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      Increased Glutamate and Homocysteine and Decreased Glutamine Levels in Autism: A Review and Strategies for Future Studies of Amino Acids in Autism

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      Author(s): 1 , 2 , *
      Publication date (Electronic):
      Journal: Disease markers
      Publisher: Hindawi Publishing Corporation

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          Abstract

          There are many reports about the significant roles of some amino acids in neurobiology and treatment of autism. This is a critical review of amino acids levels in autism. No published review article about the level of amino acids in autism was found. The levels of glutamate and homocystein are increased in autism while the levels of glutamine and tryptophan are decreased. Findings regarding the plasma levels of taurine and lysine are controversial. The urinary levels of homocysteine and essential amino acids in both the untreated and treated autistic children are significantly less than those in the controls. The current literature suffers from many methodological shortcomings which needed to be considered in future studies. Some of them are age, gender, developmental level, autism symptoms severity, type of autism spectrum disorders, medical comorbidities, intelligent quotient, diet, concomitant medications, body mass index, and technical method of assessment of amino acids.

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          Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism.

          S. Jill James, Paul Cutler, Stepan Melnyk … (2004)
          Autism is a complex neurodevelopmental disorder that usually presents in early childhood and that is thought to be influenced by genetic and environmental factors. Although abnormal metabolism of methionine and homocysteine has been associated with other neurologic diseases, these pathways have not been evaluated in persons with autism. The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism. Plasma concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were measured in 20 children with autism and in 33 control children. On the basis of the abnormal metabolic profile, a targeted nutritional intervention trial with folinic acid, betaine, and methylcobalamin was initiated in a subset of the autistic children. Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children. An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.
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            The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention.

            Amanda L. Sheldon, Michael B Robinson (2015)
            Extracellular concentrations of the predominant excitatory neurotransmitter, glutamate, and related excitatory amino acids are maintained at relatively low levels to ensure an appropriate signal-to-noise ratio and to prevent excessive activation of glutamate receptors that can result in cell death. The latter phenomenon is known as 'excitotoxicity' and has been associated with a wide range of acute and chronic neurodegenerative disorders, as well as disorders that result in the loss of non-neural cells such as oligodendroglia in multiple sclerosis. Unfortunately clinical trials with glutamate receptor antagonists that would logically seem to prevent the effects of excessive receptor activation have been associated with untoward side effects or little clinical benefit. In the mammalian CNS, the extracellular concentrations of glutamate are controlled by two types of transporters; these include a family of Na(+)-dependent transporters and a cystine-glutamate exchange process, referred to as system X(c)(-). In this review, we will focus primarily on the Na(+)-dependent transporters. A brief introduction to glutamate as a neurotransmitter will be followed by an overview of the properties of these transporters, including a summary of the presumed physiologic mechanisms that regulate these transporters. Many studies have provided compelling evidence that impairing the function of these transporters can increase the sensitivity of tissue to deleterious effects of aberrant activation of glutamate receptors. Over the last decade, it has become clear that many neurodegenerative disorders are associated with a change in localization and/or expression of some of the subtypes of these transporters. This would suggest that therapies directed toward enhancing transporter expression might be beneficial. However, there is also evidence that glutamate transporters might increase the susceptibility of tissue to the consequences of insults that result in a collapse of the electrochemical gradients required for normal function such as stroke. In spite of the potential adverse effects of upregulation of glutamate transporters, there is recent evidence that upregulation of one of the glutamate transporters, GLT-1 (also called EAAT2), with beta-lactam antibiotics attenuates the damage observed in models of both acute and chronic neurodegenerative disorders. While it seems somewhat unlikely that antibiotics specifically target GLT-1 expression, these studies identify a potential strategy to limit excitotoxicity. If successful, this type of approach could have widespread utility given the large number of neurodegenerative diseases associated with decreases in transporter expression and excitotoxicity. However, given the massive effort directed at developing glutamate receptor agents during the 1990s and the relatively modest advances to date, one wonders if we will maintain the patience needed to carefully understand the glutamatergic system so that it will be successfully targeted in the future.
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              Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices.

              S.Hossein Fatemi, Amy R Halt, Joel Stary … (2002)
              A limited number of reports have demonstrated abnormalities involving the glutamate and gamma amino butyric acid systems in blood and platelets of subjects with autism. To further investigate these studies, brain levels of rate limiting enzyme, glutamic acid decarboxylase, which is responsible for normal conversion of glutamate to gamma amino butyric acid in the brain, were investigated. Postmortem cerebellar and parietal cortices of age (mean +/- SD for controls 23 +/- 4.2, autistic 25.2 +/- 5.2 cerebellum; controls 23.5 +/- 4.8, autistic 21.6 +/- 3.8 parietal cortex), gender and postmortem interval-matched autistic and control subjects (n = 8 control, n = 5 autism, cerebellum; n = 4 control, n = 5 autism, parietal cortex) were subjected to SDS-PAGE and western blotting. Brain levels of glutamic acid decarboxylase proteins of 65 and 67 kDa and beta-actin were determined. Glutamic acid decarboxylase protein of 65 kDa was reduced by 48% and 50% in parietal and cerebellar (p <.02) areas of autistic brains versus controls respectively. By the same token, glutamic acid decarboxylase protein of 67 kDa was reduced by 61% and 51% in parietal (p <.03) and cerebellar areas of autistic brains versus controls respectively. Brain levels of beta-actin were essentially similar in both groups. The observed reductions in glutamic acid decarboxylase 65 and 67 kDa levels may account for reported increases of glutamate in blood and platelets of autistic subjects. Glutamic acid decarboxylase deficiency may be due to or associated with abnormalities in levels of glutamate/gamma amino butyric acid, or transporter/receptor density in autistic brain.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Dis Markers
                Journal ID (iso-abbrev): Dis. Markers
                Journal ID (publisher-id): DM
                Title: Disease markers
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 0278-0240
                ISSN (Electronic): 1875-8630
                Publication date (Print): 2013
                Publication date (Electronic): 12 September 2013
                Volume: 35
                Issue: 5
                Pages: 281-286
                Affiliations
                1Research Center for Psychiatry and Behavioral Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
                2Department of Psychiatry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
                Author notes

                Academic Editor: Grant Izmirlian

                Article
                DOI: 10.1155/2013/536521
                PMC ID: 3787567
                PubMed ID: 24167375
                SO-VID: d91ffa3f-ba20-4efa-95e9-955bacdb28e6
                Copyright © Copyright © 2013 Ahmad Ghanizadeh.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 11 June 2013
                Date accepted : 12 August 2013
                Categories
                Subject: Review Article

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