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Clinical Recognition and Aspects of the Cerebral Folate Deficiency Syndromes

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Clinical Recognition and Aspects of the Cerebral Folate Deficiency Syndromes DOI 10.1515/cclm-2012-0543 Clin Chem Lab Med 2012; aop Review Vincent Ramaekers* , Jeffrey M. Sequeira and Edward V. Quadros Clinical recognition and aspects of the cerebral folate deficiency syndromes Abstract: We characterized cerebral folate deficiency Jeffrey M. Sequeira and Edward V. Quadros: Departments of (CFD) as any neuro-psychiatric condition associated with Medicine/Cell Biology, SUNY-Downstate Medical Center, Brooklyn, low spinal fluid (CSF) N 5 -methyltetrahydrofolate (MTHF) NY, USA but normal folate status outside the central nervous system (CNS). The commonest cause underlying CFD syndromes is the presence of serum autoantibodies of the blocking Introduction type directed against folate receptor- α (FR α ) attached to the plasma-side of choroid plexus epithelial cells. Block- Intestinal absorption of dietary folates, composed of folic ing FR antibodies inhibit MTHF transport across the cho- acid (oxidized folate form) and its structurally derived roid plexus. Serum titers of FR antibodies may fluctuate folate compounds, is achieved by the concerted action of significantly over time. Less frequent causes of CFD are the folate receptor- α (FR α ; synonymous to FR-1; FOLR-1) FOLR-1 mutations, mitochondrial disorders and inborn and the proton-coupled folate transporter (PCFT) [ 1 – 4 ]. errors affecting folate metabolism. Maternal FR antibod- Folate uptake by cells and transport across the blood- ies have been associated with neural tube defects while brain and the placental-fetal barriers involves the follow- the presence of FR antibodies in either one or both parents ing different mechanisms composed of specific proteins, increases the risk of an offspring with infantile autism. being FR α -mediated endocytotic processes, the PCFT Recognizable CFD syndromes attributed to FR-antibod- cooperating closely with FR proteins, the reduced folate ies in childhood are infantile-onset CFD presenting 4 – 6 carrier-1 (RBC-1) and the ATP-dependent folate exporter months after birth, infantile autism with neurological [ 5 , 6 ]. FR α protein is a membrane-anchored protein and deficits, and a spastic ataxic syndrome from the age of is characterized as a high-affinity low capacity folate 1 year, while progressive dystonic or schizophrenic syn- transporter which can bind to very low folate concentra- dromes develop during adolescence. FR autoantibodies tions within the nanomolar physiologic range. FRα is are frequently found in autism spectrum disorders, in expressed by specific epithelial cells and is responsible an Aicardi-Gouti è res variant and in Rett syndrome. The in cooperation with PCFT for folate passage across intesti- heterogeneous phenotype of CFD syndromes might be nal, placental-fetal epithelial barriers and across choroid determined by different ages of onset and periods when plexus epithelial barriers to the spinal fluid compartment FR autoantibodies are generated with consequent CNS and from there across ependymal lining cells into neural folate deficiency. Folate deficiency during various critical tissues. The main folate transport to the central nervous stages of fetal and infantile development affects structural system (CNS) occurs across the choroid plexus and is and functional refinement of the brain. Awareness of CFD accomplished by FR α -mediated endocytosis and PCFT syndromes should lead to early detection, diagnosis and action. FR β (synonymous to FRβ ; FR-2 or FOLR-2) is related improved prognosis of these potentially treatable group of to FR α and expressed by both mesenchymal-derived and autoimmune and genetically determined conditions. epithelial cells. FR β expression has been demonstrated also in fetal epithelial cells, however, its functional con- Keywords: central nervous system; choline; folate; folate tribution to folate transport among human and murine receptor autoimmunity; homocysteine. species has not been resolved fully [ 5 – 7 ]. Another impor- tant folate transporter across cell membranes is the low- affinity, high capacity transporter known as the RFC-1, *Corresponding author: Prof. Vincent Ramaekers, Department of Pediatric Neurology and Center of Autism, University Hospital Li è ge, which is expressed in most cells. An ATP-dependent folate Rue de Gaillarmont, 600, 4032 Ch ê n é e, Belgium, exporter is known to regulate intracellular folate concen- Phone: + 32 4 3679405, E-mail: [email protected] trations ( Figure 1 ). 