Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder

Richard E Frye, Daniel A Rossignol, Lawrence Scahill, Christopher J McDougle, Harris Huberman, Edward V Quadros, Richard E Frye, Daniel A Rossignol, Lawrence Scahill, Christopher J McDougle, Harris Huberman, Edward V Quadros

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that currently has no approved medical therapy to address core symptoms or underling pathophysiological processes. Several compounds are under development that address both underlying pathophysiological abnormalities and core ASD symptoms. This article reviews one of these treatments, d,l-leucovorin calcium (also known as folinic acid) for treatment of folate pathway abnormalities in children with ASD. Folate is a water-soluble B vitamin that is essential for normal neurodevelopment and abnormalities in the folate and related pathways have been identified in children with ASD. One of these abnormalities involves a partial blockage in the ability of folate to be transported into the brain utilizing the primary transport mechanism, the folate receptor alpha. Autoantibodies which interfere with the function of the folate receptor alpha called folate receptor alpha autoantibodies have been identified in 58%-76% of children with ASD and independent studies have demonstrated that blood titers of these autoantibodies correlate with folate levels in the cerebrospinal fluid. Most significantly, case-series, open-label, and single and double-blind placebo-controlled studies suggest that d,l-leucovorin, a reduced folate that can bypass the blockage at the folate receptor alpha by using the reduced folate carrier, an alternate pathway, can substantially improve particular symptoms in children with ASD, especially those positive for folate receptor alpha autoantibodies. This article reviews the current evidence for treating core and associated symptoms and underlying pathophysiological mechanisms in children with ASD with d,l-leucovorin.

Conflict of interest statement

Conflict of Interest: Authors declare that they have no conflict of interest.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
The essential role of folate in metabolism. Folate is essential for a wide variety of essential metabolic systems, including DNA and RNA synthesis and methylation, redox and tetrahydrobiopterin metabolism. ATP, adenosine triphosphate; B12, Vitamin B12 (cobalamin); BH4, tetrahydrobiopterin; DHFR, dihydrofolate reductase; DNA, deoxyribonucleic acid; GTP, guanosine triphosphate; Me, methyl group; MGF, monoglutamated folate; MS, Methionine synthase; 5-MTHF, 5-methyltetrahydrofolate; MTHFR, methylenetetrahydrofolate reductase; RNA, ribonucleic acid; 5,10-CH2THF, 5,10-methylenetetrahydrofolate; THF, tetrahydrofolate.
Figure 2
Figure 2
Folate transport across the blood brain barrier and the placenta. ATP, adenosine triphosphate; FRα, folate receptor α; PCFT, Proton Coupled Folate Transporter; RFC, reduced folate carrier.
Figure 3
Figure 3
Prevalence of the folate receptor α autoantibodies in children with autism spectrum disorder in our initial study.
Figure 4
Figure 4
Improvement ratings on 9 cognitive-behavioral dimensions for folate receptor alpha autoantibody positive ASD children (n = 44) treated with d,l-leucovorin.
Figure 5
Figure 5
Leucovorin improves verbal communication more than placebo.
Figure 6
Figure 6
Percentage of families that reported agitation or excitement at each 3-week adverse effect check-in

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