Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contact us Login 
  • Users Online:689
  • Home
  • Print this page
  • Email this page


 
 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 6  |  Issue : 1  |  Page : 73-80

Dietary and antioxidant therapy for autistic children: Does it really work?


1 Department of Dietetics and Nutrition, Hamad Medical Corporation, Doha, Qatar
2 Columbus County Department of Public Health, North Carolina, USA

Date of Web Publication11-Jun-2018

Correspondence Address:
Ms. Lubna A. G. Mahmood
Department of Dietetics and Nutrition, Hamad Medical Corporation, Doha
Qatar
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_82_17

Rights and Permissions
  Abstract 


Autism or autism spectrum disorder are both general terms for a group of complex neurodevelopment disorders that are characterized by social impairments, communication difficulties, impaired social interaction, verbal and nonverbal communication, repetitive, and stereotyped behaviors as well. Autism has a significant genetic basis; even the genetics of autism are complex and mostly unclear if it is explained by rare multigene interactions of common genetic variants or rare mutations with major effects. Autism is known as a severe neurodevelopmental disorder with a poorly understood etiology. The oxidative stress in autism has been studied at both the membrane level as long as measuring products of lipid peroxidation, antioxidants, and detoxifying agents (such as glutathione) involved in the defense system against reactive oxygen species. Antioxidants have some potential therapeutic value in the treatment of certain neurodegenerative diseases though catabolizing H2O2. Since mitochondrial dysfunction is involved in the pathogenesis of many neurodegenerative diseases such as autism disorder, so developing new therapeutic strategies targeting the mitochondria may shed a new light to autism treatment. Given the evidence hinting at neurological changes following the implementation of dietary intervention in related conditions, future research might also benefit from looking at brain structural and biochemical changes in cases of altered state of consciousness (ASCs) adopting dietary intervention. Indeed, the gut-brain relationship, seemingly so important to explaining the role of dietary intervention in best-responder cases, is a woefully under-researched area with ASCs in mind.

Keywords: Antioxidants, autism, diet, gluten, therapy


How to cite this article:
Mahmood LA, Al Saadi R, Matthews L. Dietary and antioxidant therapy for autistic children: Does it really work?. Arch Med Health Sci 2018;6:73-80

How to cite this URL:
Mahmood LA, Al Saadi R, Matthews L. Dietary and antioxidant therapy for autistic children: Does it really work?. Arch Med Health Sci [serial online] 2018 [cited 2018 Dec 15];6:73-80. Available from: http://www.amhsjournal.org/text.asp?2018/6/1/73/234115




  Introduction Top


Autism spectrum disorder (ASD) is a severe neurodevelopment disorder with usual onset before 3 years of age. It is characterized by impairments in social orientation, communication, and repetitive behaviors. In addition to behavioral impairment, ASD is associated with high prevalence of autoimmune disease, gastrointestinal (GI) disease, dysbiosis, and mental retardation.[1],[2],[3],[4] The prevalence of autism has increased over the last several decades. The incidence of ASD in the United States increased in 2008 to 1 in 88 children.[5] Increased prevalence has great effects on public health implications and has stimulated intense research into potential etiologic factors.[6] Although the etiology and pathology are poorly understood, different factors have been suggested to affect autism. For example, immune factors, environmental, neurochemical, genetic factors, and oxidative stress are commonly found in patients with autism. Extensive studies have demonstrated that oxidative stress plays a vital role in the pathology of several neurological diseases such as Alzheimer's disease, Down syndrome, Parkinson's disease, schizophrenia, bipolar disorder, and autism.[7],[8]

Oxidative stress occurs when reactive oxygen species (ROS) levels exceed the antioxidant capacity of a cell. It acts as a mediator in brain injury, strokes, and neurodegenerative diseases.[9],[10],[11] Thus, the control of ROS production is necessary for physiologic cell function. The ROS within the cells are neutralized by antioxidant defense mechanisms including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) enzymes. The increased production of ROS both centrally (in the brain) and peripherally (in the plasma) may result in the reduction of brain cell numbers leading to autism pathology and apoptosis.[8],[9],[10],[11],[12] Some studies showed that a specific antioxidant supplement and some dietary managements may be an effective therapy for some features of autism and lower irritability in children with autism as well as reduced the children's repetitive behaviors. However, the researchers emphasized that the findings must be confirmed in a larger trial before supplements can be recommended for children with autism. Therefore, the purpose of this review article is to collate and critically evaluate published scientific data pertaining to the novel and emerging nonconventional dietary treatments for ASD.[13]


  Research Criteria and Methodology Top


A search of periodical literature by the author involving dietary therapy and autistic children was carried out. Items were identified initially through health-oriented indexing services such as Medline, Health STAR and Cinahl, using the identifiers “dietary therapy,” “autism,” “children,” “antioxidant,” and “gluten/casein-free diet.” An extensive search was also carried out on educational database ERIC. Through an electronic search, 55 studies were identified.


