Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial

Abstract

Background. In contrast to multiple rare monogenetic abnormalities, a common biomarker among children with infantile autism and their parents is the discovery of serum autoantibodies directed to the folate receptor alpha (FRα) localized at blood-brain and placental barriers, impairing physiologic folate transfer to the brain and fetus. Since outcome after behavioral intervention remains poor, a trial was designed to treat folate receptor alpha (FRα) autoimmunity combined with correction of deficient nutrients due to abnormal feeding habits. Methods. All participants with nonsyndromic infantile autism underwent a routine protocol measuring CBC, iron, vitamins, coenzyme Q10, metals, and trace elements. Serum FRα autoantibodies were assessed in patients, their parents, and healthy controls. A self-controlled therapeutic trial treated nutritional derangements with addition of high-dose folinic acid if FRα autoantibodies tested positive. The Childhood Autism Rating Scale (CARS) monitored at baseline and following 2 years of treatment was compared to the CARS of untreated autistic children serving as a reference. Results. In this self-controlled trial (82 children; mean age ± SD: 4.4 ± 2.3 years; male:female ratio: 4.8:1), FRα autoantibodies were found in 75.6 % of the children, 34.1 % of mothers, and 29.4 % of fathers versus 3.3 % in healthy controls. Compared to untreated patients with autism (n=84) whose CARS score remained unchanged, a 2-year treatment decreased the initial CARS score from severe (mean ± SD: 41.34 ± 6.47) to moderate or mild autism (mean ± SD: 34.35 ± 6.25; paired t-test p<0.0001), achieving complete recovery in 17/82 children (20.7 %). Prognosis became less favorable with the finding of higher FRα autoantibody titers, positive maternal FRα autoantibodies, or FRα antibodies in both parents. Conclusions. Correction of nutritional deficiencies combined with high-dose folinic acid improved outcome for autism, although the trend of a poor prognosis due to maternal FRα antibodies or FRα antibodies in both parents may warrant folinic acid intervention before conception and during pregnancy.

Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder

“…Overall, untreated patients, on average, did not demonstrate a change in CARS scores whereas children who underwent treatment demonstrated a decrease in CARS scores from severe to mild-to-moderate ASD. 56 Although this study is not specific for treatment with d,l -leucovorin, it does demonstrate that including d,l -leucovorin in a comprehensive treatment protocol can improve outcomes in core ASD symptoms. In a recent small (n = 19) French study, children with ASD were treated with 5 mg of d,l -leucovorin twice a day or placebo for 12 weeks under single-blind conditions.…”

“… 55 In another study from Belgium, 2 groups of children with ASD demonstrated a 71.4% (n = 84) and 75.6% (n = 82) prevalence of at least one FRAA as compared to 3% of healthy children. 56 In a recent study from France, 58% of children with ASD were positive for at least one FRAA. 57 In a recent study from the New York City Metropolitan area, the prevalence of one or more FRAAs was 76% in children with ASD.…”

“… 80 This is consistent with the recent observation that children with ASD with mothers who have FRAAs have more severe ASD symptoms as rated by the CARS. 56 …”

Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers

“…Another possible explanation could be disturbed folate uptake from blood into cells. Recently, ASD onset has been related to FRα-autoantibodies, that seem to be prevalent in children with ASD and their relatives including their mothers [132][133][134][135][136]. Folate receptors alpha (FR )-autoantibodies prevent normal folate transport across the blood-brain barrier while normal content is observed in the blood [137] and may be a reason of folate insufficiency in cells with simultaneous high folate levels in blood.…”

Autism Spectrum Disorder from the Womb to Adulthood: Suggestions for a Paradigm Shift

“…Maternal autoantibodies targeted against the Folate Receptor α (FRα) deserve to be mentioned in this section. Folate plays a key role in neural development during the embryo-fetal period and the early years of life [ 78 ]. Folate plays an essential role in cell-to-cell communication and in purine, methylation, and redox metabolic pathways.…”