2 Ramaekers et al.: Clinical recognition and aspects of the CFD syndromes Vectorial folate transport by FR endocytosis across choroid plexus Intestinal lumen Blood CSF Neuronal tissues Diet PCFT F FR1 F F F FR1 PCFT F F ATP RFC FR2 RFC F F F consumption RBC Catabolism DHFR Ependymal lining DHF Intestinal barrier Choroid plexus epithelial cells RFC F F Blood-CSF barrier Neuronal cells FR1 antibodies, FOLR-1 gene defects or mitochondrial dysfunction at the basis of CFD Mitochondrial dysfunction F F ATP F F F Endocytosis FOLR1 gene defect Loss of FR1 function due to: -Truncated FR1 protein -Mistargetting to membranes FR1 antibodies Ramaekers et al.: Clinical recognition and aspects of the CFD syndromes 3 stored as polyglutamate folate forms within the cyto- novo purine synthesis, while 5,10-methylene-THF partici- plasm and mitochondria after attachment of multiple pates in the de novo thymidine synthesis. Thus DNA rep- glutamate residues by the ATP-dependent enzyme folyl- lication and formation of RNA transcripts needed for cell polyglutamate synthetase. Brain folate reserves have proliferation and maturation of the developing nervous been estimated to remain adequately replete for a period system depends on an adequate pool of various reduced of about 100 days. FR α is highly expressed in reproduc- folate forms. tive tissues and plays a major role in providing folate to Moreover, epigenetic control of neuronal gene the embryo and fetus. expression and transcription repression of other genes The various reduced folate forms serve as essential is indirectly linked to MTHF as SAM is the substrate for co-factors in many metabolic processes [ 8 ]. After intesti- DNA-methyltransferase-I which enzymatically transfers a nal uptake, folic acid is reduced by the enzyme dihydro- methyl-group to the CpG islands and thereby methylates folate reductase (DHFR) and part of this will be methyl- gene promoter regions in order to initiate the process of ated to MTHF. In the brain, expression of DHFR enzyme is gene transcription repression. extremely low in humans so that the brain depends on the In neurologically handicapped patients, CSF meas- daily transport of MTHF and other reduced folate forms urements have detected low MTHF values while plasma ( Figure 2 ). Among many metabolic functions, MTHF is and red blood cell folate, homocysteine and vitamin B12 needed as substrate for the conversion of homocysteine levels were normal. This group of neurological disorders to methionine by the B12-dependent enzyme methionine can be defined as the Cerebral Folate Deficiency (CFD) synthase. Through this latter enzymatic homocysteine syndromes and represent different clinical phenotypes degradation, MTHF transfers it s methyl-group to methio- [ 10 , 11 ]. The most common cause of CFD identified thus nine which enters into the adenosyl cycle and will be far, is the presence in serum of circulating folate receptor converted to the activated methyl-group donor S-aden- (FR) autoantibodies that cross react with soluble FR found osyl-methionine (SAM), used in over 100 methylation in animal-derived milk (bovine, goat or camel milk), reactions. The resulting product tetrahydrofolate (THF) which has high structural homology with the human FR is recycled again to MTHF after recharging with methyl- antigen [ 12 , 13 ]. Less frequent causes of CFD are mitochon- groups originating from serine-glycine interconversion. drial disorders and abnormalities of the FOLR-1 gene [ 7 , Another folate form 10-formyl-THF is necessary for de 14 ]. This paper reviews the salient clinical features of this Methyl-transfer reactions Dopamine Purine BH4 synthesis serotonin S-adenosyl synthesis SAM CO2 Adenosyl cycle Methionine SAH DHFR DHF MS 10-formyl-THF THF Homocysteine B12 5-formyl-THF Ser B6 Thymidine 5-methyl-THF Gly synthesis MTHFR B2 5,10-methenyl-THF Ependymal linings 5,10-methylene-THF Blood-CSF barriers FR endocytosis Plasma 5-methyl-THF Figure 2 Pathways of folate transport and metabolism. B2, riboflavine; B6, pyridoxine; B12, cobalamine and methyl-cobalamin; BH4, tetrahydrobiopterine; CSF, cerebrospinal fluid; DHF, dihydro- folate; DHFR, dihydrofolate reductase; FR, folate receptor; Gly, glycine; MS, methionine synthase; MTHFR, 5,10-methylene-tetrahydrofolate reductase; Ser, serine; THF, tetrahydrofolate. 4 Ramaekers et al.: Clinical recognition and aspects of the CFD syndromes new emerging group of disorders, its diagnosis and dif- antibodies can be measured by specific assays described ferential diagnosis, diagnostic guidelines and therapeutic and exert their pathological effects either by functional strategies as well as new findings about these FR autoanti- blocking of folate transport or by disrupting the FR by an bodies. We also discuss the possible reasons for the emer- antigen-antibody mediated inflammatory response. We gence of different clinical phenotypes at different ages. have identified both IgG and IgM autoantibodies in these conditions [ 15 – 17 ]. History and epidemiology Assay for blocking autoantibodies to FRα The first patients with the infantile-onset CFD associated with low CSF folate
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