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.

Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical and radiological recovery with oral folinic acid therapy and review of the literature

“…Delayed myelination with or without cerebellar atrophy was seen in four patients [ 2 , 13 ]. Apart from the two patients described in this study, infratentorial hypomyelination was described only in one patient [ 23 ], while thinning of the corpus callosum was reported in one other [ 2 ]. MRS values before treatment showed low white matter choline and/or inositol in all patients except for five, which were normal [ 2 , 15 , 19 ].…”

“…Cerebellar atrophy was absent in seven patients [ 12 , 13 , 15 , 16 , 22 ]. Four patients also had basal ganglia calcifications [ 9 , 16 , 21 , 23 ], one patient had accompanied bilateral temporal cortical laminar necrosis and ulegyria [ 10 ], while one other patient had white matter encephalomalacia [ 17 ]. Two patients had no myelin abnormalities but cerebellar atrophy with or without cerebral calcifications [ 2 , 9 ], and one had cerebral cortical atrophy only [ 22 ].…”

Folate regulation of planar cell polarity pathway and F‐actin through folate receptor alpha

“…For example, the affinity of FOLR1 for FA is 14‐fold higher than for 5mTHF 33 . It has also been shown that FOLR1 represents the highest‐affinity folate transport system compared to RFC and PCFT, 34 and also has a higher affinity to FA at neutral pH compared with other folate transporters 35 . Based on this evidence, we speculated that FA could be more readily transported into cells compared with 5mTHF at the same supplemented concentrations due to its higher affinity to FOLR1.…”

Next-Generation Sequencing Technologies and Neurogenetic Diseases

“…FOLR1 mutations are a rare cause of CFD, and most patients with these mutations share similar clinical phenotypes as those with other common causes, such as frequent epileptic seizures [ 90 , 91 , 92 ]. Mafi et al [ 93 ] attributed the observed myoclonic seizures to the novel variant (c.197 G>A) in FOLR1 identified by WES ( Table 1 ).…”