  What Is Autism? Top


Autism or ASD are both general terms for a group of complex neurodevelopment disorders that are characterized by social impairments, communication difficulties, impaired social interactions, verbal and nonverbal communication, and repetitive and stereotyped behaviors. Autism can also be called an autistic disorder, or a classical ASD, which is the most severe form of ASD. Other conditions can be a milder form known as the Asperger syndrome, pervasive developmental disorder or childhood disintegrative disorder.[1] ASD varies extensively in symptoms and severity and may go unrecognized, especially when it is masked by more debilitating handicaps in mildly affected children. Experts have estimated that by age 8, one out of 88 children will have an ASD. Often, it can be diagnosed even by parents through very early indicators. However, an evaluation by experts usually includes: No babbling or pointing by age 1, no response to name, poor eye contact, no single words by 16 months or two-word phrases by age 2, excessive lining up of toys or objects, loss of language or social skills, and no smiling or social responsiveness.[2]

In addition, there are many later indicators that can be distinguished. These include impaired ability to make friends with peers, absence or impairment of imaginative and social play, inflexible adherence to specific routines or rituals, restricted patterns of interest that are abnormal in intensity or focus, impaired ability to initiate or sustain a conversation with others. Stereotyped, repetitive, or unusual use of language and preoccupation with certain objects or subjects are also seen.[3]

Autistic individuals may display many forms of repetitive or restricted behavior, which can be categorized as follows: stereotypy is repetitive movement, such as head rolling, body rocking, or hand flapping; sameness is resistance to change; refusing to be interrupted or insisting that the furniture not be moved. Self-injury includes the movements that can injure the person such as skin-picking, head-banging, hand-biting, and eye-poking. In addition, ritualistic behavior involves an unvarying pattern of daily activities, such as a dressing ritual or unchanging menu. This is strictly associated with independent validation and has suggested combining the two factors.[4] Compulsive behavior can be intended and appears to follow the rules, such as arranging objects in lines or stacks. Restricted behavior is limited in activity, focus, or interest, such as preoccupation with a single television program, game, or toy. There is no single self-injurious or repetitive behavior that seems to be specific to autism, but only autism appears to have an elevated pattern of occurrence and severity of these behaviors.[5]


  Autism's Causes and Symptoms Top


It has long been presumed that there is a significant common cause at the genetic or cognitive level as long as neural levels for autism's characteristic triad of symptoms. However, there is growing suspicion that autism is instead a complex disorder whose core aspects have distinct causes that often cooccur.[6] Autism has a significant genetic basis; however, the genetics of autism are complex and mostly unclear if they are explained by rare multigene interactions of common genetic variants or rare mutations with major effects. This complexity is due to different interactions among multiple genes, epigenetic factors, and the environment. They do not change the DNA sequences but still they are heritable and may influence the gene expression.[7] Naturally, autism disorder cannot be traced to a single chromosome abnormality or a mendelian mutation; in which stable and undecomposable characters controlled entirely or overwhelmingly by a single genetic locus are transmitted over many generations. While none of the genetic syndromes associated with ASDs have been shown to selectively cause ASD. Numerous genes have been located, with only small effects attributable to any particular gene. The wide range of autistic individuals with unaffected family members can result from spontaneous duplications or deletions in genetic material during meiosis.[8] Other evidence regarding environmental causes has not been confirmed by reliable studies. Environmental factors may have a wide range starting from some infectious diseases, solvents, phthalates, diesel exhaust polychlorinated biphenyls, and phenols that are used in plastic products, pesticides, some drugs and vaccines, prenatal stress, and brominated flame retardants.[9]


  The Mechanisms of Autism Disorder Top


Autism's mechanism can be divided into two areas: the neuropsychological linkages between brain structures and behaviors and the pathophysiology of brain structures and processes associated with autism. Unlike other neurodevelopmental disorders, autism does not have a significant and clear mechanism at either systems level, cellular, or molecular. It is primarily known as an intellectual disability. Autism typically includes a large set of disorders with diverse mechanisms or it may be a combination of a few disorders caused by some mutations on a few common molecular pathways.[10] ASD appears as a result of developmental factors affecting many of the functional brain systems while disturbing the brain development timing. Neuroanatomical studies suggested that the ASD mechanism may include brain development alteration soon after conception. The brains of autistic children tend to grow faster than usual just after birth and are then followed by relatively slower growth during childhood.[11]

