Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease

Abstract

Cerebral folate deficiency (CFD) is a neurological disorder characterized by low levels of 5-methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid (CSF). The prevalence of this autosomal recessive disorder is estimated to be <1/1,000,000. Fifteen different pathogenic variants in the folate receptor 1 gene (FOLR1) encoding the receptor of folate α (FRα) have already been described. We present a new pathogenic variation in the FOLR1 in a childhood-stage patient. We aim to establish the core structure of the FRα protein mandatory for its activity. A three-year-old child was admitted at hospital for a first febrile convulsions episode. Recurrent seizures without fever also occurred a few months later, associated with motor and cognitive impairment. Various antiepileptic drugs failed to control seizures. Magnetic resonance imaging (MRI) showed central hypomyelination and biological analysis revealed markedly low levels of 5-MTHF in CSF. Next generation sequencing (NGS) confirmed a CFD with a FOLR1 homozygous variation (c.197 G > A, p.Cys66Tyr). This variation induces an altered folate receptor α protein and underlines the role of a disulfide bond: Cys66-Cys109, essential to transport 5-MTHF into the central nervous system. Fortunately, this severe form of CFD had remarkably responded to high doses of oral folinic acid combined with intravenous administrations.

Keywords: FOLR1 variant; FRα protein crystallographic structure; cerebral folate deficiency; epilepsy; neurodegenerative disorder; pediatric.

Figure 1

Folic acid metabolism and 5-MTHF transport across the choroid plexus epithelium in the brain. Red arrows and red crosses indicate the alternative pathway induced by FRα deficiency. Blue arrows indicate effects of folinic acid treatment. KEYS: 5-MTHF: 5-methylenetetrahydrofolate; B6: Vitamin B6; B12: Vitamin B12; CSF: cerebrospinal fluid; DHFR: dihydrofolate reductase; FRα: receptor of folate alpha; Gly: glycine; GSH: glutathione reduced states; GSSG: Glutathione oxidized states; MS: methionine synthase; MTHFD: methylenetetrahydrofolate dehydrogenase; MTHFR: methylenetetrahydrofolate reductase; MTHFS: methylenetetrahydrofolate synthetase; PC: phosphatidylcholine; PCFT: proton coupled folate transporter; PI: phosphatidylinositol; RFC: reduced folate carrier; SAH: S-adenosyl homocysteine; SAM: S-adenosyl-methionine; Ser: Serine; SHMT: serine-hydroxy methyl transferase; SM: sphingomyelin.

Figure 2

Brain MRI performed at 4 and 12 years old with FLAIR (A–C,G–I) and T2 (D–F,J–L) sequences. Red arrows show diffuse white matter abnormalities linked to an hypomyelination.

Figure 3

Cerebral CT-scan at 4 years old. Red arrows show brain calcifications (A) and diffuse white matter abnormalities (B).

Figure 4

Crystallographic structure of FRα protein, from the Protein Data Band (4LRH). The folate is in green, the folate binding site is colored in orange. The Cys66Tyr substitution position induced by the pathogenic variant described in our case report is represented in red while the disulfide bond between Cys66 and Cys109 is in dark blue.