepsy. CSF analysis revealed high 5MTHF levels following intravenous infusion (180 nmol/l). Treatment continued with monthly intravenous administrations of 20-25 mg/kg folinic acid. At 2 years post-treatment, clinical improvement was confirmed.
CONCLUSIONS: This report illustrates that cerebral folate transporter deficiency caused by FOLR-1 mutations is a treatable condition and can potentially be cured by folinic acid treatment. As already reported, early effective treatment is known to improve outcomes in affected children. In our study, intravenous high-dose folinic acid infusions appeared to optimize clinical response.

Abstract

BACKGROUND: Cerebral folate transporter deficiency caused by FOLR-1 mutations has been described in 2009. This condition is characterized by a 5MTHF level <5 nmol/l in the CSF, along with regression of acquisition in the second year of life, ataxia, and refractory myoclonic epilepsy. Oral or intravenous folinic acid (5-formyltetrahydrofolate) treatment has been shown to improve clinical status.
CASE PRESENTATION: We present the cases of two sisters with cerebral folate transport deficiency caused by mutation in the folate receptor 1 (FOLR1) gene (MIM *136430). Following recommendations, we administered oral folinic acid at 5 mg/kg/day, resulting in some initial clinical improvement, yet severe epilepsy persisted. During treatment, cerebrospinal fluid (CSF) analysis revealed normal 5-methyltetrahydrofolate (5MTHF) levels (60.1 nmol/l; normal range: 53-182 nmol/l). Epilepsy proved difficult to control and the younger patient exhibited neurological regression. We then administered high-dose folinic acid intravenously over 3 days (6 mg/kg/day for 24 h, then 12 mg/kg/day for 48 h), which significantly improved clinical status and epilepsy. CSF analysis revealed high 5MTHF levels following intravenous infusion (180 nmol/l). Treatment continued with monthly intravenous administrations of 20-25 mg/kg folinic acid. At 2 years post-treatment, clinical improvement was confirmed.
CONCLUSIONS: This report illustrates that cerebral folate transporter deficiency caused by FOLR-1 mutations is a treatable condition and can potentially be cured by folinic acid treatment. As already reported, early effective treatment is known to improve outcomes in affected children. In our study, intravenous high-dose folinic acid infusions appeared to optimize clinical response.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:September 2016
Deposited On:26 Jan 2017 16:28
Last Modified:26 Jan 2017 16:28
Publisher:Elsevier
ISSN:1090-3798
Publisher DOI:https://doi.org/10.1016/j.ejpn.2016.05.021
PubMed ID:27328863

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