Different hypotheses of the molecular and cellular bases of the pathological early overgrowth include an excess of neurons that may cause a local overconnectivity in the key brain regions, unbalanced excitatory and inhibitory networks, disturbance in the neuronal migration during early gestation, or abnormal formation of dendritic spines or synapses which may contribute to epilepsy. This finding helps to explain why ASD and epilepsy can be associated.[12] The autism disorder-related patterns of the aberrant activation and low function of the brain differ depending on whether brain activity is nonsocial or doing social tasks. There is evidence for reduced functional connectivity of the default network, social or emotional processing, and goal-directed thinking.[13] The underconnectivity theory of autism indicated that this condition is marked by an excess of low-level processes, along with under-functioning high-level neural connections and synchronization.[14] Functional neuroimaging and brainwave studies suggested that adults with autism disorder have localized overconnectivity in the cortex with weak functional connections between the frontal lobe and the rest of the cortex. Other evidence has demonstrated that underconnectivity is mainly within each hemisphere of the cortex while autism is mainly a disorder of the association cortex.[8] Other researchers have found that during the transient changes to the brain's electrical activity in response to stimuli, there is some evidence for differences in individuals with autism in respect to their attention, information storage, visual stimuli, novelty detection, orientation to auditory, language, and face processing.[15] On the other hand, in the area of genetics, there appears to be a relationship between schizophrenia and autism due to duplication and deletion of some chromosomes. Researchers have noticed that autism is significantly more common in a combination with 1q21.1 deletion syndrome, while chromosome 15 (15q13.3), chromosome 16 (16p13.1), and chromosome 17 (17p12) are inconclusive [Table 1].[16],[17]
Table 1: Chromosomal abnormalities in Autism

Click here to view


The cognitive theories have proposed a link with two major categories autistic brain and behavior. The first category focuses on deficits in social cognition; however, most studies have demonstrated no evidence of impairment in autistic individuals' ability to understand other people's basic intentions or goals, while other studies suggested that impairments are found mostly in understanding the complex social emotions or in considering individuals' viewpoints.[16],[17] The second category focuses on the general and nonsocial processing including the working memory, inhibition, and planning. This category is not satisfactory on its own as nonsocial theories have difficulty in explaining communication difficulties and social impairment while the social cognition theories poorly address the repetitive behavior and autism's rigid and repetitive behaviors. That's why the combined theory which, based on multiple deficits, can prove to be more useful in assessing progress and autism's disorder mechanism.[18]


  Oxidative Stress in Autism Top


Autism is known as a severe neurodevelopmental disorder with a poorly understood etiology. The oxidative stress in autism has been studied at the membrane level by measuring products of lipid peroxidation, antioxidants, and detoxifying agents (such as glutathione) involved in the defense system against ROS. Lipid peroxidation markers are mostly elevated in autism indicating that oxidative stress is increased in this disease. The levels of major antioxidant serum proteins, which include ceruloplasmin (copper-binding protein) and transferrin (iron-binding protein) are decreased in children with autism.[19] There is a positive correlation between the reduced levels of loss of previously acquired language skills in children with autism and these proteins. The alterations in transferrin and ceruloplasmin levels can lead to abnormal copper and iron metabolism in autism.[20] The membrane phospholipids which are the prime target of ROS are altered in autism. The levels of phosphatidylserine are increased while the level of phosphatidylethanolamine are decreased in the erythrocyte membrane of children with autism as compared to their unaffected siblings.[21]

Several studies have shown that in autism, alterations occur in the activity of antioxidant enzymes such as SOD, catalase, and GSH-Px. Moreover, the altered glutathione levels as well as the homocysteine/methionine metabolism, excitotoxicity (is the pathological process by which neurons are damaged and killed by the over activations of receptors), appear to increase inflammation, along with mitochondrial and environmental factors that can increase vulnerability to the oxidative stress in autism disorder. Many studies have suggested that the increase in oxidative stress in autism might contribute to the development of this disorder.[22] This mechanism links oxidative stress with the abnormalities of membrane lipids, aberrant immune response, inflammation, excitotoxicity, and impaired energy metabolism. This may lead to pathogenesis and clinical symptoms of autism.[22],[23],[24]


  Dietary Therapy Top


Gluten/casein-free diet

The gluten-free casein-free (GFCF) diet is a diet which involves avoiding all foodstuffs which contain gluten and casein. Gluten is a protein found in some cereals such as wheat, oats, rye, and barley. While, casein is a protein found in some dairy products such as milk, butter, and yoghurt. Some researchers believe that autistic people are unable to digest gluten and/or casein properly and that any undigested gluten and casein (in the form of harmful peptides) enter the central nervous system (CNS) and damage the brain. The GFCF diet is designed to remove all gluten and/or casein, which is supposed to lead to improvements in areas such as IQ, communication, and social skills.[25]

