Treatments for biomedical abnormalities associated with autism spectrum disorder

Abstract

Recent studies point to the effectiveness of novel treatments that address physiological abnormalities associated with autism spectrum disorder (ASD). This is significant because safe and effective treatments for ASD remain limited. These physiological abnormalities as well as studies addressing treatments of these abnormalities are reviewed in this article. Treatments commonly used to treat mitochondrial disease have been found to improve both core and associated ASD symptoms. Double-blind, placebo-controlled (DBPC) studies have investigated l-carnitine and a multivitamin containing B vitamins, antioxidants, vitamin E, and co-enzyme Q10 while non-blinded studies have investigated ubiquinol. Controlled and uncontrolled studies using folinic acid, a reduced form of folate, have reported marked improvements in core and associated ASD symptoms in some children with ASD and folate related pathway abnormities. Treatments that could address redox metabolism abnormalities include methylcobalamin with and without folinic acid in open-label studies and vitamin C and N-acetyl-l-cysteine in DBPC studies. These studies have reported improved core and associated ASD symptoms with these treatments. Lastly, both open-label and DBPC studies have reported improvements in core and associated ASD symptoms with tetrahydrobiopterin. Overall, these treatments were generally well-tolerated without significant adverse effects for most children, although we review the reported adverse effects in detail. This review provides evidence for potentially safe and effective treatments for core and associated symptoms of ASD that target underlying known physiological abnormalities associated with ASD. Further research is needed to define subgroups of children with ASD in which these treatments may be most effective as well as confirm their efficacy in DBPC, large-scale multicenter studies.

Keywords: autism spectrum disorders; folate metabolism; folate receptor alpha; folinic acid; mitochondria; oxidative stress; redox regulation; tetrahydrobiopterin.

Figure 1

Pathways affected in autism spectrum disorder that are discussed in this article as well as the treatments discussed with their points of action. Pathways are outlined in blue while treatments are outlined in green. Oxidative stress is outlined in red and the red arrows demonstrate how it can negatively influence metabolic pathways. Certain pathways such as glutathione and tetrahydrobiopterin pathways have an antioxidant effect and a reciprocal relationship with oxidative stress such that they can improve oxidative stress but at the same time oxidative stress has a direct detrimental effect on them. Mitochondrial dysfunction and oxidative stress have mutually negative effects on each other such that oxidative stress causes mitochondrial dysfunction while mitochondrial dysfunction worsens oxidative stress. Dihydrofolate reductase (DHFR) is colored in red since polymorphisms in this gene, that are commonly seen in individuals with autism, have a detrimental effect on the reduction of folic acid such that the entry of folic acid into the folate cycle is decreased. Folinic acid enters the folate cycle without requiring this enzyme. Similarly the folate receptor alpha can be impaired in individuals with autism by autoantibodies and by mitochondrial dysfunction. In such cases, folinic acid can cross the blood–brain barrier by the reduced folate carrier. Methionine synthase (MS) connects the folate and methylation cycles and requires methylcobalamin as a cofactor.