RARE DISEASE
Neurodegenerative syndrome due to cerebral folate transport deficiency
Neurodegenerative syndrome due to cerebral folate transport deficiency
Neurodegenerative syndrome due to cerebral folate transport deficiency
Synonyms: Cerebral folate deficiency, Cerebral folate transport deficiency, Folate receptor alpha deficiency
Synonyms: Cerebral folate deficiency, Cerebral folate transport deficiency, Folate receptor alpha deficiency
Synonyms: Cerebral folate deficiency, Cerebral folate transport deficiency, Folate receptor alpha deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Neurodegenerative syndrome due to cerebral folate transport deficiency is a rare autosomal recessive disorder caused by FOLR1 gene mutations, impairing folate transport across the blood-brain barrier. This results in cerebral folate deficiency despite normal serum folate levels. Affected children exhibit developmental regression, seizures, ataxia, and leukodystrophy from age 2. Early diagnosis and folinic acid supplementation (3–5 mg/kg/day) can stabilize or reverse symptoms, though delayed treatment leads to progressive neurological decline [1][2][5][19].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
107 drug discovery papers about Neurodegenerative syndrome due to cerebral folate transport deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
107 drug discovery papers about Neurodegenerative syndrome due to cerebral folate transport deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-18 | Remarkable Clinical Improvement After Folinic Acid Supplementation in Cerebral Folate Transport Deficiency and Epileptic Encephalopathy: A Case Report
Introduction: Folate plays a critical role in central nervous system development, particularly in myelin synthesis and neurotransmitter metabolism. Cerebral folate transport deficiency (CFTD), most often caused by biallelic pathogenic variants in the FOLR1 gene, results in markedly reduced cerebrospinal fluid (CSF) folate levels despite normal systemic folate status. Affected individuals typically present with developmental regression, seizures, and movement disorders. Early diagnosis and folinic acid supplementation have been shown to reverse neurological symptoms, emphasizing the importance of prompt recognition. Case Presentation: We describe a 6-year-old girl born to consanguineous parents who initially presented with autism spectrum disorder and drug-resistant epilepsy. Her seizures included myoclonic–atonic, generalized myoclonic, and focal seizures, with subsequent gait instability and ataxia. Neuroimaging revealed diffuse cerebral atrophy and white matter signal abnormalities. Subsequent genetic testing identified a homozygous FOLR1 missense likely pathogenic variant (c.544T>A; p.Phe182Ile). The diagnosis was further confirmed by CSF analysis showing severe folate deficiency (5-MTHF: 4 nmol/L). Following initiation of oral folinic acid (4 mg/kg/day), seizures resolved completely, and substantial improvements were observed in ambulation, speech, and social interaction. Conclusion: This case illustrates that folinic acid supplementation can lead to remarkable neurological recovery, even with substantial diagnostic delay. FOLR1-related CFTD should be considered in children with refractory epilepsy and developmental regression
2026-06-09 | Use of Leucovorin After the FDA Announcement of Its Use for Autism Spectrum Disorders.
Leucovorin, or folinic acid (vitamin B9), is approved by the Food and Drug Administration (FDA) to reduce adverse effects from antifolate cancer treatments including methotrexate. In September 2025, the FDA announced that it would expand the label of leucovorin to include treating an extremely rare neurologic condition, cerebral folate deficiency, which shares some symptoms with autism spectrum disorder (ASD).1 The FDA's announcement was accompanied by a widely-publicized White House press conference in which the use of leucovorin for ASD was touted and was preceded by national media reports of the potential benefits of leucovorin for treating ASD in February 2025.2 We measured changes in leucovorin prescriptions in the US during this period of heightened political attention and media coverage.