The GFCF diet is widely used by families of children with ASDs. Despite its popularity, there is limited evidence in support of the diet. Studies on the GFCF dietary intervention for children with ASDs suggest that some children may positively respond to implementation of the dietary intervention. Other research suggests that children diagnosed with ASD can be classified into subpopulations based on various factors including GI abnormalities and immune function. A cross-sectional study analyzes parental report data collected using a 90-item online questionnaire from 387 parents or primary caregivers of children diagnosed with ASD on the efficacy of the GFCF diet. Results showed that diet efficacy among children whose parents reported the presence of GI symptoms, food allergy diagnoses, and suspected food sensitivities included greater improvement in ASD behaviors, physiological symptoms, and social behaviors compared with children whose parents reported none of these symptoms, diagnoses, or sensitivities. Parental report of strict diet implementation, indicated by complete gluten/casein elimination and infrequent diet errors during and outside of parental care, also corresponded to improvement in ASD behaviors, physiological symptoms, and social behaviors. These findings suggest that various intricacies related to diet implementation and GI and immune factors may play a role in differentiating diet responders from diet nonresponders and substantiate the importance of further investigations into the various, nuanced factors that influence efficacy of the intervention among children with ASDs.[52] Feeding and nutrition are major issues for many children with autism. These new studies showed that both nutritional deficiencies and nutritional excesses are common whereas the consequences of all these nutritional imbalances have not been defined yet.[26]

In the early 1990s, Knivsberg and Reichelt et al. based at various sites in Norway published initial and follow-up behavioral and psychometric data for a small group of people (n = 15) with altered state of consciousness (ASCs) on a GFCF diet. For many, these studies were the first primary evidence for the potential effectiveness of a GFCF diet for ASCs adding scientific validity to the array of anecdotal observations previously described and strengthened by the long period of dietary exclusion between publications. The downside to these initial studies lay predominantly with the open, nonrandomized methodology employed together with a lack of suitable blinding; thus introducing potential bias into the interpretation of results obtained. The Norwegian team has subsequently been involved in further experimental studies of GFCF dietary intervention for ASCs. Two of these studies were randomized controlled trials (RCTs) lasting for 1 and 2 years, respectively. Both studies indicated significant positive group effects on several measures of behavior and development indicative of potential improvements to symptoms for some children with ASCs on diet.[27]

There is a continued requirement for further study on the potential role of dietary intervention for ASCs. Future controlled trials including blinded and placebo elements are necessary carrying appropriate power of study by sample size and duration. Further thought should also be given to the concept of best-and non-responders to this type of intervention. So for example, (1) screening for GI and/or potentially relevant pathogenic comorbidity, (2) measuring gut hyperpermeability, (3) examining gut microbial populations and food-related enzyme activities, and (4) ascertaining the presence of inflammatory processes, either peripherally in GI tissue or more centrally, might all be included as parameters for future dietary investigations. Similarly, measuring any relationship between behavior and GI function over the course of dietary intervention may offer some information about any connection between these factors.[27],[28],[29]

One more new study compared anthropometric values, nutrient intake, the healthy-eating index and food variety in children with ASD, 20 on a GFCF diet and 85 on a regular diet in Valencia (Spain) using 3-day food diaries. Those on the GFCF diet had a lower weight, body mass index, and total energy, pantothenic acid, calcium, phosphorus, and sodium intake, but a higher intake of fiber, legumes, and vegetables. Further, the GFCF diet group had a better quality of fat intake, but needed supplementation with Vitamin D. RCTs are required to explore not only the long-term effects of this diet on anthropometric and nutritional status but also behavioral symptoms, in children with ASD.[28]

Dietary supplement

Several dietary supplements have been also shown to provide treatment of autism. Omega-3 polyunsaturated fatty acids have been shown to inhibit amyloidosis and beta-amyloid (Aβ) production in cells. Omega-3 supplements have antioxidant properties and have been suggested to reduce the brain Aβ levels for early-onset autism.[29] In addition, there is substantial in vitro data indicating that curry omega-3 supplement is a promising agent in the treatment or prevention of autism. It has anti-inflammatory, antioxidant, and anti-amyloid pathology activity. Various other factors along with those supplements have been shown to interact with antioxidants in attenuating autism neuropath physiology.[30] Nonetheless, important information regarding its bioavailability, tolerance, safety, is lacking. Few children with ASD need most of the micronutrients they are commonly given as multivitamins. This often leads to excess intake that may place children at risk for adverse effects. When supplements are used, careful attention should be given to adequacy of Vitamin D and calcium intake.[31]


  Antioxidant Therapy in the Treatment of Autism Top


Antioxidants are exogenous or endogenous compounds that can either react with free radicals to neutralize them or to reduce their formation. Therefore, they are potentially protecting the cell from oxidative injury.[32] Free radicals, including ROS, may start chain reactions that are very damaging to cells as well as tissues. Since the biochemistry of free radicals injury is complex, many substances might be acting as potential antioxidants and providing protection against diseases and limiting their consequences. The classification of antioxidants is based on whether compounds are primarily exogenous or endogenous along with their underlying mechanisms of action.[33] In order for the antioxidant compound to enter the brain parenchyma, it must penetrate the blood–brain barrier (BBB) to allow for a critical therapeutic concentration inside the CNS. Antioxidants can be lipid soluble or water soluble which results in varying degrees of BBB penetration. Those which can readily pass through the BBB are good therapeutic candidates to be used in the neurologic disorders.[34] Coenzyme Q10 (CoQ10) (ubiquinone) is a lipid-soluble mitochondrial antioxidant cofactor which readily crosses the BBB and has been shown to be neuroprotective in several animal models with neurodegenerative diseases and neurodevelopmental disorders.[35]

