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Think of the Cerebral Folate Deficiency, a Treatable Disease

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Think of the Cerebral Folate Deficiency, a Treatable Disease brain sciences Case Report Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease Sarah Mafi 1,Cécile Laroche-Raynaud 2,3, Pauline Chazelas 1,4, Anne-Sophie Lia 1,4,5, Paco Derouault 5, Franck Sturtz 1,4 , Yasser Baaj 1, Rachel Froget 2,6, Marlène Rio 7, Jean-François Benoist 8, François Poumeaud 4 , Frédéric Favreau 1,4 and Pierre-Antoine Faye 1,4,* 1 CHU de Limoges, Service de Biochimie et Génétique Moléculaire, F-87000 Limoges, France; sarah.mafi@chu-limoges.fr (S.M.); [email protected] (P.C.); [email protected] (A.-S.L.); [email protected] (F.S.); [email protected] (Y.B.); [email protected] (F.F.) 2 CHU de Limoges, Service de Pédiatrie, F-87000 Limoges, France; [email protected] (C.L.-R.); [email protected] (R.F.) 3 CHU de Limoges, Centre de Compétence des Maladies Héréditaires du Métabolisme, F-87000 Limoges, France 4 Faculté de Médecine, EA6309 Maintenance Myélinique et Neuropathies Périphériques, Université de Limoges, F-87000 Limoges, France; [email protected] 5 CHU Limoges, UF de Bioinformatique, F-87000 Limoges, France; [email protected] 6 CHU Limoges, INSERM CIC 1435, F-87000 Limoges, France 7 CHU Necker, Enfants Malades, Paris, APHP, Service de Génétique, F-75743 Paris, France; [email protected] 8 CHU Necker, Enfants Malades, Paris, APHP, Service de Biochimie Métabolomique, F-75743 Paris, France; [email protected] * Correspondence: [email protected] Received: 25 September 2020; Accepted: 19 October 2020; Published: 22 October 2020 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: 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 Brain Sci. 2020, 10, 762; doi:10.3390/brainsci10110762 www.mdpi.com/journal/brainsci Brain Sci. 2020, 10, x FOR PEER REVIEW 2 of 10 Brain1. Sci.Introduction2020, 10, 762 2 of 10 Folates or vitamin B9 (B9) are essential to many biological processes such as DNA synthesis and neurotransmittersrepair, regulation synthesis of gene [1 ].expression, They are alsoamino well acids known (AA) to be metabolism, involved in themyelin neural formation tube formation and duringneurotransmitters embryogenesis synthesis [2]. [1]. They are also well known to be involved in the neural tube formation duringAlthough embryogenesis the fact that [2]. folates naturally exist in a variety of foods [3], deficiencies in humans can occur. TheyAlthough are absorbed the fact that in the folates intestine naturally and then exist metabolized in a variety of in foods the liver [3], into deficiencies 5-methyltetrahydrofolate in humans can (5-MTHF).occur. They Folate are is a familyabsorbed of B vitaminin the foundintestine in humanand then food asmetabolized folinic acid (5-formyl-THF)in the liver into converted 5‐ methyltetrahydrofolate (5‐MTHF). Folate is a family of B vitamin found in human food as folinic acid into 5-MTHF or in synthetic folic acid supplementation. Folic acid is reduced to 7,8-dihydrofolate (5‐formyl‐THF) converted into 5‐MTHF or in synthetic folic acid supplementation. Folic acid is (DHF) and then into 5,6,7,8-tetrahydrofolate (THF) by dihydrofolate reductase (DHFR) [4]. A carbon reduced to 7,8‐dihydrofolate (DHF) and then into 5,6,7,8‐tetrahydrofolate (THF) by dihydrofolate unit is transferred from serine to THF by serine-hydroxy methyl transferase (SHMT). This reaction reductase (DHFR) [4]. A carbon unit is transferred from serine to THF by serine‐hydroxy methyl produces glycine and 5,10-methylene-tetrahydrofolate, which is involved in nucleic acid synthesis transferase (SHMT). This reaction produces glycine and 5,10‐methylene‐tetrahydrofolate, which is andinvolved repair. in The nucleic latter acid product synthesis is then and converted repair. The to 5-MTHF latter product by methylenetetrahydrofolate is then converted to 5‐MTHF reductase by (MTHFR).methylenetetrahydrofolate Folinic acid can either reductase be