2026-04-10 | Folic acid modulates the Notch1/NF-κB pathway in a rat model of lipopolysaccharide-activated hippocampal microglia
Introduction Lipopolysaccharide (LPS) induces neuronal injury by stimulating microglia, which release pro-inflammatory markers and neurotoxic factors. Folate deficiency induces microglial activation and modulates nuclear factor-κB (NF-κB) p65 and neurogenic locus Notch homolog protein 1 (Notch1) expression in the hippocampus. This study investigated the neuroprotective effect of folic acid against LPS-induced neurotoxicity in rats, focusing on its modulation of microglial activation and the Notch1, NF-κB, and p65 signaling pathways. Methods A total of 24 Sprague–Dawley male rats were assigned to four groups: control, folic acid, LPS, and folic acid + LPS. After sacrifice, the left cerebral hemisphere was subjected to histopathological assessment using hematoxylin and eosin (H&E) staining and immunohistochemical assessment using anti-GFAP, anti-Iba1, anti-cyclooxygenase-2 (COX-2), anti-tumor necrosis factor- α (TNF-α), and anti-NF-κB antibodies. The hippocampus was extracted from the right hemisphere and used to assess the gene expression of Notch1, TNF-α, interleukin-6 (IL-6), and COX-2 markers using real-time reverse transcription PCR. Results Folic acid ameliorated LPS-induced neuronal damage in the hippocampus, suppressed microglial activation (GFAP and Iba-1), downregulated Notch1 and NF-κB p65, and improved neuroinflammatory responses (TNF-α, IL-6, and COX-2), regardless of the region. Conclusion Folic acid exerted an equivalent neuroprotective effect in both the CA1 and CA3 regions by suppressing microglial activation and modulating the Notch1/NF-κB signaling pathway, thereby reducing neuroinflammation. These findings suggest that folic acid may serve as a potential adjuvant neuroprotective agent against inflammation-mediated neuronal injury.
2026-04-08 | FDA reverses course, won't approve leucovorin for autism
The Trump administration has changed direction from its prior intent to approve an indication for the folic acid derivative leucovorin that had raised serious concern in the research and legal communities (see April 2026 issue of the Update). The Food and Drug Administration (FDA) announced in March that it will not approve leucovorin for the treatment of some patients with autism. The FDA had announced at a September 2025 press conference that it intended to approve leucovorin, marketed as Wellcovorin, in autism treatment despite no evidence of benefit from any randomized controlled trial. Critics of the announcement pointed out that the FDA appeared to be basing its decision-making solely on evidence from case reports and mechanistic data — a much lower standard than the randomized trial evidence customarily required for drug approvals. Now the FDA says its scientific review has determined that there is not enough evidence to support the use of leucovorin to treat patients with autism. The agency is approving a new indication for the drug in treating cerebral folate deficiency in patients with a rare variant in the folate receptor 1 gene. In announcing this new indication, the FDA stated that the approval was based on a systematic review of published case reports and mechanistic data, with no data from clinical trials cited.
2026-03-05 | P364: Variable presentation of FOLR1 related cerebral folate transport deficiency In two sisters
of malignancy, particularly myeloproliferative disorders.While most cases harbor germline heterozygous SETBP1 variants, mosaic presentations are less common and may result in variable expressivity.We report a male infant with a pathogenic SETBP1 mosaic variant detected by exome sequencing, presenting with a classic SGS phenotype and multiple congenital anomalies, including cardiac, renal, skeletal, and neurologic involvement.Case Presentation: A 5-month-old male, born at 38.5 weeks via cesarean section to non-consanguineous parents, was referred for evaluation of a possible genetic syndrome.Neonatal course was initially uneventful, but by day 9 he developed respiratory distress and required hospitalization for sepsis and conjunctivitis.At 4 months he was diagnosed with severe coarctation of the aorta with interruption of the descending aorta, requiring surgical reconstruction.Developmentally, he exhibited global delay, with absence of head control, rolling, sitting, crawling, or speech.Feeding and sleep were reported as normal.His medical history includes recurrent seizures, bilateral decreased vision, hip dysplasia, bilateral cryptorchidism, a horseshoe kidney with renal ectopia, coxa valga, metatarsus varus, and multiple congenital malformations.He receives physical therapy but shows no acquisition of motor milestones.Diagnostic Workup: Imaging revealed severe aortic coarctation with hypoplastic arch, corrected surgically, while brain CT/angiotomography was normal.Renal studies confirmed a horseshoe kidney and left crossed ectopia.Scrotal Doppler identified bilateral cryptorchidism.Audiologic testing showed bilaterally inactive otoacoustic emissions, suggesting cochlear dysfunction.EEG was normal.Laboratory evaluation revealed anemia but was otherwise unremarkable.Clinical exome sequencing identified a pathogenic SETBP1 variant in somatic mosaic state, consistent with Schinzel-Giedion syndrome.A concurrent heterozygous ABL1 variant (somatic) was detected, associated with congenital heart defects and increased risk for myeloid malignancy.Buccal swab testing for SETBP1 was negative, confirming mosaicism restricted to somatic tissues.Maternal testing for ABL1 was negative, indicating a de novo somatic event.