Antioxidants are also known as “free radical scavengers” since they terminate these chain reactions by inhibiting further oxidation reactions and removing free radical intermediates. Antioxidants are produced by the body and are found in various plants and foods. During a homeostatic state, there is a balance of antioxidants and ROS so no damage is occurring. Tissue damage occurs only when free radicals overwhelm the antioxidant reserves in the body.[36] Several double-blind and placebo-controlled therapeutic trials of the use of potent antioxidants such as Vitamin C, carnosine, zinc, reduced glutathione, fish oil (rich in EPA), melatonin, and Vitamin B6 in combination with magnesium in autism are ongoing.[37] In double-blind, placebo-controlled clinical trials, treatment with high-dose Vitamin C, carnosine or combined Vitamin B6 and magnesium improved the behavior of individuals with autism. In addition, melatonin has been reported to be useful in the treatment of sleep disorders in autism.[37]

Vitamins, minerals and carotene

Antioxidants can be lipid soluble (i.e., Vitamin A and E) or water soluble (i.e., Vitamin C and B complex) and possess varying degrees of BBB penetrance. Vitamin C, Vitamin E (α-tocopherol), and β-carotene are known to be as exogenous chain-breaking antioxidants helping to inhibit dementia pathogenesis in mammalian cells and decrease the free-radical-mediated damages caused by toxic chain reactions in neuronal cells.[32] The most important lipid-phase antioxidant is α-tocopherol since it is a powerful lipid-soluble chain-breaking antioxidant which is found in lipid membranes and circulating the lipoproteins and low-density lipoprotein particles as well.[33] In experimental studies, Vitamin E has been shown to attenuate toxic effects of β-amyloid and improve cognitive performance in patients with moderately severe neurological impairment. Treatment with α-tocopherol (2000 IU a day) reduces neuronal damage and slows the progression of the diseases, which indicates that the use of α-tocopherol may delay clinically important functional deterioration in autistic patients.[34]

Vitamins suppress brain lipid peroxidation and significantly reduce the Aβ levels. However, if Vitamin E supplementation is started after amyloid plaques are already deposited, no significant effect is observed on the amyloidotic phenotype despite a reduction in brain oxidative stress.[35],[36],[37],[38],[39],[40] Any mechanistic hypothesis for autism must accommodate the successful application of high-dose of B complex vitamins. Multiple controlled trials have demonstrated that Vitamin B6 in combination with magnesium can improve the behavior in many autistic children. B complex vitamins can lower the excitotoxic threshold.[40] However, treatment with those vitamins is highly vulnerable to any damage caused by the oxidative species (i.e., hydroxyl and singlet oxygen) and any deficiency in the level of B complex vitamins can impair the myriad enzymes along with neurotransmitters in autism.[41]

Decreased zinc status in autism has been clearly established as a potentiator of oxidative stress. Zinc deficiency increases lipid peroxidation and free radicals in cell membranes, mitochondria, and other tissues. It also decreases the total glutathione, glutathione-S-transferase, Vitamin E, and SOD levels. On the other hand, copper excess is evident in autism disorder. Higher levels of total serum copper, higher unbound serum copper, and lower ceruloplasmin are found in groups of autistic children. Copper is highly pro-oxidant and this is especially true of unbound copper; however, supplemental copper is rarely need in autism. Even small doses of copper have been suggested to produce negative behavioral effects.[42] Hypothetically, oxidative stress can decrease the clinical zinc retention; therefore, it seems that zinc is an essential constituent of copper-zinc SOD, which is a key antioxidant enzyme.[43]

Enzymes and mitochondria-targeted antioxidants

Preventive antioxidants, including GSH-Px, metal chelators, SOD enzymes, and a pro-survival mitochondrial antioxidant enzyme-MnSOD along with cytoplasmic antioxidant enzyme-copper-zinc SOD, repair enzymes such as lipases and DNA repair enzymes. All have been shown to be effective in neuronal protection against many oxidative damages and can be used to treat behavioral and cognitive symptoms of autism disorder.[40] Other antioxidants such as CoQ10, NADH, α-lipoic acid (LA), glutathione and Mito Q, Szeto Schiller peptide all have some potential therapeutic value in the treatment of certain neurodegenerative diseases through catabolizing H2O2[Table 2].[43] Mitochondrial dysfunction is involved in the pathogenesis of many neurodegenerative diseases such as autism disorder, so developing new therapeutic strategies targeting the mitochondria may shed a new light to on autism treatment.[41],[42],[43],[44],[45],[46],[47],[48],[49],[50] Since the overproduction of ROS by mitochondria can be considered one of the major factors that contribute to the autism disorder, many of the drugs targeting mitochondria that have been tested or are in development belong to metabolic antioxidants. Those antioxidants including R-α-LA as well as CoQ10 can easily penetrate not only the cell, but also the mitochondria to provide the greatest protection.[51]
Table 2: Autism-related antioxidants

