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[NFB Forum]

Response from Gayle Nicholas Scott, PharmD
Assistant Professor, Eastern Virginia Medical School, Norfolk, Virginia; Clinical Pharmacist, Chesapeake Regional Medical Center, Chesapeake, Virginia

Autism spectrum disorder (ASD) includes classic autism, Asperger syndrome, and pervasive developmental disorder. ASD is a group of heterogeneous conditions characterized by impaired social interaction, difficulties with language and communication, repetitive stereotypical behaviors, and/or a very limited range of interests. Severity ranges from severe mental disability to so-called "high functioning autism," which describes a person with ASD and normal or high intelligence but social difficulty. More than 70% of people with ASD have comorbid conditions such as seizure disorders, attention-deficit disorder, anxiety, and sleep disorders.[1,2]

The cost of supporting someone with an ASD and intellectual disability during his or her lifespan is $2.4 million in the United States; ASD without intellectual disability costs $1.4 million. Education services and parental productivity loss contributed to the largest costs for children with ASD, and residential care or supportive living accommodation and individual productivity loss contributed to the largest costs for adults with ASD.[3]

The incidence of ASD is 1 in 68, and it is 4 times more common in males.[2,4] Despite increasing diagnoses of ASD, the etiology of ASD or the biochemical mechanisms responsible for its manifestation have not been identified. Genetic factors appear to be responsible for about 50% of autism cases, with the remainder caused by environmental factors occurring early in fetal development.[2,5] Some environmental factors that have been associated with ASD risk include rubella infection, exposure during the first trimester of pregnancy to thalidomide or valproic acid, untreated phenylketonuria, prematurity, twins or multiple pregnancy, and advanced maternal or paternal age at conception.[6]

Several proposed causes have been ruled out, including mental illness, poor parenting, and vaccines.[1] The myth that vaccines can cause ASD persists despite conclusive evidence that ASD is unrelated to vaccination. Outbreaks of preventable diseases continue to occur, fostered by parental fear of ASD and refusal of childhood immunizations.[7,8]

Pharmacotherapy of ASD is limited to treatment of symptoms such as irritability, aggression, and hyperactivity, which occur in some patients with ASD. Currently, no medication is available to cure autism or for the treatment of core symptoms of autism such as impaired social interaction, language difficulties, and repetitive behaviors. Research is ongoing to examine the use of cholinergic and glutaminergic agents and oxytocin for core ASD symptoms.[9]

Although ASD is not caused by nutritional deficiency, selective eating patterns common in patients with ASD and dietary restrictions (eg, casein-free or gluten-free diet) imposed by parents with the intent of improving behavior or gastrointestinal symptoms may result in nutritional inadequacy. Some research suggests that ASD patients consume less dairy and vegetables than peers without ASD.[10] In a study comparing 55 children with ASD vs 44 neurotypical children, mean levels of vitamins and minerals were within published reference ranges.[11]

Only 2 clinical trials of vitamin/mineral supplements in ASD have been published, both by the same research group. Both studies were randomized and placebo-controlled; the first was a pilot study with a total of 20 children, and the second was a larger study with 141 children and adults.[12,13] The pilot study reported better sleep and improved gastrointestinal symptoms.[12] The second study showed no meaningful improvements in autism symptoms in 3 of 4 assessments but did find modest improvements on the Parental Global Impressions-Revised questionnaire in areas of hyperactivity, tantrums, and receptive language.[13] The study product contained a total of 34 vitamins, minerals, and other ingredients such as coenzyme Q-10 and n-acetylcysteine; the rationale for dosages and components is unclear.

Methylcobalamin (also called methyl B12 and mecobalamin) is a form of vitamin B12, which is a cofactor for the regeneration of methionine from homocysteine and for glutathione metabolism. Research in small numbers of children suggests that children with ASD have reduced glutathione levels and, theoretically, increased oxidative stress.[14] Short-term studies have been reported with mixed results.[14,15] One study, which used subcutaneous methylcobalamin and oral folinic acid, showed improvement in the Vineland Adaptive Behavior Scale and glutathione metabolites.[14]

The other study, which also used subcutaneous methylcobalamin, found no statistically significant differences in behavior tests or in glutathione status between active and placebo groups. Nine (30%) patients showed improvement on the Clinical Global Impression-Improvement Scale and at least 2 behavioral and language measures; the 9 responders had increased concentrations of glutathione and its metabolites compared with the nonresponders, suggesting a possible effect in some subgroups of ASD.[15] Oral methylcobalamin, which is available as a dietary supplement, has not been studied. Injectable methylcobalamin must be obtained from a compounding pharmacy.