immediately (MTHFR). Folinic available acid forcan metaboliceither be immediately processes or available be converted for intometabolic 5,10-methylene-THF processes or consecutivebe converted activities into 5,10 of‐methylene MTHF synthetase‐THF consecutive and MTHF-dehydrogenase activities of MTHF [ 5]. Duringsynthetase the conversion and MTHF‐ ofdehydrogenase 5-MTHF to THF, [5]. During a methyl the conversion group is released. of 5‐MTHF This to THF, group a methyl is used group for the homocysteineis released. This remethylation group is used leading for the to homocysteine methionine which remethylation is the precursor leading of to S-adenosyl-methionine methionine which is (SAM),the precursor the universal of S‐ one-carbonadenosyl‐methionine donor involved (SAM), in the the methylationuniversal one of‐carbon DNA, RNA,donor lipids, involved proteins in the and neurotransmittersmethylation of DNA, [6] (Figure RNA, 1lipids,). proteins and neurotransmitters [6] (Figure 1). FigureFigure 1. 1.Folic Folic acid acid metabolism metabolism and and 5-MTHF 5‐MTHF transport transport across across the the choroid choroid plexus plexus epithelium epithelium in thein the brain. Redbrain. arrows Red and arrows red and crosses red indicatecrosses indicate the alternative the alternative pathway pathway induced induced by FR byα deficiency. FRα deficiency. Blue Blue arrows indicatearrows e ffindicateects of foliniceffects acidof folinic treatment. acid treatment. KEYS: 5-MTHF: KEYS: 5-methylenetetrahydrofolate;5‐MTHF: 5‐methylenetetrahydrofolate; B6: Vitamin B6: B6; B12:Vitamin Vitamin B6; B12; B12: CSF: Vitamin cerebrospinal B12; CSF: cerebrospinal fluid; DHFR: dihydrofolatefluid; DHFR: dihydrofolate reductase; FR reductase;α: receptor FR ofα folate: receptor alpha; Gly:of folate glycine; alpha; GSH: Gly: glutathione glycine; GSH: reduced glutathione states; reduced GSSG: states; Glutathione GSSG: Glutathione oxidized states; oxidized MS: states; methionine MS: synthase;methionine MTHFD: synthase; methylenetetrahydrofolate MTHFD: methylenetetrahydrofolate dehydrogenase; MTHFR: dehydrogenase; methylenetetrahydrofolate MTHFR: reductase;methylenetetrahydrofolate MTHFS: methylenetetrahydrofolate reductase; MTHFS: synthetase; methylenetetrahydrofolate PC: phosphatidylcholine; synthetase; PCFT: protonPC: coupledphosphatidylcholine; folate transporter; PCFT: PI: proton phosphatidylinositol; coupled folate RFC:transporter; reduced PI: folate phosphatidylinositol; carrier; SAH: S-adenosyl RFC: homocysteine;reduced folate SAM: carrier; S-adenosyl-methionine; SAH: S‐adenosyl homocysteine; Ser: Serine; SAM: SHMT: S‐adenosyl serine-hydroxy‐methionine; methyl Ser: transferase; Serine; SM:SHMT: sphingomyelin. serine‐hydroxy methyl transferase; SM: sphingomyelin. InIn the the central central nervous nervous system, system, diff erentdifferent folate folate transport transport systems systems are found, are found, including including the reduced the folatereduced carrier folate (RFC), carrier the proton(RFC), the coupled proton folate coupled transporter folate transporter (PCFT) and (PCFT) the receptor and the of receptor folate alpha of folate (FR α). FRalphaα represents (FRα). FR theα higherrepresents affinity the folatehigher transport affinity folate system transport compared system to RFC, compared and PCFT. to RFC, 5-MTHF and PCFT. uptake into5‐MTHF the brain uptake is mainly into the mediated brain is mainly by FRα mediatedand PCFT by inFR theα and basolateral PCFT in the membrane basolateral of membrane choroid plexus of epithelialchoroid cells plexus and epithelial by FRα andcells RFC and atby the FRα apicaland RFC brush at borderthe apical [6]. brush The mechanism border [6]. The of these mechanism transporters of these transporters involved in 5‐MTHF flux across the blood‐brain‐barrier is not yet fully understood, involved in 5-MTHF flux across the blood-brain-barrier is not yet fully understood, but some but some mechanisms have been proposed for
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