Click here to view


Estrogen

Estrogen has been shown to perform as an antioxidant to protect the neurons from the Aβ toxicity. Although estrogen might have neuroprotective effects, it does not appear to improve either the cognition or functional problems in patients with autism disease.[52],[53],[54] One study has cited a link between the X chromosome (one of the two sex chromosomes in humans) and autism and evaluated the incidence of autism in turner syndrome. It has been demonstrated that estrogen therapy might be initiated in coordination with the final phase of growth hormone therapy and they are often begun at the time of normal puberty, around 12 years of age.[54] AT present, there is no evidence that suggests or supports the use of estrogen as an antioxidant for decreasing the risk of autism or slowing the progression of existing autism. Consequently, additional studies need to be conducted for the determination of whether the treatment with estrogen can prevent or delay the onset of autism or reduce its severity.[55]


  Conclusion Top


Antioxidants have some potential therapeutic value in the treatment of certain neurodegenerative diseases though catabolizing H2O2. Since mitochondrial dysfunction is involved in the pathogenesis of many neurodegenerative diseases such as autism disorder, developing new therapeutic strategies targeting the mitochondria may shed a new light autism treatment. However, there is a need for large, well-designed studies that link metabolites, cofactors, and gene pathways with the clinical and behavioral outcomes to be conducted in children with ASDs. Future risk factor analysis of ASDs should include consideration of multiple biomarkers of nutrients involved in pathways and the interaction of genotypes with nutritional status. Finally, but perhaps just as important, is a need to focus on the measurement of clinical changes to symptoms alongside statistical changes to psychometric or other assessment tools in view of the restrictiveness of the dietary regime. This point in particular reflects the fact that not everyone who might potentially benefit from dietary intervention will necessarily be able to implement such a restrictive regime, or indeed, want to.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Caronna EB, Milunsky JM, Tager-Flusberg H. Autism spectrum disorders: Clinical and research frontiers. Arch Dis Child 2008;93:518-23.  Back to cited text no. 1
[PUBMED]    
2.
Rutter M. Incidence of autism spectrum disorders: Changes over time and their meaning. Acta Paediatr 2005;94:2-15.  Back to cited text no. 2
[PUBMED]    
3.
Levy SE, Mandell DS, Schultz RT. Autism. Lancet 2009;374:1627-38.  Back to cited text no. 3
[PUBMED]    
4.
Gerber JS, Offit PA. Vaccines and autism: A tale of shifting hypotheses. Clin Infect Dis 2009;48:456-61.  Back to cited text no. 4
[PUBMED]    
5.
Johnson CP, Myers SM; American Academy of Pediatrics Council on Children with Disabilities. Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007;120:1183-215.  Back to cited text no. 5
[PUBMED]    
6.
Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK, Levy SE, et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health 2007;28:235-58.  Back to cited text no. 6
[PUBMED]    
7.
Happé F, Ronald A. The 'fractionable autism triad': A review of evidence from behavioural, genetic, cognitive and neural research. Neuropsychol Rev 2008;18:287-304.  Back to cited text no. 7
    
8.
Buxbaum JD. Multiple rare variants in the etiology of autism spectrum disorders. Dialogues Clin Neurosci 2009;11:35-43.  Back to cited text no. 8
[PUBMED]    
9.
Abrahams BS, Geschwind DH. Advances in autism genetics: On the threshold of a new neurobiology. Nat Rev Genet 2008;9:341-55.  Back to cited text no. 9
[PUBMED]    
10.
Penn HE. Neurobiological correlates of autism: A review of recent research. Child Neuropsychol 2006;12:57-79.  Back to cited text no. 10
[PUBMED]    
11.
London E. The role of the neurobiologist in redefining the diagnosis of autism. Brain Pathol 2007;17:408-11.  Back to cited text no. 11
[PUBMED]    
12.
Geschwind DH. Autism: Many genes, common pathways? Cell 2008;135:391-5.  Back to cited text no. 12
[PUBMED]    
13.
Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci 2008;31:137-45.  Back to cited text no. 13
[PUBMED]    
14.
Casanova MF. The neuropathology of autism. Brain Pathol 2007;17:422-33.  Back to cited text no. 14
[PUBMED]    
15.
Blumberg SJ, Bramlett MD, Kogan MD, Schieve LA, Jones JR, Lu MC, et al. Changes in prevalence of parent-reported autism spectrum disorder in school-aged U.S. Children: 2007 to 2011-2012. Natl Health Stat Report 2013;65:1-7.  Back to cited text no. 15
    
