Remarkable Clinical Improvement after Folinic Acid Supplementation in Cerebral Folate Transport Deficiency and Epileptic Encephalopathy: A Case Report

06/08/2026

AI Summary

FOLR1 biallelic pathogenic variants cause cerebral folate transport deficiency with low CSF 5-MTHF despite normal systemic folate.
Children present with developmental regression, drug-resistant epilepsy, movement disorder and white matter changes on MRI.
Folinic acid can produce remarkable neurological recovery, including seizure resolution and improved ambulation, speech and social interaction, even after diagnostic delay.

Mol Syndromol. 2026 Jun 18. doi: 10.1159/000553193. Online ahead of print.

ABSTRACT

INTRODUCTION: Folate plays a critical role in central nervous system development, particularly in myelin synthesis and neurotransmitter metabolism. Cerebral folate transport deficiency (CFTD), most often caused by biallelic pathogenic variants in the FOLR1 gene, results in markedly reduced cerebrospinal fluid (CSF) folate levels despite normal systemic folate status. Affected individuals typically present with developmental regression, seizures, and movement disorders. Early diagnosis and folinic acid supplementation have been shown to reverse neurological symptoms, emphasizing the importance of prompt recognition.

CASE PRESENTATION: We describe a 6-year-old girl born to consanguineous parents who initially presented with autism spectrum disorder and drug-resistant epilepsy. Her seizures included myoclonic-atonic, generalized myoclonic, and focal seizures, with subsequent gait instability and ataxia. Neuroimaging revealed diffuse cerebral atrophy and white matter signal abnormalities. Subsequent genetic testing identified a homozygous FOLR1 missense likely pathogenic variant (c.544T>A; p.Phe182Ile). The diagnosis was further confirmed by CSF analysis showing severe folate deficiency (5-MTHF: 4 nmol/L). Following initiation of oral folinic acid (4 mg/kg/day), seizures resolved completely, and substantial improvements were observed in ambulation, speech, and social interaction.

CONCLUSION: This case illustrates that folinic acid supplementation can lead to remarkable neurological recovery, even with substantial diagnostic delay. FOLR1-related CFTD should be considered in children with refractory epilepsy and developmental regression.

PMID:42553823 | PMC:PMC13436976 | DOI:10.1159/000553193

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