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

Abstract

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.

A Personalized Approach to Evaluating and Treating Autism Spectrum Disorder

“…One article discusses FRα autoantibodies in a broad context, discussing the overlap with cerebral folate deficiency (CFD) and neural tube defects and a subgroup of ASD patients who may be more severely affected due to both prenatal and postnatal autoantibody exposure [15]. Another article conducts a meta-analysis on the available data to provide more concrete prevalence values of FRα autoantibodies in children with ASD and their families [16]. Interestingly, the prevalence rates suggest that FRα autoantibodies have a familial component, although the mechanism of this is not well understood and may be polygenic with environmental influences.…”

“…Five papers describe treatments addressing specific metabolic defects. Building on the subgroup of children with FRα autoantibodies, one paper provides insight into the potential prenatal and postnatal treatment to prevent and treat ASD [15], while a second paper uses meta-analysis to document evidence for effectiveness and efficiency of d,l-leucovorin, the major treatment for children with ASD and FRα autoantibodies, across published clinical trials [16]. In another systematic review and meta-analysis, the effectiveness of cobalamin, a treatment that targets dysfunctional methylation and redox pathways, is analyzed, along with an examination of its metabolic effects [18].…”

“…Perhaps most apparent, these articles underline the primacy of mitochondria in ASD, including oxidative stress and redox regulation, which are themselves major functions of mitochondria. Although the connection between ASD and this important cellular organelle is hardly new, this collection of papers serves to demonstrate the ubiquitous nature of the connection, which ranges from mitochondrial aspects in the prenatal and environmental risk factors/exposures [2,3,8] to biomarkers/metabolites [5,8,[12][13][14][15][16], enzymology [12], and the positive response to therapy, at least in part targeting the mitochondria [8,11,12,15,16,18,19].…”

“…Many papers also relate to another potential etiology of ASD, particularly the immune system, in which multiple interactive domains are highlighted, including innate immunity, immune deficiency, autoimmunity, inflammation, and mast cell activation [7,8,10,11,15,16]. However, similarly to neurons, leukocytes are highly dependent on energy metabolism, and the connections between energy and immunity are many and important.…”

“…However, similarly to neurons, leukocytes are highly dependent on energy metabolism, and the connections between energy and immunity are many and important. In one example, folate transport to brain is affected predominately by autoimmunity and mitochondrial function [16].…”