Cerebral folate transporter deficiency: a potentially treatable neurometabolic disorder

Kanmaz, Seda; Şimşek, Erdem; Yılmaz, Sanem; Durmaz, Asude; Serin, Hepsen Mine; Gökben, Sarenur

doi:10.1007/s13760-021-01700-7

Cited by 6 publications

(14 citation statements)

References 14 publications

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“…Two case-series [34,68], two case-reports [36,69] and four prospective cohortstudies [37,45,70,71] described 172 individuals with idiopathic ASD who had CSF measurements (See Supplementary Table S3). The pooled prevalence of CFD in ASD was 38% (11%, 71%) with a significant variation across studies due to heterogeneity driven by three studies with very high prevalence rates [34,36,68] and four studies with very low prevalence rates [37,45,70,71].…”

Section: Cerebral Folate Deficiency In Autism Spectrum Disordermentioning

confidence: 99%

“…As seen in Figure 1, 20 studies were identified which studied d,l-leucovorin treatment in individuals with ASD including four placebo-controlled studies [72][73][74][75], three prospective, controlled studies [37,44,76], nine prospective studies without a control group [20,21,[33][34][35][77][78][79][80] (two studies examined the same cohort of patients [78,79]), and four case reports/series [36,[67][68][69].…”

Section: Treatment Of Asd With Dl-leucovorinmentioning

confidence: 99%

“…Each of these approaches to using d,l-leucovorin is outlined in separate sections below. S2 and S3) [20,21,[33][34][35][36][67][68][69]. Two studies, one [36] case report and one case series [33], reported on the same child.…”

Section: Treatment Of Asd With Dl-leucovorinmentioning

confidence: 99%

“…A metaanalysis was conducted to determine the prevalence of improvement in symptoms as a result of d,l-leucovorin treatment in children with CFD with and without ASD (See Table 3; Supplementary Table S5). Six studies [21,[33][34][35]67,69] reported a response rate of 67% for improvement in ASD symptoms with d,l-leucovorin treatment. Response to d,l-leucovorin in irritability was studied in children with ASD in three studies [21,34,35] and in children without ASD in three studies [21,33,35].…”

Section: Treatment Of Asd With Dl-leucovorinmentioning

confidence: 99%

“…Six studies examined epilepsy response for those with ASD [21,[33][34][35]67,69] while four studies examined response to epilepsy for those without ASD [21,33,35,67]. Epilepsy improved in 75% of children with ASD, but the response rate was somewhat lower (54%) and much more variable for those without ASD since there was a large variation across studies, perhaps driven by the overall small number of cases.…”

Section: Treatment Of Asd With Dl-leucovorinmentioning

confidence: 99%

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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: Cerebral Folate Deficiency In Autism Spectrum Disordermentioning

confidence: 99%

Section: Treatment Of Asd With Dl-leucovorinmentioning

confidence: 99%

Section: Treatment Of Asd With Dl-leucovorinmentioning

confidence: 99%

Section: Treatment Of Asd With Dl-leucovorinmentioning

confidence: 99%

Section: Treatment Of Asd With Dl-leucovorinmentioning

confidence: 99%

See 3 more Smart Citations

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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Reanalysis of exome sequencing data reveals a treatable neurometabolic origin in two previously undiagnosed siblings with neurodevelopmental disorder

et al. 2023

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Deconstructing the functional neuroanatomy of the choroid plexus: an ontogenetic perspective for studying neurodevelopmental and neuropsychiatric disorders

2022

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The choroid plexus (CP) is a delicate and highly vascularized structure in the brain comprised of a dense network of fenestrated capillary loops that help in the synthesis, secretion and circulation of cerebrospinal fluid (CSF). This unique neuroanatomical structure is comprised of arachnoid villi stemming from frond-like surface projections—that protrude into the lumen of the four cerebral ventricles—providing a key source of nutrients to the brain parenchyma in addition to serving as a ‘sink’ for central nervous system metabolic waste. In fact, the functions of the CP are often described as being analogous to those of the liver and kidney. Beyond forming a barrier/interface between the blood and CSF compartments, the CP has been identified as a modulator of leukocyte trafficking, inflammation, cognition, circadian rhythm and the gut brain-axis. In recent years, advances in molecular biology techniques and neuroimaging along with the use of sophisticated animal models have played an integral role in shaping our understanding of how the CP–CSF system changes in relation to the maturation of neural circuits during critical periods of brain development. In this article we provide an ontogenetic perspective of the CP and review the experimental evidence implicating this structure in the pathophysiology of neurodevelopmental and neuropsychiatric disorders.

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Cerebral folate transporter deficiency: a potentially treatable neurometabolic disorder

Cited by 6 publications

References 14 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

Reanalysis of exome sequencing data reveals a treatable neurometabolic origin in two previously undiagnosed siblings with neurodevelopmental disorder

Deconstructing the functional neuroanatomy of the choroid plexus: an ontogenetic perspective for studying neurodevelopmental and neuropsychiatric disorders

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