Autism: Review of a Groundbreaking Study on Vitamins, Minerals, and Metabolism This is a summary of some of the findings of a 2011 study published in Nutrition and Metabolism that concluded that, “The autism group had many statistically significant differences in their nutritional and metabolic status, including biomarkers indicative of vitamin insufficiency, increased oxidative stress, reduced capacity for energy transport, sulfation, and detoxification. Several of the biomarker groups were significantly associated with variations in the severity of autism. These nutritional and metabolic differences are generally in agreement with other published results and are likely amenable to nutritional supplementation. Research investigating treatment and its relationship to the comorbidities and etiology of autism is warranted.” Any nutrition professional who works with children with autism is urged to read this research in its entirety. Levels of vitamin B12, folate, and methionine were similar between autistic and neurotypical children. The children with autism, on average, had lower levels of biotin and trended toward lower levels of vitamin B5, vitamin E, and total carotenoids (these nutrients were also more likely to fall below reference range in the neurotypical children). Vitamin A did not differ between groups. The autistic children had somewhat higher levels of vitamin C than the neurotypical children. It seems that some children with autism need more vitamin B6, but another subset of autistic children has high levels of vitamin B6. In numerous double-blind, placebo-controlled studies, about 50% of children or adults with autism benefitted from megadoses of vitamin B6—doses of 500 to 1000 milligrams (mg), which is 250 to 500 times the Recommended Dietary Allowance (RDA). However, the authors of this study speculate that perhaps megadoses are not necessary and that high doses (20 to 40 times the RDA) would suffice. Autistic children had higher levels of total choline, which is hypothesized to relate to an impairment in the conversion of choline to acetylcholine. Contrary to some other research, in this study plasma vitamin D levels did not differ in the autistic group, when compared to the control group. N-methylnicotinamide (a metabolite of vitamin B3) was higher in the autism group, although blood niacin levels were very similar between groups. In regression analysis, vitamin B6, vitamin C, N-methlynicotinamide, and vitamin K were the most consistently significant variables. The children in this study had lower levels of lithium, consistent with previous research showing the same. Animals fed a lithium-deficient diet were shown to have lower levels of immunity and more infections; in previous studies, children with autism were found to have more ear infections than children who do not have autism. Animals that are lithium deficient also have decreased monoamine oxidase activity, which can have repercussions on neurotransmitter activity; low lithium levels are associated with many psychiatric disorders. The authors of this study state that, “low-level lithium supplementation may be beneficial for mood stabilization in this group.” Serum iron and ferritin levels were not different between the children with autism and those without in this study; however, other researchers have found that autistic children are at higher risk for anemia. The authors of this study hypothesize that anemia is possibly more of a problem among younger children than it is for older children. Elevated red blood cell (RBC) iron correlated with severity of autism in this study, although the clinical significance of this is unclear. The children with autism had a slightly higher level of copper, a slightly lower level of magnesium, and slightly higher levels of RBC potassium, RBC phosphorus, and RBC boron. The slightly higher levels of RBC phosphorus, potassium, and boron are perhaps a statistic artifact, because they are minor fluctuations. Although the slightly lower level of magnesium in whole blood suggests that magnesium supplementation might prove beneficial, the RBC magnesium was normal, so at most this suggests only a minor need. From a combination of results from this study and from previous research, it appears that there is a “significant subset of children with autism with low levels of iodine, which is one of the leading causes of mental retardation worldwide.” The authors of this study call for further investigation of iodine status and thyroid status. Age differences, study size, or geographic/dietary differences may explain the differences between this study and other research. In regression analysis, the most consistently significant variables were RBC calcium, RBC iron, whole blood and RBC zinc, and RBC potassium. Roughly 80% of sulfate is produced by oxidation of methionine or cysteine, which comes from dietary proteins. Sulfation is important for detoxification, inactivation of catecholamines, synthesis of brain tissue, and sulfation of mucin proteins (line the gastrointestinal tract). In this study and others, total plasma sulfate and sulfate in the plasma were lower in children with autism, compared to neurotypical controls. In another study, high sulfate was found in the urine of children with autism. It was suggested that low levels of adenosine triphosphate (ATP) are a significant contributor to decreased sulfate in children with autism. In one study, 38% of children had improved levels of