16.
Arndt TL, Stodgell CJ, Rodier PM. The teratology of autism. Int J Dev Neurosci 2005;23:189-99.  Back to cited text no. 16
[PUBMED]    
17.
Hamilton AF. Goals, intentions and mental states: Challenges for theories of autism. J Child Psychol Psychiatry 2009;50:881-92.  Back to cited text no. 17
[PUBMED]    
18.
Baron-Cohen S. Autism: The empathizing-systemizing (E-S) theory [PDF]. Ann N Y Acad Sci 2009;1156:68-80.  Back to cited text no. 18
[PUBMED]    
19.
Abha C, Ved C. Oxidative stress in autism. Pathophysiology 2006;13:171-81.  Back to cited text no. 19
    
20.
Hill EL. Executive dysfunction in autism. Trends Cogn Sci 2004;8:26-32.  Back to cited text no. 20
[PUBMED]    
21.
O'Hearn K, Asato M, Ordaz S, Luna B. Neurodevelopment and executive function in autism. Dev Psychopathol 2008;20:1103-32.  Back to cited text no. 21
    
22.
Zoroglu SS, Armutcu F, Ozen S, Gurel A, Sivasli E, Yetkin O, et al. Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism. Eur Arch Psychiatry Clin Neurosci 2004;254:143-7.  Back to cited text no. 22
[PUBMED]    
23.
Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids 2005;73:379-84.  Back to cited text no. 23
[PUBMED]    
24.
Kern JK. Purkinje cell vulnerability and autism: A possible etiological connection. Brain Dev 2003;25:377-82.  Back to cited text no. 24
[PUBMED]    
25.
Baird G, Simonoff E, Pickles A, Chandler S, Loucas T, Meldrum D, et al. Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: The Special Needs and Autism Project (SNAP). Lancet 2006;368:210-5.  Back to cited text no. 25
[PUBMED]    
26.
Baron-Cohen S, Scott FJ, Allison C, Williams J, Bolton P, Matthews FE, et al. Prevalence of autism-spectrum conditions: UK school-based population study. Br J Psychiatry 2009;194:500-9.  Back to cited text no. 26
[PUBMED]    
27.
Jones DP. Redefining oxidative stress. Antioxid Redox Signal 2006;8:1865-79.  Back to cited text no. 27
[PUBMED]    
28.
Yorbik O, Sayal A, Akay C, Akbiyik DI, Sohmen T. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot Essent Fatty Acids 2002;67:341-3.  Back to cited text no. 28
[PUBMED]    
29.
Söğüt S, Zoroğlu SS, Ozyurt H, Yilmaz HR, Ozuğurlu F, Sivasli E, et al. Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism. Clin Chim Acta 2003;331:111-7.  Back to cited text no. 29
    
30.
Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L. Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem 2009;42:1032-40.  Back to cited text no. 30
[PUBMED]    
31.
Jung HA, Min BS, Yokozawa T, Lee JH, Kim YS, Choi JS, et al. Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol Pharm Bull 2009;32:1433-8.  Back to cited text no. 31
    
32.
Nakamura YK, Read MH, Elias JW, Omaye ST. Oxidation of serum low-density lipoprotein (LDL) and antioxidant status in young and elderly humans. Arch Gerontol Geriatr 2006;42:265-76.  Back to cited text no. 32
[PUBMED]    
33.
Dumont M, Lin MT, Beal MF. Mitochondria and antioxidant targeted therapeutic strategies for Alzheimer's disease. J Alzheimers Dis 2010;20 Suppl 2:S633-43.  Back to cited text no. 33
[PUBMED]    
34.
Montiel T, Quiroz-Baez R, Massieu L, Arias C. Role of oxidative stress on beta-amyloid neurotoxicity elicited during impairment of energy metabolism in the hippocampus: Protection by antioxidants. Exp Neurol 2006;200:496-508.  Back to cited text no. 34
[PUBMED]    
35.
Devore EE, Grodstein F, van Rooij FJ, Hofman A, Stampfer MJ, Witteman JC, et al. Dietary antioxidants and long-term risk of dementia. Arch Neurol 2010;67:819-25.  Back to cited text no. 35
[PUBMED]    
36.
Fusco D, Colloca G, Lo Monaco MR, Cesari M. Effects of antioxidant supplementation on the aging process. Clin Interv Aging 2007;2:377-87.  Back to cited text no. 36
[PUBMED]    
37.
Kamat CD, Gadal S, Mhatre M, Williamson KS, Pye QN, Hensley K, et al. Antioxidants in central nervous system diseases: Preclinical promise and translational challenges. J Alzheimers Dis 2008;15:473-93.  Back to cited text no. 37
    
