Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status
Treatments targeting metabolic abnormalities in children with autism are limited. Previously we reported that a nutritional treatment significantly improved glutathione metabolism in children with autistic disorder. In this study we evaluated changes in adaptive behaviors in this cohort and determined whether such changes are related to changes in glutathione metabolism. Thirty-seven children diagnosed with autistic disorder and abnormal glutathione and methylation metabolism were treated with twice weekly 75？μg/Kg methylcobalamin and twice daily 400？μg folinic acid for 3 months in an open-label fashion. The Vineland Adaptive Behavior Scale (VABS) and glutathione redox metabolites were measured at baseline and at the end of the treatment period. Over the treatment period, all VABS subscales significantly improved with an average effect size of 0.59, and an average improvement in skills of 7.7 months. A greater improvement in glutathione redox status was associated with a greater improvement in expressive communication, personal and domestic daily living skills, and interpersonal, play-leisure, and coping social skills. Age, gender, and history of regression did not influence treatment response. The significant behavioral improvements observed and the relationship between these improvements to glutathione redox status suggest that nutritional interventions targeting redox metabolism may benefit some children with autism. 1. Introduction Autism is a neurodevelopmental disorder characterized by significant impairment in reciprocal social interaction and communication as well as restricted interests and repetitive behaviors. An estimated 1 of 88 individuals in the United States is affected with an autism spectrum disorder (ASD) [1]. Although several genetic syndromes are associated with ASD, all of these genetic syndromes together only account for a minority of ASD cases [2]. Other areas of novel research have concentrated on systemic physiological abnormalities, such as mitochondrial dysfunction [3, 4], oxidative stress [5–7], and inflammation/immune dysregulation [8–10]. These novel areas of research have substantially grown over the last decade [11]. These emerging areas of research have provided a new understanding of the diverse mechanisms involved in ASD and have promoted the idea that the autism spectrum is composed of several subgroups or endophenotypes [12]. Several lines of evidence support the notion of an ASD endophenotype with abnormal redox and methylation metabolism. In two case-control studies we reported that redox and methylation
References
[1]
C. Rice, “Autism, Developmental Disabilities Monitoring Network Surveillance Year Principal I, Centers for Disease C, Prevention: prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network, United States, 2006,” Morbidity and Mortality Weekly Report, vol. 58, no. 10, pp. 1–20, 2009.
[2]
G. B. Schaefer and N. J. Mendelsohn, “Clinical genetics evaluation in identifying the etiology of autism spectrum disorders,” Genetics in Medicine, vol. 10, no. 4, pp. 301–305, 2008.
[3]
R. E. Frye and D. A. Rossignol, “Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders,” Pediatric Research, vol. 69, no. 5, pp. 41R–47R, 2011.
[4]
D. A. Rossignol and R. E. Frye, “Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis,” Molecular Psychiatry, vol. 17, no. 3, pp. 290–314, 2012.
[5]
S. J. James, S. Melnyk, S. Jernigan, A. Hubanks, S. Rose, and D. W. Gaylor, “Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism,” Journal of Autism and Developmental Disorders, vol. 38, no. 10, pp. 1966–1975, 2008.
[6]
S. J. James, S. Melnyk, S. Jernigan et al., “Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism,” American Journal of Medical Genetics Part B, vol. 141, no. 8, pp. 947–956, 2006.
[7]
S. Melnyk, G. J. Fuchs, E. Schulz et al., “Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism,” Journal of Autism and Developmental Disorders, vol. 42, no. 3, pp. 367–377, 2012.
[8]
P. Ashwood, B. A. Corbett, A. Kantor, H. Schulman, J. van de Water, and D. G. Amaral, “In search of cellular immunophenotypes in the blood of children with autism,” PLoS ONE, vol. 6, no. 5, Article ID e19299, 2011.
[9]
P. Ashwood, P. Krakowiak, I. Hertz-Picciotto, R. Hansen, I. N. Pessah, and J. Van de Water, “Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders,” Journal of Neuroimmunology, vol. 232, no. 1-2, pp. 196–199, 2011.
[10]
P. Ashwood, P. Krakowiak, I. Hertz-Picciotto, R. Hansen, I. N. Pessah, and J. Van de Water, “Altered T cell responses in children with autism,” Brain, Behavior, and Immunity, vol. 25, no. 5, pp. 840–849, 2011.
[11]
D. A. Rossignol and R. E. Frye, “A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures,” Molecular Psychiatry, vol. 17, no. 4, pp. 389–401, 2012.
[12]
E. Viding and S.-J. Blakemore, “Endophenotype approach to developmental psychopathology: implications for autism research,” Behavior Genetics, vol. 37, no. 1, pp. 51–60, 2007.
[13]
S. J. James, P. Cutler, S. Melnyk et al., “Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism,” American Journal of Clinical Nutrition, vol. 80, no. 6, pp. 1611–1617, 2004.
[14]
S. J. James, S. Rose, S. Melnyk et al., “Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism,” FASEB Journal, vol. 23, no. 8, pp. 2374–2383, 2009.