Several other vitamins, alone or in combination with minerals, have been suggested for ASD. Pyridoxine (vitamin B6) given in combination with magnesium to reduce the adverse effects of high-dose pyridoxine has been suggested for the treatment of autism.[16] Systematic reviews have found no benefit of the combination of pyridoxine and magnesium for ASD.[16,17] Vitamin A and vitamin C are sometimes used for ASD,[18] but there is no reliable clinical research to support these treatments.[19]

In summary, ASD is likely caused by genetic and environmental factors. Factors such as nutritional deficiencies and vaccines do not cause autism. There is no compelling evidence that specific vitamins improve ASD symptoms, although study groups have been small, and subpopulations of patients who might benefit could exist. For patients with severely selective eating habits, supplementation with specific vitamins may be required to prevent deficiency.[20-22] For patients with less severe selective eating behaviors or those on restrictive diets, a multivitamin/mineral supplement seems reasonable as long as no ingredient exceeds the tolerable upper intake level. Overzealous administration of supplements can lead to hypervitaminosis.[23]

References

Baker JP. Autism at 70 -- redrawing the boundaries. N Engl J Med. 2013;369:1089-1091. Abstract

Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383:896-910. Abstract

Buescher AV, Cidav Z, Knapp M, Mandell DS. Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr. 2014 Jun 9. [Epub ahead of print]

Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators. Prevalence of autism spectrum disorder among children aged 8 years -- autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ. 2014;63(Suppl 2):1-21.

Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014;311:1770-1777. Abstract

Harrington JW, Allen K. The clinician's guide to autism. Pediatr Rev. 2014;35:62-78. Abstract

DeStefano F, Price CS, Weintraub ES. Increasing exposure to antibody-stimulating proteins and polysaccharides in vaccines is not associated with risk of autism. J Pediatr. 2013;163:561-567. Abstract

Stratton K, Ford, A, Rusch E, Wright Clayton E, eds; Committee to Review Adverse Effects of Vaccines; Institute of Medicine. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: National Academies Press (US); 2012.

Farmer C, Thurm A, Grant P. Pharmacotherapy for the core symptoms in autistic disorder: current status of the research. Drugs. 2013;73:303-314. Abstract

Graf-Myles J, Farmer C, Thurm A, et al. Dietary adequacy of children with autism compared with controls and the impact of restricted diet. J Dev Behav Pediatr. 2013;34:449-459. Abstract

Adams JB, Audhya T, McDonough-Means S, et al. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab (Lond). 2011;8:34.

Adams JB, Holloway C. Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder. J Altern Complement Med. 2004;10:1033-1039. Abstract

Adams JB, Audhya T, McDonough-Means S, et al. Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatr. 2011;11:111.

Frye RE, Melnyk S, Fuchs G, et al. Effectiveness of methylcobalamin and folinic acid treatment on adaptive behavior in children with autistic disorder is related to glutathione redox status. Autism Res Treat. 2013;2013:609705.

Bertoglio K, Jill James S, Deprey L, Brule N, Hendren RL. Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism. J Altern Complement Med. 2010;16:555-560. Abstract

Nye C, Brice A. Combined vitamin B6-magnesium treatment in autism spectrum disorder. Cochrane Database Syst Rev. 2005;(4):CD003497.

Murza KA, Pavelko SL, Malani MD, Nye C. Vitamin B6-magnesium treatment for autism: the current status of the research. Magnes Res. 2010;23:115-117. Abstract

Hendren RL. Autism: biomedical complementary treatment approaches. Child Adolesc Psychiatr Clin N Am. 2013;22:443-456. Abstract

Parr J. Autism. Clin Evid (Online). 2010 Jan 7. [Epub ahead of print]

Tanoue K, Matsui K, Takamasu T. Fried-potato diet causes vitamin A deficiency in an autistic child. JPEN J Parenter Enteral Nutr. 2012;36:753-755. Abstract

Keown K, Bothwell J, Jain S. Nutritional implications of selective eating in a child with autism spectrum disorder. BMJ Case Rep. 2014 Mar 20. [Epub ahead of print]

Lewis CD, Traboulsi EI, Rothner AD, Jeng BH. Xerophthalmia and intracranial hypertension in an autistic child with vitamin A deficiency. J Pediatr Ophthalmol Strabismus. 2010 Mar 26. [Epub ahead of print]

Vyas AK, White NH. Case of hypercalcemia secondary to hypervitaminosis in a 6-year-old boy with autism. Case Rep Endocrinol. 2011;2011:424712.