proteins
2022-11-23 | Novel localization of folate transport systems in the murine central nervous system
Folates are a family of B9 vitamins that serve as one-carbon donors critical to biosynthetic processes required for the development and function of the central nervous system (CNS) in mammals. Folate transport is mediated by three highly specific systems: (1) folate receptor alpha (FRα; FOLR1/Folr1), (2) the reduced folate-carrier (RFC; SLC19A1/Slc19a1) and (3) the proton-coupled folate transporter (PCFT; SLC46A1/Slc46a1). Folate transport into and out of the CNS occurs at the blood-cerebrospinal fluid barrier (BCSFB), mediated by FRα and PCFT. Impairment of folate transport at the BCSFB results in cerebral folate deficiency in infants characterized by severe neurological deficiencies and seizures. In contrast to the BCSFB, CNS folate transport at other brain barriers and brain parenchymal cells has not been extensively investigated. The aim of this study is to characterize folate transport systems in the murine CNS at several known barriers encompassing the BCSFB, arachnoid barrier (AB), blood-brain barrier (BBB) and parenchymal cells (astrocytes, microglia, neurons).Applying immunohistochemistry, localization of folate transport systems (RFC, PCFT, FRα) was examined at CNS barriers and parenchymal sites in wildtype (C57BL6/N) mice. Subcellular localization of the folate transport systems was further assessed in an in vitro model of the mouse AB. Gene and protein expression was analyzed in several in vitro models of brain barriers and parenchyma by qPCR and western blot analysis.RFC, PCFT, and FRα expression was localized within the BCSFB and BBB consistent with previous reports. Only RFC and PCFT expression was detected at the AB. Varied levels of RFC and PCFT expression were detected in neuronal and glial cells.Localization of RFC and PCFT within the AB, described here for the first time, suggest that AB may contribute to folate transport between the peripheral circulation and the CSF. RFC and PCFT expression observed in astrocytes and microglia is consistent with the role that one or both of these transporters may play in delivering folates into cells within brain parenchyma. These studies provide insights into mechanisms of folate transport in the CNS and may enhance our understanding of the critical role folates play in neurodevelopment and in the development of novel treatment strategies for disorders of brain folate deficiency due to impaired transporter function.
2017-11-17 | Folate deprivation induces cell cycle arrest at G0/G1 phase and apoptosis in hippocampal neuron cells through down-regulation of IGF-1 signaling pathway.
Folate deficiency contributes to impaired adult hippocampal neurogenesis, yet the mechanisms remain unclear. Here we use HT-22 hippocampal neuron cells as model to investigate the effect of folate deprivation (FD) on cell proliferation and apoptosis, and to elucidate the underlying mechanism. FD caused cell cycle arrest at G0/G1 phase and increased the rate of apoptosis, which was associated with disrupted expression of folate transport and methyl transfer genes. FOLR1 and SLC46A1 were (P<0.01) down-regulated, while SLC19A1 was up-regulated (P<0.01) in FD group. FD cells exhibited significantly (P<0.05) higher protein content of BHMT, MAT2b and DNMT3a, as well as increased SAM/SAH concentrations and global DNA hypermethylation. The expression of the total and all the 3 classes of IGF-1 mRNA variants was significantly (P<0.01) down-regulated and IGF-1 concentration was decreased (P<0.05) in the culture media. IGF-1 signaling pathway was also compromised with diminished activation (P<0.05) of STAT3, AKT and mTOR. CpG hypermethylation was detected in the promoter regions of IGF-1 and FOLR1 genes, while higher SLC19A1 mRNA corresponded to hypomethylation of its promoter. IGF-1 supplementation in FD media significantly abolished FD-induced decrease in cell viability. However, IGF-1 had limited effect in rescuing the cell phenotype when added 24h after FD. Taken together, down-regulation of IGF-1 expression and signaling is involved in FD-induced cell cycle arrest and apoptosis in HT-22 hippocampal neuron cells, which is associated with an abnormal activation of methyl transfer pathway and hypermethylation of IGF-1 gene promoter.