urinary sulfite and sulfate levels after being given 50 micrograms (mcg) of molybdenum. This study showed only a weak correlation of RBC molybdenum with plasmafree sulfate and no significant correlation with plasma total sulfate. Consistent with other research, the children with autism in this study had decreased reduced glutathione, increased oxidized glutathione, and increased ratio of oxidized/reduced glutathione. This children with autism also had decreased S-adenosylmethionine (SAM) in RBC, which is consistent with other studies. SAM is converted to S-adenosylhomocysteine (SAH) by the transfer of a methyl group; the ratio of SAM/SAH is a measure of methylation capacity. In this study and another, the children with autism had a slightly higher level of SAH in plasma, but in two other studies no differences were found. In several studies, children with autism were found to have a decreased SAM/SAH ratio, although the size of the decrease has varied. In addition, the finding of very high plasma uridine suggests confirmation of impaired methylation among the children with autism. In this study, 33% of the children had elevated plasma adenosine in the autism group, which is consistent with two previous studies and seems to suggest an impairment in adenosine deaminase (adenosine levels are normal). This may partially explain the decreased SAM/SAH ratio. The finding of increased nitrotyrosine is a good marker for oxidative stress in children with autism, and is consistent with other measurements of oxidative stress. The authors of this study contend that “the problems with SAM, glutathione, and oxidative stress suggest that children with autism need increased antioxidant support, folinic acid (not folic), and vitamin B12 to support the methionine cycle.” In a study done in 2004, 16 of the 20 children with autism were taking a multivitamin and mineral supplement containing 400 micrograms (μg) of folic acid and 3 μg of vitamin B12, but they still had abnormal methylation. Folinic acid was necessary to normalize methylation. In regression analysis, free sulfate was the most consistently significant variable, followed by oxidized glutathione, and SAM. The children in the autism group had lower levels of ATP, nicotinamide adenine dinucleotide (NADH), and nicotinamide adenine dinucleotide phosphate (NADPH), but had normal levels of niacin, which the authors hypothesize might suggest an impairment in the formation of NADH from niacin. Decreased levels of ATP might cause the decreased muscle tone and endurance often seen in children with autism and also may relate to the impaired mitochondrial function reported in some children with autism. It seems likely that increased oxidative stress is related to the decreased levels of plasma ATP, NADH, and NADPH. In regression analysis, NADH and ATP were the two significant variables. The patients with autism had elevated glutamate, which is the most prominent neurotransmitter in charge of modulating synaptic plasticity (very important for memory, learning, and regulation, as well as gene expression modulation and postsynaptic excitation/inhibition). Too much glutamate can lead to oxidative stress and mitochondrial damage, and may play a role in neurodegeneration. Peripherally, glutamate plays a role in taste, skin pain sensation, and pancreatic exocrine function. Glutamate also is possibly linked to behavioral problems and may indicate an increased need for vitamin B6, which is necessary for conversion of glutamate to glutamine. The children in the autism spectrum disorder group also had decreased tryptophan, perhaps secondary to decreased protein intake and/or impaired digestion of protein. However, because most of the other amino acids were within normal limits, it was more likely impaired digestion. Decreased tryptophan is likely to impair serotonin synthesis. In a previous double-blind, placebocontrolled crossover study, a 24-hour diet low in tryptophan followed by a tryptophan-deficient amino acid drink led to a significant worsening in behavior among adults with autism. The autism spectrum disorder group also had slightly increased serine and slightly decreased phenylalanine and tyrosine, which probably are related because tyrosine is derived from phenylalanine. The authors conclude that some children with autism would benefit from either increased protein intake, use of digestive enzymes containing proteases, and/or supplements of tryptophan and phenylalanine. Among secondary amino acids, the children in the autism group had increased betaaminoisobutyrate, which could indicate either an increased rate of DNA turnover or an inhibition of the conversion of beta-aminoisobutyrate into the intermediates that eventually lead to the citric acid cycle. The children in the autism group also had significantly lower levels of taurine, possibly because of an impairment of the conversion of methionine first to cysteine and then to taurine or because of increased wasting of taurine in the urine, as found in previous research. In regression analysis, the most consistently significant variables among the primary amino acids were proline and serine. Among secondary amino acids, ethanolamine and beta-aminoisobutyrate were the most consistently significant variables. Reference and recommended reading 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 (London). 2011;8(1):34. doi:10.1186/1743-7075-8-34. Contributed by Elaine M. Koontz, RD, LD/N Review Date 3/13 K-0670