Sarah Mafi et al.

“ Indeed, FRβ is highly expressed during the fetal and postnatal periods and it has an important homology with FRα (70% of AA identity) [25] . Supplementation with folinic acid has been reported to be efficient with a rapid reverse of neurological symptoms and an improvement of brain function. This molecule is known to pass across the non-specific pathways of PCFT and RFC directly into CSF where it is immediately available for folate metabolism [10,25,29,30] . It is established that the earlier treatment is administered the better the response is [6] . ”

“ Thus, we hypothesize that the Cys66Tyr mutation mostly affects protein dynamics which in turn may modulate the function of FRα. Thus, this altered protein most likely leads to an interruption of folate transport into the brain and a depletion of 5-MTHF in the cerebral compartment [27,28] .
According to Steinfeld R. et al. [25] , a 5-MTHF deficiency in the brain leads to disorders of myelin synthesis, which could be explained by the brain specific biochemical pathway connecting folate to choline metabolism based on methyl group transfer. ”

“ Red arrows show diffuse white matter abnormalities linked to an hypomyelination. At five years of age, an increase in seizure frequency was observed. Bilateral brain calcifications of globus pallidus and subcortical structures in parietal and occipital lobes were revealed by a cerebral CT-scan (Figure 3) . Slow activity and a spike-and-wave pattern associated with an epileptiform activity, in particular in hypomyelination areas, were observed on an electroencephalogram. ”

“ It is unusually rich in disulfide-bonds with eight of them in this protein. Protein disulfide-bonds are formed by two oxidized cysteine residues which significantly stabilize the protein structure. Normal and stable FRα structure is essential for maintaining an effective binding site and allowing therefore a normal 5-MTHF transport capacity. In our case the mutation of Cys 66 to Tyr lead to the absence of disulfide bond which, in turn, is likely to significantly modify the conformation of FRα. ”

“ A three-year-old girl was admitted to pediatric emergency room for a first febrile seizure episode. She is the only child of a non-consanguineous couple. She was eutrophic full-term born with a normal vitality index. ”

“ S-adenosyl homocysteine; SAM: S-adenosyl-methionine; Ser: Serine; SHMT: serine-hydroxy methyl transferase; SM: sphingomyelin. In the central nervous system, different folate transport systems are found, including the reduced folate carrier (RFC) , the proton coupled folate transporter (PCFT) and the receptor of folate alpha (FRα) . FRα represents the higher affinity folate transport system compared to RFC, and PCFT. 5-MTHF uptake into the brain is mainly mediated by FRα and PCFT in the basolateral membrane of choroid plexus epithelial cells and by FRα and RFC at the apical brush border [6] . ”

“ 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 ”

“ 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: cerebral folate deficiency; FOLR1 variant; neurodegenerative disorder; epilepsy; FRα protein crystallographic structure; pediatric
1. Introduction Folates or vitamin B9 (B9) are essential to many biological processes such as DNA synthesis and repair, regulation of gene expression, amino acids (AA) metabolism, myelin formation and neurotransmitters synthesis [1] . ”

“ 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. Table 2 Table 3 3. Discussion We describe a new pathogenic variant (c.197 G > A, p.Cys66Tyr (NM_016724.2) ) in FOLR1, associated with a severe form of CFD. As of today, reported variations in FOLR1 have been splice-site, stop, missense mutations (most common) or duplications. ”

“ These results suggested that folinic acid is efficient with more than a 50% reduction in seizure rates [33] . Intravenous injections of calcium folinate were finally given at a 500 mg/week dose to optimize therapy. Cognitive functions, language skills and walking ability were improved underlining the role of an early diagnosis (Table 4) .
Table 4 4. Conclusions This case highlights that CFD due to FOLR1 gene variation c.197 G > A inducing p.Cys66Tyr substitution, is a rare but treatable neurodegenerative disorder of early childhood. ”