2010-09-14 | A folate receptor defect that causes treatable neurological disorder in children.
Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism Steinfeld et al. (2009) The American Journal of Human Genetics 85: 354-363.
gene therapies
2025-03-30 | Analysis of the Association Between the SLC19A1 Genetic Variant (rs1051266) and Autism Spectrum Disorders, Cerebral Folate Deficiency, and Clinical and Laboratory Parameters.
Autism spectrum disorders (ASD) are characterized by clinical heterogeneity and may be associated with cerebral folate deficiency (CFD). Among the causes, folate receptor alpha autoantibodies (FRAA) and variants of the SLC19A1 gene are commonly highlighted. The aim of this study was to analyze the rs1051266 variant of the SLC19A1 gene in patients with ASD and CFD and to determine its relationship with clinical and laboratory parameters. The study included 227 children with ASD, 156 of whom had CFD. FRAA detection, genotyping of the rs1051266 variant, and folate metabolism marker measurement (homocysteine, vitamins B9, B12, B6) were performed. FRAA binding was detected in 39.2% of ASD patients, blocking FRAA in 3.5%, and a specific soluble folate receptor in 13.2%. The 80GA genotype was the most common (46.3%), and homocysteine levels tended to be moderately elevated (upper quartile - 7.0). Significant correlations were found between homocysteine levels and vitamins B9, B12, and B6 (p < 0.05) and between verbal impairments and vitamin B12 (p = 0.043). In ASD and CFD patients, the 80GG genotype was more frequent (p = 0.03) and vitamin B12 levels were elevated (p = 0.021). In the ASD group, correlations were found between the 80AA genotype and demyelination (p = 0.020) and between homocysteine levels and demyelination (p = 0.042). In conclusion, the rs1051266 variant of the SLC19A1 gene modifies the clinical course of ASD. Patients with ASD and CFD exhibited high variability in folate metabolism markers. These findings underline the need for further research on folate transport genetics for personalized prevention and treatment strategies for ASD and CFD.
small molecules
2026-06-18 | Remarkable Clinical Improvement After Folinic Acid Supplementation in Cerebral Folate Transport Deficiency and Epileptic Encephalopathy: A Case Report
Introduction: Folate plays a critical role in central nervous system development, particularly in myelin synthesis and neurotransmitter metabolism. Cerebral folate transport deficiency (CFTD), most often caused by biallelic pathogenic variants in the FOLR1 gene, results in markedly reduced cerebrospinal fluid (CSF) folate levels despite normal systemic folate status. Affected individuals typically present with developmental regression, seizures, and movement disorders. Early diagnosis and folinic acid supplementation have been shown to reverse neurological symptoms, emphasizing the importance of prompt recognition. Case Presentation: We describe a 6-year-old girl born to consanguineous parents who initially presented with autism spectrum disorder and drug-resistant epilepsy. Her seizures included myoclonic–atonic, generalized myoclonic, and focal seizures, with subsequent gait instability and ataxia. Neuroimaging revealed diffuse cerebral atrophy and white matter signal abnormalities. Subsequent genetic testing identified a homozygous FOLR1 missense likely pathogenic variant (c.544T>A; p.Phe182Ile). The diagnosis was further confirmed by CSF analysis showing severe folate deficiency (5-MTHF: 4 nmol/L). Following initiation of oral folinic acid (4 mg/kg/day), seizures resolved completely, and substantial improvements were observed in ambulation, speech, and social interaction. Conclusion: This case illustrates that folinic acid supplementation can lead to remarkable neurological recovery, even with substantial diagnostic delay. FOLR1-related CFTD should be considered in children with refractory epilepsy and developmental regression
2026-06-09 | Use of Leucovorin After the FDA Announcement of Its Use for Autism Spectrum Disorders.
