**1. Introduction**

Autism Spectrum Disorders (ASD) consist of a set of complex neurodevelopmental disorders characterised by impaired communication and social behaviour, and repetitive or stereotyped pattern of behaviour. The prevalence of ASD has increased in recent decades to 0.6-1% [1-3]. Broadening of the diagnostic criteria and increased awareness of autism among parents and health professionals likely contribute to the prevalence increase. However, the reason for the increase is not completely understood. Alterations of developmental processes and gene expression profiles have been identified in ASD but neuronal mechanisms and perturbations of neuronal networks underlying the ASD phenotype are unclear. ASD varies in severity and the clinical phenotype reflects multifactorial background [4]. Co-morbidity with some genetic syndromes and autism exist [5]. Affected males outnumber females roughly 4:1 [6-8]. The family studies imply that the autism has a strong genetic basis but no single high risk genes for ASD are identified [9]. Hundreds of de novo mutations with extreme locus heterogeneity have been identified in genes encoding protein network ranked for autism candidate genes [10]. Recent studies suggest that environmental factors could play a much larger role in susceptibility to ASD than earlier expected [4]. Since the population's genetic inheritance is relatively constant over longer periods, the increased incidence rate of autism during last decades could indicate that there is an important environmental component in the etiology of autism [11].

The symptoms of ASD appear in childhood and persist throughout the person's lifetime. Since there is evidence that an initiating event for autism may appear early in intrauterine life, an

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early diagnosis and treatment could be possible. However, the early diagnostic uncertainties and the nature of deficits unfortunately often delay the diagnosis. Besides limited social and communication skills, behavioural and emotional symptoms, abnormal sensory responses and activity levels often seen as attention deficits are common in ASD individuals [12-14]. Intel‐ lectual disability associates often with autism (30-60%) and epilepsy is seen in about 25% of individuals diagnosed with ASD [1, 8, 15]. Many autistic children exhibit behavioural and sleep problems and aggression towards others or self as symptoms of their condition.

physiological functions occur through the action of proteins involved in the regulation of zinc homeostasis such as metallothioneins which bind zinc with high affinity but, at the same time, release free zinc ions in response to oxidative/nitrosative stress that modulates the expression of zinc-dependent genes, activates antioxidant enzymes and has impact on immune response [21]. Zinc may induce the synthesis of metallothionein that act as a scavengers of metals and free radicals [22, 23]. The release of zinc from metallothioneins represents an intracellular response to stress. Biochemical modification of stress-related proteins might represent a useful

Oxidative Stress and Dietary Interventions in Autism: Exploring the Role of Zinc, Antioxidant Enzymes and Other…

http://dx.doi.org/10.5772/57512

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A number of studies have implicated disturbed zinc metabolism to the neurobiology of autism. Many children with ASD are shown to suffer from zinc deficiency and excess copper levels [24, 25]. Low levels of zinc during development can adversely affect learning, memory, and attention [26]. Zinc deficiency has also been shown to associate with a behavioural syndrome characterized by reduced activity levels and slower response times [27]. Zinc is an important nutrient for the immune system, and supplementation with this mineral has been shown to reduce the duration of the common cold by suppressing the viral inflammation in the respi‐ ratory tract [28-30]. Zinc deficiency can result in a weakened intestinal immune system, which makes the digestive tract more prone to infection with certain parasites [31]. It is also reported in maldigestion and/or malabsorption that often associate with autism [32, 33]. There is evidence that zinc is required for intestinal wound healing and zinc is necessary to maintain

A variety of environmental factors that affect brain development during embryonic and perinatal periods may play a part in autism. These risk factors could be influenced by genetic mutations in genes involved in the inflammatory response such as TNF-alpha and interleukin 6 (IL-6) and in the maintenance of zinc homeostasis such as metallothioneins [34]. Il-6 has been associated with neurodegenerative disorders and autism [35, 36]. In genetic studies, measur‐ able differences associated with genes that encode enzymes and other proteins impacting the methylation cycle, the folate metabolism and the glutathione system are reported between children with autism and healthy controls [37]. In particular differences in allele frequency and/or significant gene-gene interactions for genes encoding the reduced folate carrier (RFC), transcobalamin II (TCN2), catechol-O-methyltransferase (COMT), methylenetetrahydrofolate reductase (MTHFR), and one of the glutathione transferases (GST M1) are found. These genetic results, combined with the biochemical observations of dysfunction in the methylation cycle, strongly suggest that variations in genes associated with this cycle and its related biochemistry

How genetic mutations contribute to autism is not clearly understood. A hypothesis for treatment of a genetic form of autism with intellectual disability and epilepsy caused by BCKDH (Branched Chain Ketoacid Dehydrogenase Kinase) mutations by dietary amino acid supplementation was recently put forward [38]. Mutations inactivating a protein called BCKDkinase prevent the breakdown of branched-chain amino acids. Normally, the amino acids are transported across the blood-brain barrier by special transporters. Since plasma amino acids compete with each other for transportation into the brain, the brain amino acid concentration will be substantially changed by low levels of branched-chain amino acids that affect the

target to influence zinc homeostasis and related mechanisms in autism.

the health and integrity of epithelial cells that line the intestines.

are involved in the genetic predisposition to developing autism.

Unfortunately, there is no cure for autism and symptomatic treatment optimal for autistic individuals without major side effects is lacking. Improvement in patient care – both treatment and rehabilitation – directly influence the prospects of individuals with neurological disorders, including their abilities to integrate to the society and need for life-time support. Behavioural problems in ASD increase stress of people who take care of autistic children and dealing with these problems can be extremely challenging. The child's symptoms might result from an overload of demands (allergens, infectious agents, toxins, psychosocial stresses, inflammation, oxidative stress) in combination with weakness or susceptibilities, which impaired ability to respond to the demands (impaired energy production, inherited enzyme weakness, nutritional deficiencies, osteopathic disorders, sleep deficits, hormone imbalances, etc.) and increased vulnerability. There is evidence that many interrelated environmental factors may act as risk factors to development of autism [16].