[15]
S. Rose, S. Melnyk, T. A. Trusty, et al., “Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism,” Autism Research and Treatment, vol. 2012, Article ID 986519, 10 pages, 2012.
[16]
W. Droge and R. Breitkreutz, “Glutathione and immune function,” Proceedings of the Nutrition Society, vol. 59, no. 4, pp. 595–600, 2000.
[17]
A. Pastore, G. Federici, E. Bertini, and F. Piemonte, “Analysis of glutathione: implication in redox and detoxification,” Clinica Chimica Acta, vol. 333, no. 1-2, pp. 19–39, 2003.
[18]
S. Biswas, A. S. Chida, and I. Rahman, “Redox modifications of protein-thiols: emerging roles in cell signaling,” Biochemical Pharmacology, vol. 71, no. 5, pp. 551–564, 2006.
[19]
F. Q. Schafer and G. R. Buettner, “Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple,” Free Radical Biology and Medicine, vol. 30, no. 11, pp. 1191–1212, 2001.
[20]
M. Reid and F. Jahoor, “Glutathione in disease,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 4, no. 1, pp. 65–71, 2001.
[21]
S. Rose, S. Melnyk, O. Pavliv, et al., “Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain,” Translational Psychiatry, vol. 2, article e134, 2012.
[22]
A. Chauhan and V. Chauhan, “Oxidative stress in autism,” Pathophysiology, vol. 13, no. 3, pp. 171–181, 2006.
[23]
S. J. James, S. Melnyk, G. Fuchs et al., “Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism,” American Journal of Clinical Nutrition, vol. 89, no. 1, pp. 425–430, 2009.
[24]
S. Melnyk, M. Pogribna, I. Pogribny, R. J. Hine, and S. J. James, “A new HPLC method for the simultaneous determination of oxidized and reduced plasma aminothiols using coulometric electrochemical detection,” Journal of Nutritional Biochemistry, vol. 10, no. 8, pp. 490–497, 1999.
[25]
S. Melnyk, M. Pogribna, I. P. Pogribny, P. Yi, and S. J. James, “Measurement of plasma and intracellular S-adenosylmethionine and S-adenosylhomocysteine utilizing coulometric electrochemical detection: alterations with plasma homocysteine and pyridoxal 5′-phosphate concentrations,” Clinical Chemistry, vol. 46, no. 2, pp. 265–272, 2000.
[26]
S. Sparrow, D. Cicchetti, and D. Balla, Vineland Adaptive Behavior Scales, P. Assessment, Minneapolis, Minn, USA, 2nd edition, 2005.
[27]
N. M. Laird and J. H. Ware, “Random-effects models for longitudinal data,” Biometrics, vol. 38, no. 4, pp. 963–974, 1982.
[28]
R. E. Frye, R. DeLatorre, H. B. Taylor, et al., “Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study,” Translational Psychiatry, vol. 3, article e237, 2013.
[29]
S. M. Melnyk, K. F. More, and E. F. Miles, “Idiopathic radiation recall dermatitis developing nine months after cessation of Cisplatin therapy in treatment of squamous cell carcinoma of the tonsil,” Case Reports in Oncological Medicine, vol. 2012, Article ID 271801, 3 pages, 2012.
[30]
R. E. Frye, J. M. Sequeira, E. V. Quadros, S. J. James, and D. A. Rossignol, “Cerebral folate receptor autoantibodies in autism spectrum disorder,” Molecular Psychiatry, vol. 18, no. 3, pp. 369–381, 2013.
[31]
A. Y. Hardan, L. K. Fung, R. A. Libove et al., “A randomized controlled pilot trial of oral N-acetylcysteine in children with autism,” Biological Psychiatry, vol. 71, no. 11, pp. 956–961, 2012.
[32]
J. B. Adams and C. Holloway, “Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder,” Journal of Alternative and Complementary Medicine, vol. 10, no. 6, pp. 1033–1039, 2004.
[33]
J. B. Adams, T. Audhya, S. McDonough-Means et al., “Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity,” Nutrition and Metabolism, vol. 8, article 34, 2011.
[34]
R. E. Frye, R. DeLatorre, and H. B. Taylor, “Redox metabolism abnormalities in autistic children associated with mitochondrial disease,” Translational Psychiatry, 2013.
[35]
N. Lofthouse, R. Hendren, E. Hurt, I. E. Arnold, and E. Butter, “A review of complementary and alternative treatments for autism spectrum disorders,” Autism Research and Treatment, 2012.
[36]
D. A. Rossignol, “Novel and emerging treatments for autism spectrum disorders: a systematic review,” Annals of Clinical Psychiatry, vol. 21, no. 4, pp. 213–236, 2009.
[37]
J. M. Perrin, D. L. Coury, S. L. Hyman, L. Cole, A. M. Reynolds, and T. Clemons, “Complementary and alternative medicine use in a large pediatric autism sample,” Pediatrics, vol. 130, pp. S77–S82, 2012.
[38]
S. L. Hyman and S. E. Levy, “Introduction: novel therapies in developmental disabilities—hope, reason, and evidence,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 11, no. 2, pp. 107–109, 2005.