Leucovorin, or folinic acid (vitamin B9), is approved by the Food and Drug Administration (FDA) to reduce adverse effects from antifolate cancer treatments including methotrexate. In September 2025, the FDA announced that it would expand the label of leucovorin to include treating an extremely rare neurologic condition, cerebral folate deficiency, which shares some symptoms with autism spectrum disorder (ASD).1 The FDA's announcement was accompanied by a widely-publicized White House press conference in which the use of leucovorin for ASD was touted and was preceded by national media reports of the potential benefits of leucovorin for treating ASD in February 2025.2 We measured changes in leucovorin prescriptions in the US during this period of heightened political attention and media coverage.
2026-04-10 | Folic acid modulates the Notch1/NF-κB pathway in a rat model of lipopolysaccharide-activated hippocampal microglia
Introduction Lipopolysaccharide (LPS) induces neuronal injury by stimulating microglia, which release pro-inflammatory markers and neurotoxic factors. Folate deficiency induces microglial activation and modulates nuclear factor-κB (NF-κB) p65 and neurogenic locus Notch homolog protein 1 (Notch1) expression in the hippocampus. This study investigated the neuroprotective effect of folic acid against LPS-induced neurotoxicity in rats, focusing on its modulation of microglial activation and the Notch1, NF-κB, and p65 signaling pathways. Methods A total of 24 Sprague–Dawley male rats were assigned to four groups: control, folic acid, LPS, and folic acid + LPS. After sacrifice, the left cerebral hemisphere was subjected to histopathological assessment using hematoxylin and eosin (H&E) staining and immunohistochemical assessment using anti-GFAP, anti-Iba1, anti-cyclooxygenase-2 (COX-2), anti-tumor necrosis factor- α (TNF-α), and anti-NF-κB antibodies. The hippocampus was extracted from the right hemisphere and used to assess the gene expression of Notch1, TNF-α, interleukin-6 (IL-6), and COX-2 markers using real-time reverse transcription PCR. Results Folic acid ameliorated LPS-induced neuronal damage in the hippocampus, suppressed microglial activation (GFAP and Iba-1), downregulated Notch1 and NF-κB p65, and improved neuroinflammatory responses (TNF-α, IL-6, and COX-2), regardless of the region. Conclusion Folic acid exerted an equivalent neuroprotective effect in both the CA1 and CA3 regions by suppressing microglial activation and modulating the Notch1/NF-κB signaling pathway, thereby reducing neuroinflammation. These findings suggest that folic acid may serve as a potential adjuvant neuroprotective agent against inflammation-mediated neuronal injury.
2026-04-08 | FDA reverses course, won't approve leucovorin for autism
The Trump administration has changed direction from its prior intent to approve an indication for the folic acid derivative leucovorin that had raised serious concern in the research and legal communities (see April 2026 issue of the Update). The Food and Drug Administration (FDA) announced in March that it will not approve leucovorin for the treatment of some patients with autism. The FDA had announced at a September 2025 press conference that it intended to approve leucovorin, marketed as Wellcovorin, in autism treatment despite no evidence of benefit from any randomized controlled trial. Critics of the announcement pointed out that the FDA appeared to be basing its decision-making solely on evidence from case reports and mechanistic data — a much lower standard than the randomized trial evidence customarily required for drug approvals. Now the FDA says its scientific review has determined that there is not enough evidence to support the use of leucovorin to treat patients with autism. The agency is approving a new indication for the drug in treating cerebral folate deficiency in patients with a rare variant in the folate receptor 1 gene. In announcing this new indication, the FDA stated that the approval was based on a systematic review of published case reports and mechanistic data, with no data from clinical trials cited.
