Folinic acid therapy in cerebral folate deficiency: marked improvement in an adult patient

Karin, Ivan; Borggraefe, Ingo; Catarino, Claudia B.; Kuhm, Christoph; Hoertnagel, Konstanze; Biskup, Saskia; Opladen, Thomas; Blau, Nenad; Heinen, Florian; Klopstock, Thomas

doi:10.1007/s00415-016-8387-6

Cited by 15 publications

(14 citation statements)

References 16 publications

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“…d,l-leucovorin is a reduced (active) form of folate which can enter the CNS through the RFC and has been reported to normalize 5-MTHF levels in the CSF in individuals with CFD [21]. In some cases, clinical response to d,l-leucovorin is dramatic, especially if this treatment is started early in life [19,28] but sometimes improvements can be marked even in adults [29]. d,l-leucovorin consists of two diastereomers designated as d-leucovorin and l-leucovorin.…”

Section: Introductionmentioning

confidence: 99%

Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis

Rossignol¹,

Frye

2021

JPM

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The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency (CFD). CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid). One cause of CFD is an autoantibody that interferes with the function of the FRα. FRα autoantibodies (FRAAs) have been reported in ASD. A systematic review was performed to identify studies reporting FRAAs in association with ASD, or the use of d,l-leucovorin in the treatment of ASD. A meta-analysis examined the prevalence of FRAAs in ASD. The pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38% (with a significant variation across studies due to heterogeneity). The etiology of CFD in ASD was attributed to FRAAs in 83% of the cases (with consistency across studies) and mitochondrial dysfunction in 43%. A significant inverse correlation was found between higher FRAA serum titers and lower 5-MTHF CSF concentrations in two studies. The prevalence of FRAA in ASD was 71% without significant variation across studies. Children with ASD were 19.03-fold more likely to be positive for a FRAA compared to typically developing children without an ASD sibling. For individuals with ASD and CFD, meta-analysis also found improvements with d,l-leucovorin in overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%). Twenty-one studies (including four placebo-controlled and three prospective, controlled) treated individuals with ASD using d,l-leucovorin. d,l-Leucovorin was found to significantly improve communication with medium-to-large effect sizes and have a positive effect on core ASD symptoms and associated behaviors (attention and stereotypy) in individual studies with large effect sizes. Significant adverse effects across studies were generally mild but the most common were aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%). Taken together, d,l-leucovorin is associated with improvements in core and associated symptoms of ASD and appears safe and generally well-tolerated, with the strongest evidence coming from the blinded, placebo-controlled studies. Further studies would be helpful to confirm and expand on these findings.

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Section: Introductionmentioning

confidence: 99%

Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis

Rossignol¹,

Frye

2021

JPM

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“…Folinic acid is a reduced form of folate, intake of folinic acid could normalize folate-dependent one-carbon metabolism that may help stabilize cerebrospinal fluid (CSF) folate concentrations and significantly improve neurological symptoms ( 52 – 54 ). Folinic acid can readily enter the folate cycle without reduction ( 54 ).…”

Section: Resultsmentioning

confidence: 99%

Dietary Supplement for Core Symptoms of Autism Spectrum Disorder: Where Are We Now and Where Should We Go?

2017

Front. Psychiatry

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Autism spectrum disorders (ASDs) are a class of severe and chronic conditions and core symptoms are deficits in social interaction, language communication impairments, and repetitive/stereotyped behavior. Given the limitations of available treatments and substantially increased prevalence of the disease, additional interventions are needed. Since the use of dietary supplements for ASD is of high prevalence, up-to-date information about those supplements are required for both parents and clinicians. Relevant articles were identified through a systematic search of PubMed, EMBASE, Cochrane library, and PsychINFO databases (through May 2017). Current best evidences of 22 randomized controlled trials on 8 different dietary supplements for core symptoms of ASD were reviewed. For each supplement, this report focuses on the definition and potential therapeutic mechanisms, the latest advances, and discussion of study limitations and future directions. Most studies were small and short term, and there is little evidence to support effectiveness of dietary supplements for children with ASD.

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“…Additionally, we found no significant difference in tissue levels of folate, indicating that the changes seen are likely to be a response to ineffective gene products and/or to physiological changes in metabolism rather than folate supply. These significant changes in metabolic profile may provide early markers of at-risk individuals who may therefore be protected by appropriate metabolic support, including perhaps folate supplements [12,[87][88][89].…”

Section: Discussionmentioning

confidence: 99%

Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimer’s Disease with a Change in Metabolic Profile

Miyan

Buttercase

Beswick³

et al. 2022

Metabolites

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Metabolic disorders may be important potential causative pathways to Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) decreasing output, raised intracranial pressure, and ventricular enlargement have all been linked to AD. Cerebral folate metabolism may be a key player since this is significantly affected by such changes in CSF, and genetic susceptibilities may exist in this pathway. In the current study, we aimed to identify whether any single nucleotide polymorphism (SNPs) affecting folate and the associated metabolic pathways were significantly associated with AD. We took a functional nutrigenomics approach to look for SNPs in genes for the linked folate, methylation, and biogenic amine neurotransmitter pathways. Changes in metabolism were found with the SNPs identified. An abnormal SNP in methylene tetrahydrofolate dehydrogenase 1 (MTHFD1) was significantly predictive of AD and associated with an increase in tissue glutathione. Individuals without these SNPs had normal levels of glutathione but significantly raised MTHFD1. Both changes would serve to decrease potentially neurotoxic levels of homocysteine. Seven additional genes were associated with Alzheimer’s and five with normal ageing. MTHFD1 presents a strong prediction of susceptibility and disease among the SNPs associated with AD. Associated physiological changes present potential biomarkers for identifying at-risk individuals.

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Folinic acid therapy in cerebral folate deficiency: marked improvement in an adult patient

Cited by 15 publications

References 16 publications

Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis

Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis

Dietary Supplement for Core Symptoms of Autism Spectrum Disorder: Where Are We Now and Where Should We Go?

Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimer’s Disease with a Change in Metabolic Profile

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