38.
Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 2002;287:3230-7.  Back to cited text no. 38
[PUBMED]    
39.
Siedlak SL, Casadesus G, Webber KM, Pappolla MA, Atwood CS, Smith MA, et al. Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer's disease. Free Radic Res 2009;43:156-64.  Back to cited text no. 39
[PUBMED]    
40.
James AM, Sharpley MS, Manas AR, Frerman FE, Hirst J, Smith RA, et al. Interaction of the mitochondria-targeted antioxidant MitoQ with phospholipid bilayers and ubiquinone oxidoreductases. J Biol Chem 2007;282:14708-18.  Back to cited text no. 40
[PUBMED]    
41.
Liu S, Kawai K, Tyurin VA, Tyurina YY, Borisenko GG, Fabisiak JP, et al. Nitric oxide-dependent pro-oxidant and pro-apoptotic effect of metallothioneins in HL-60 cells challenged with cupric nitrilotriacetate. Biochem J 2001;354:397-406.  Back to cited text no. 41
[PUBMED]    
42.
Acar G, Idiman F, Idiman E, Kirkali G, Cakmakçi H, Ozakbaş S, et al. Nitric oxide as an activity marker in multiple sclerosis. J Neurol 2003;250:588-92.  Back to cited text no. 42
    
43.
Thirumalai SS, Shubin RA, Robinson R. Rapid eye movement sleep behavior disorder in children with autism. J Child Neurol 2002;17:173-8.  Back to cited text no. 43
[PUBMED]    
44.
Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T, et al. Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol 2009;157:1270-7.  Back to cited text no. 44
[PUBMED]    
45.
Noseworthy MD, Bray TM. Zinc deficiency exacerbates loss in blood-brain barrier integrity induced by hyperoxia measured by dynamic MRI. Proc Soc Exp Biol Med 2000;223:175-82.  Back to cited text no. 45
[PUBMED]    
46.
Rosseneau S. Aerobic Throat and Gut Flora in Children with Regressive Autism and Gas-Trointestinal Signs. Defeat Autism Now (DAN) Conference. Washington, D.C. April 16-19, 2004 Defeat Autism Now Conference; 2004. p. 101-5.  Back to cited text no. 46
    
47.
Kruidenier L, Kuiper I, Lamers CB, Verspaget HW. Intestinal oxidative damage in inflammatory bowel disease: Semi-quantification, localization, and association with mucosal antioxidants. J Pathol 2003;201:28-36.  Back to cited text no. 47
[PUBMED]    
48.
Dhillon S, Hellings JA, Butler MG. Genetics and mitochondrial abnormalities in autism spectrum disorders: A review. Curr Genomics 2011;12:322-32.  Back to cited text no. 48
[PUBMED]    
49.
Marco EJ, Skuse DH. Autism-lessons from the X chromosome. Soc Cogn Affect Neurosci 2006;1:183-93.  Back to cited text no. 49
[PUBMED]    
50.
Raymond LJ, Deth RC, Ralston NV. Potential role of selenoenzymes and antioxidant metabolism in relation to autism etiology and pathology. Autism Res Treat 2014;2014:164938.  Back to cited text no. 50
[PUBMED]    
51.
Whiteley P, Shattock P, Knivsberg AM, Seim A, Reichelt KL, Todd L, et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci 2012;6:344.  Back to cited text no. 51
[PUBMED]    
52.
Pennesi CM, Klein LC. Effectiveness of the gluten-free, casein-free diet for children diagnosed with autism spectrum disorder: Based on parental report. Nutr Neurosci 2012;15:85-91.  Back to cited text no. 52
[PUBMED]    
53.
Stewart PA, Hyman SL, Schmidt BL, Macklin EA, Reynolds A, Johnson CR, et al. Dietary supplementation in children with autism spectrum disorders: Common, insufficient, and excessive. J Acad Nutr Diet 2015;115:1237-48.  Back to cited text no. 53
[PUBMED]    
54.
Whiteley P, Haracopos D, Knivsberg AM, Reichelt KL, Parlar S, Jacobsen J, et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci 2010;13:87-100.  Back to cited text no. 54
[PUBMED]    
55.
Marí-Bauset S, Llopis-González A, Zazpe I, Marí-Sanchis A, Suárez-Varela MM. Nutritional impact of a gluten-free casein-free diet in children with autism spectrum disorder. J Autism Dev Disord 2016;46:673-84.  Back to cited text no. 55
    



 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Research Criteri...
What Is Autism?
Autism's Cau...
The Mechanisms o...
Oxidative Stress...
Dietary Therapy
Antioxidant Ther...
Conclusion
References
Article Tables

 Article Access Statistics
    Viewed676    
    Printed27    
    Emailed0    
    PDF Downloaded84    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]