2026-03-05 | P364: Variable presentation of FOLR1 related cerebral folate transport deficiency In two sisters
of malignancy, particularly myeloproliferative disorders.While most cases harbor germline heterozygous SETBP1 variants, mosaic presentations are less common and may result in variable expressivity.We report a male infant with a pathogenic SETBP1 mosaic variant detected by exome sequencing, presenting with a classic SGS phenotype and multiple congenital anomalies, including cardiac, renal, skeletal, and neurologic involvement.Case Presentation: A 5-month-old male, born at 38.5 weeks via cesarean section to non-consanguineous parents, was referred for evaluation of a possible genetic syndrome.Neonatal course was initially uneventful, but by day 9 he developed respiratory distress and required hospitalization for sepsis and conjunctivitis.At 4 months he was diagnosed with severe coarctation of the aorta with interruption of the descending aorta, requiring surgical reconstruction.Developmentally, he exhibited global delay, with absence of head control, rolling, sitting, crawling, or speech.Feeding and sleep were reported as normal.His medical history includes recurrent seizures, bilateral decreased vision, hip dysplasia, bilateral cryptorchidism, a horseshoe kidney with renal ectopia, coxa valga, metatarsus varus, and multiple congenital malformations.He receives physical therapy but shows no acquisition of motor milestones.Diagnostic Workup: Imaging revealed severe aortic coarctation with hypoplastic arch, corrected surgically, while brain CT/angiotomography was normal.Renal studies confirmed a horseshoe kidney and left crossed ectopia.Scrotal Doppler identified bilateral cryptorchidism.Audiologic testing showed bilaterally inactive otoacoustic emissions, suggesting cochlear dysfunction.EEG was normal.Laboratory evaluation revealed anemia but was otherwise unremarkable.Clinical exome sequencing identified a pathogenic SETBP1 variant in somatic mosaic state, consistent with Schinzel-Giedion syndrome.A concurrent heterozygous ABL1 variant (somatic) was detected, associated with congenital heart defects and increased risk for myeloid malignancy.Buccal swab testing for SETBP1 was negative, confirming mosaicism restricted to somatic tissues.Maternal testing for ABL1 was negative, indicating a de novo somatic event.
proteins
2022-11-23 | Novel localization of folate transport systems in the murine central nervous system
Folates are a family of B9 vitamins that serve as one-carbon donors critical to biosynthetic processes required for the development and function of the central nervous system (CNS) in mammals. Folate transport is mediated by three highly specific systems: (1) folate receptor alpha (FRα; FOLR1/Folr1), (2) the reduced folate-carrier (RFC; SLC19A1/Slc19a1) and (3) the proton-coupled folate transporter (PCFT; SLC46A1/Slc46a1). Folate transport into and out of the CNS occurs at the blood-cerebrospinal fluid barrier (BCSFB), mediated by FRα and PCFT. Impairment of folate transport at the BCSFB results in cerebral folate deficiency in infants characterized by severe neurological deficiencies and seizures. In contrast to the BCSFB, CNS folate transport at other brain barriers and brain parenchymal cells has not been extensively investigated. The aim of this study is to characterize folate transport systems in the murine CNS at several known barriers encompassing the BCSFB, arachnoid barrier (AB), blood-brain barrier (BBB) and parenchymal cells (astrocytes, microglia, neurons).Applying immunohistochemistry, localization of folate transport systems (RFC, PCFT, FRα) was examined at CNS barriers and parenchymal sites in wildtype (C57BL6/N) mice. Subcellular localization of the folate transport systems was further assessed in an in vitro model of the mouse AB. Gene and protein expression was analyzed in several in vitro models of brain barriers and parenchyma by qPCR and western blot analysis.RFC, PCFT, and FRα expression was localized within the BCSFB and BBB consistent with previous reports. Only RFC and PCFT expression was detected at the AB. Varied levels of RFC and PCFT expression were detected in neuronal and glial cells.Localization of RFC and PCFT within the AB, described here for the first time, suggest that AB may contribute to folate transport between the peripheral circulation and the CSF. RFC and PCFT expression observed in astrocytes and microglia is consistent with the role that one or both of these transporters may play in delivering folates into cells within brain parenchyma. These studies provide insights into mechanisms of folate transport in the CNS and may enhance our understanding of the critical role folates play in neurodevelopment and in the development of novel treatment strategies for disorders of brain folate deficiency due to impaired transporter function.
