Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism

Department of Pediatrics and Pediatric Neurology, Georg August University Göttingen, Göttingen, Germany.
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2009; 85(3):354-63. DOI: 10.1016/j.ajhg.2009.08.005
Source: PubMed


Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FRalpha or FRbeta could rescue folate binding. Furthermore, CSF folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the folate metabolic pathways involved in postnatal myelination and brain development.

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    • "Consequently, negligible MeTHF enters brain directly from blood [62]. Consistent with this model is that human KO’s of either FRα or PCFT manifest central folate deficiency (CFD) states, characterized by very low CSF folate concentrations and severe neurological disease or death [63-65]. Early treatment with mega-doses of reduced folates ameliorates CFD, however, and when started early enough, prevents CNS damage [64]. "
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    ABSTRACT: The purpose of this review is to discuss the implications of the 2009 discovery of the sixth deoxyribonucleoside (dN) [5-hydroxymethyldeoxycytidine (hmdC)] in DNA which is the most abundant in neurons. The concurrent discovery of the three ten-eleven translocation enzymes (TET) which not only synthesize but also oxidize hmdC in DNA, prior to glycosylase removal and base excision repair, helps explain many heretofore unexplained phenomena in brain including: 1) the high concentration of ascorbic acid (AA) in neurons since AA is a cofactor for the TET enzymes, 2) the requirement for reduced folates and the dN synthetic enzymes in brain, 3) continued DNA synthesis in non-dividing neurons to repair the dynamic formation/removal of hmdC, and 4) the heretofore unexplained mechanism to remove 5-methyldeoxycytidine, the fifth nucleoside, from DNA. In these processes, we also describe the important role of choroid plexus and CSF in supporting vitamin homeostasis in brain: especially for AA and folates, for hmdC synthesis and removal, and methylated deoxycytidine (mdC) removal from DNA in brain. The nexus linking AA and folates to methylation, hydroxymethylation, and demethylation of DNA is pivotal to understanding not only brain development but also the subsequent function.
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    • "There is a specific inability to transport 5-MTHF across the blood–brain barrier, resulting in a host of neurological sequelae including seizures, delayed motor and cognitive development, autistic features, poor head growth, cerebellar ataxia, visual and hearing impairment, dyskinesia and spasticity (Pé rez-Dueñ as et al., 2011). An antibody-mediated process, with antibodies generated to FR, was thought to be responsible, but more recently mutations in FOLR1, the gene encoding FR, have been described in a number of cases of cerebral folate deficiency (Cario et al., 2009; Steinfeld et al., 2009). Other conditions associated with cerebral folate deficiency include dihydropteridine reductase deficiency; Rett's syndrome; Aicardi-Goutiere's syndrome ; hypomyelination with atrophy of the basal ganglia; Kearns-Sayre syndrome and several other mitochondrial respiratory chain diseases (Pé rez-Dueñ as et al., 2011). "

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    • "Cloning of FR complementary DNA has been described previously (Steinfeld et al., 2009). Mutations were introduced into human FR cloned into the expression vector pcDNA3.1( "
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    ABSTRACT: Cerebral folate transport deficiency is an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 gene coding for folate receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the folate receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of folate receptor alpha for all detected folate receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of folate receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral folate transport deficiency.
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