Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status

Frye, Richard E.; Melnyk, Stepan; Fuchs, George J.; Reid, Tyra; Jernigan, Stefanie; Pavliv, Oleksandra; Hubanks, Amanda; Gaylor, David W.; Walters, Laura M.; James, S. Jill

doi:10.1155/2013/609705

Cited by 59 publications

(92 citation statements)

References 37 publications

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“…Other studies found alterations in some markers related to oxidative stress (i.e. reduced free glutathione and decrease in the ratio between reduced and oxidised glutathione) in blood of patients with ASD and no changes in other markers of oxidative stress such as 3-nitrotyrosine as reported here and in agreement with findings reported by another group (Frye et al, 2013a). A double-blind, placebo controlled study found a reduction of autism severity (measured by Ritvo-Freeman scale) after 30-week administration of high dose of vitamin C (110 mg/kg) (Dolske et al, 1993).…”

Section: Introductionsupporting

confidence: 93%

Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder

Puig-Alcaraz¹,

Fuentes-Albero²,

Calderón³

et al. 2015

Psychiatry Research

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Section: Introductionsupporting

confidence: 93%

Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder

Puig-Alcaraz¹,

Fuentes-Albero²,

Calderón³

et al. 2015

Psychiatry Research

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“…In a description of the behavioral changes in 37 children with ASD out of this cohort, children showed improvements in all of the subscales of the Vineland Adaptive Behavior Scale and an average improvement in the overall age-equivalent score of 7.7 months during the 3 month study. In this analysis, improvements in plasma glutathione levels were significantly correlated with improvements in expressive communication, personal and domestic daily living skills, and interpersonal, play-leisure, and coping social skills as measured by the Vineland Adaptive Behavior Scale (Frye et al 2013). …”

Section: Introductionmentioning

confidence: 81%

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism

Widjaja

et al. 2016

Journal of Child and Adolescent Psychopharmacology

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100

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Objective: Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress. We sought to determine if methyl B12, a key metabolic cofactor for cellular methylation reactions and antioxidant defense, could improve symptoms of ASD. Methods: A total of 57 children with ASD were randomly assigned to 8 weeks of treatment with methyl B12 (75 lg/kg) or saline placebo every 3 days in a subcutaneous injection. The primary outcome measure was overall improvement in symptoms of ASD as measured by the Clinical Global Impressions-Improvement (CGI-I) score. Secondary outcome measures included changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Laboratory measures of methionine methylation and antioxidant glutathione metabolism were assessed at baseline and 8 weeks.Results: A total of 50 children (mean age 5.3 years, 79% male) completed the study. The primary outcome measure -the clinician rated CGI-I score -was statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2-0.2, p = 0.005). Clinical improvement among children treated with methyl B12 was positively correlated with increases in plasma methionine ( p = 0.05), decreases in S-adenosyl-lhomocysteine (SAH) ( p = 0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH ( p = 0.007), indicating an improvement in cellular methylation capacity. No improvements were observed in the parent-rated ABC or SRS. Conclusions: Methyl B12 treatment improved clinician-rated symptoms of ASD that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity. Clinical Trial Registry: Efficacy Study of Subcutaneous Methyl B12 in Children with Autism: NCT01039792 (clinical trials.gov1).

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“…Glutathione is essential for detoxification and enzyme regulation [26]. Oral low-dose folinic acid given concurrently with subcutaneously injected methylcobalamin increases glutathione production and improves development in children with ASD [27].…”

Section: Folate One Of the Body's Most Important Vitaminsmentioning

confidence: 99%

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

2017

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Autism spectrum disorder (ASD) has been linked to abnormalities in folate metabolism. Polymorphisms in folate genes may act in complex polygenic ways to increase the risk of developing ASD. Autoantibodies that block folate transport into the brain have been associated with ASD and children with ASD and these autoantibodies respond to high doses of a reduced form of folate known as folinic acid (leucovorin calcium). Some of the same abnormalities are also found in mothers of children with ASD and supplementing folate during preconception and gestational periods reduces the risk to the offspring from developing ASD. These data suggest that folate pathway abnormalities may be a major metabolic disturbance underlying ASD that can be leveraged as biomarkers to improve symptoms and prevent ASD. Autism spectrum disorder: an emerging disorder with unclear etiology Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 2% of children in the USA [1]. Although it is defined through observation of the presence of abnormal behavior and absence of typical developmental milestones, ASD is associated with a wide range of medical abnormalities such as sleep, immune and gastrointestinal disorders and epilepsy. In addition to medical comorbidities, many children with ASD have disruptions in body physiology such as abnormalities in folate, cobalamin, tetrahydrobiopterin (BH 4 ), neurotransmitter, carnitine, redox and mitochondrial metabolism [2]. The connection between underlying physiological abnormalities and behavior is an area of active research. In this review, we will provide evidence that abnormalities of one-carbon folate metabolism are particularly important in ASD.Although the etiology of ASD is not known, genetics has been the focus of ASD research for many decades [3]. A notion of a pure genetic etiology is tempered by the fact that single gene and chromosomal defects are found in a minority of ASD cases, accounting for only 15.8% of cases when both chromosomal microarray and whole exome sequencing were used in one recent large study [4]. ASD has also been associated with exposures to numerous environmental agents during the prenatal and postnatal period [5]. Studies that have examined the contribution of the environmental and genetic components highlight that ASD arises as a consequence of complicated interactions between genetic predisposition and environmental factors [6,7]. As we will outline in this review, abnormalities in folate metabolism provide an excellent model of how environment factors can interact with genetic predisposition to cause ASD.At this time, the standard of care for ASD treatment is applied behavioral analysis and other equivalent behavioral interventions along with educational, developmental, occupational and speech therapy. Optimal application of behavioral therapy requires full-time one-on-one therapist for many years; however, even when this optimal therapy is applied, suboptimal outcomes are common. In addition, controlled studies examining the efficacy of variou...

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Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status

Cited by 59 publications

References 37 publications

Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder

Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

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