2017-11-17 | Folate deprivation induces cell cycle arrest at G0/G1 phase and apoptosis in hippocampal neuron cells through down-regulation of IGF-1 signaling pathway.
Folate deficiency contributes to impaired adult hippocampal neurogenesis, yet the mechanisms remain unclear. Here we use HT-22 hippocampal neuron cells as model to investigate the effect of folate deprivation (FD) on cell proliferation and apoptosis, and to elucidate the underlying mechanism. FD caused cell cycle arrest at G0/G1 phase and increased the rate of apoptosis, which was associated with disrupted expression of folate transport and methyl transfer genes. FOLR1 and SLC46A1 were (P<0.01) down-regulated, while SLC19A1 was up-regulated (P<0.01) in FD group. FD cells exhibited significantly (P<0.05) higher protein content of BHMT, MAT2b and DNMT3a, as well as increased SAM/SAH concentrations and global DNA hypermethylation. The expression of the total and all the 3 classes of IGF-1 mRNA variants was significantly (P<0.01) down-regulated and IGF-1 concentration was decreased (P<0.05) in the culture media. IGF-1 signaling pathway was also compromised with diminished activation (P<0.05) of STAT3, AKT and mTOR. CpG hypermethylation was detected in the promoter regions of IGF-1 and FOLR1 genes, while higher SLC19A1 mRNA corresponded to hypomethylation of its promoter. IGF-1 supplementation in FD media significantly abolished FD-induced decrease in cell viability. However, IGF-1 had limited effect in rescuing the cell phenotype when added 24h after FD. Taken together, down-regulation of IGF-1 expression and signaling is involved in FD-induced cell cycle arrest and apoptosis in HT-22 hippocampal neuron cells, which is associated with an abnormal activation of methyl transfer pathway and hypermethylation of IGF-1 gene promoter.
2010-09-14 | A folate receptor defect that causes treatable neurological disorder in children.
Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism Steinfeld et al. (2009) The American Journal of Human Genetics 85: 354-363.
gene therapies
2025-03-30 | Analysis of the Association Between the SLC19A1 Genetic Variant (rs1051266) and Autism Spectrum Disorders, Cerebral Folate Deficiency, and Clinical and Laboratory Parameters.
Autism spectrum disorders (ASD) are characterized by clinical heterogeneity and may be associated with cerebral folate deficiency (CFD). Among the causes, folate receptor alpha autoantibodies (FRAA) and variants of the SLC19A1 gene are commonly highlighted. The aim of this study was to analyze the rs1051266 variant of the SLC19A1 gene in patients with ASD and CFD and to determine its relationship with clinical and laboratory parameters. The study included 227 children with ASD, 156 of whom had CFD. FRAA detection, genotyping of the rs1051266 variant, and folate metabolism marker measurement (homocysteine, vitamins B9, B12, B6) were performed. FRAA binding was detected in 39.2% of ASD patients, blocking FRAA in 3.5%, and a specific soluble folate receptor in 13.2%. The 80GA genotype was the most common (46.3%), and homocysteine levels tended to be moderately elevated (upper quartile - 7.0). Significant correlations were found between homocysteine levels and vitamins B9, B12, and B6 (p < 0.05) and between verbal impairments and vitamin B12 (p = 0.043). In ASD and CFD patients, the 80GG genotype was more frequent (p = 0.03) and vitamin B12 levels were elevated (p = 0.021). In the ASD group, correlations were found between the 80AA genotype and demyelination (p = 0.020) and between homocysteine levels and demyelination (p = 0.042). In conclusion, the rs1051266 variant of the SLC19A1 gene modifies the clinical course of ASD. Patients with ASD and CFD exhibited high variability in folate metabolism markers. These findings underline the need for further research on folate transport genetics for personalized prevention and treatment strategies for ASD and CFD.
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