Fundamental Role of Neurochemicals Aberration in the Pathogenesis of Autism Spectrum Disorders

AIM: The aim of this research was to establish the perturbation of reliable biomarkers implicated in the pathophysiology of autism to help in the early diagnosis and to be as targets in the treatment of autism spectrum disorders (ASDs) in children and to spotlight into the complex crosstalk between these biomarkers. PATIENS AND METHODS: This study included 90 autistic children aged from 2 to 7 years old, who were classified into two groups, the atypical autism of 30 children and the childhood autism. The childhood autism group was further divided into mild-moderate autism group and severe autism group each of 30 children. The control group included 30 matched healthy children. All the participants were subjected to full psychiatric examinations, psychological investigations, and biochemical measurements, including gamma-aminobutaric acid (GABA), serotonin, dopamine (DA) in plasma, and brain-derived neurotrophic factor (BDNF) in serum. RESULTS: The autistic groups showed a highly significant increase in GABA, serotonin, DA, and BDNF levels compared to the control. Of note, the levels of GABA, DA, and BDNF were significantly increased with the increased disease severity. Furthermore, a significant positive correlation between BDNF levels and both GABA and DA levels in the childhood autism group has been recorded. CONCLUSION: The present clinical setting provides new insight into the fundamental role of BDNF in the brain of autistic children as any alterations of its level due to GABA increment cause change in serotonin and DA levels which have empirical evidence in the pathophysiology of ASD. The results received in this research, create a fertile base for the setup of particular targets in the intervention of this ailment

Autism and Fragile X: Is There a Neurochemical Link?

BACKGROUND:Autism and Fragile X syndrome are intertwined. This study aimed at assessing Serotonin, Glutamate, and Gama Amino Butyric Acid (GABA) in autism and Fragile X syndrome patients and to detect possible neurochemical similarities between the 2 disorders that can be used as metabolic biomarkers.DESIGN AND METHODS: Eighty subjects divided into four groups, two diseased groups (20 male patients with Autism and 20 males with Fragile X syndrome) and two control groups (20 neurotypical male controls and 20 Down syndrome male patients) were included. Estimation of Serotonin, Glutamate and GABA were done using Enzyme linked Immunosorbent Assay (ELISA), Tandem Mass Spectrometry and high-pressure liquid chromatography (HPLC), respectively.RESULTS: Serotonin was, exclusively, significantly low in autistic children. GABA was significantly high in both autistic and Fragile X children only, but not in Down syndrome children. Glutamate was significantly high in children with autism, Fragile X and Down syndrome Children.CONCLUSIONS: Autism and Fragile X syndrome share some neurochemical similarities with regards of high Glutamate and GABA levels while Serotonin was significantly different in the 2 disorders and may be used a unique biomarker for autism

Serum Interleukin-5 Changes in Partly Controlled Atopic Asthmatic Children

BACKGROUND: Cytokines including Interleukin-5 play a key role in orchestrating the chronic inflammation of asthma. We aimed to determine the level of serum IL-5 in partly controlled atopic asthma in children and to assess the effect of different therapies on their levels.METHODS: The study included 40 children aged 6-12 years with partly controlled asthma. Cases were randomly divided into two groups; group ‘A’ receiving Leukotriene modifiers and group ‘B’ receiving inhaled corticosteroids; each for two months. They were compared to 20 healthy non-asthmatic, matched controls. Serum IL-5 was measured for cases on the first visit and two months after therapy. Absolute eosinophilic count and serum Ig-E were determined. Pulmonary function testing was performed using spirometer at the beginning and two months after regular therapy.RESULTS: Serum Interleukin-5 was significantly increased in asthmatic children during exacerbation and was significantly decreased after treatment. ROC curve analysis showed significant difference of IgE and PEFR after treatment with leukotriene modifier only.CONCLUSION: Serum IL-5 seems to have a role in asthma pathogenesis. Efficiency of the two therapies (ICs & LTA) was similar in this group of patients. Both treatments led to significant decline in serum IL-5, IgE levels and eosinophilic count

Screening of dystrophin gene deletions in Egyptian patients with DMD/BMD muscular dystrophies

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations within the dystrophin gene. Our study has identified 100 Egyptian families collected from the Human Genetics Clinic, National Research Center, Cairo. All cases were subjected to complete clinical evaluation pedigree analysis, electromyography studies, estimation of serum creatine phosphokinase enzyme (CPK) levels and DNA analysis. Multiplex PCR using 18 pairs of specific primers were used for screening of deletion mutations within the dystrophin gene. A frequency of 55% of deletions were found among the families. Sixty per cent of detected deletions involved multiple exons spanning the major or the minor hot spot of the dystrophin gene. The remainder 40% involved single exon deletions, which mainly involved exon 45. Comparing these findings with frequencies of other countries it was found that our figures fall within the reported range of 40%-60% for deletions. The distribution of deletions in our study and other different studies was variable and specific ethnic differences do not apparently account for specific deletions. In addition this study concluded that employment of the 18 exon analysis is a cost effective and a highly accurate (97% detection rate) method to be considered when planning to launch a nationwide program

A study of blood serotonin and serotonin transporter promoter variant (5-HTTLPR) polymorphism in Egyptian autistic children

Background: Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder with onset during early childhood. Most studies have reported an elevation in platelet serotonin in persons with autism. The serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain uptakes 5-HT from extracellular spaces. It is also present in platelets, where it takes up 5-HT from plasma. Polymorphisms in serotonin transporter gene (SLC6A4) were frequently studied in many neuropsychiatric disorders. Materials and Methods: We have measured the plasma 5-HT levels in 20 autistic male children and 20 control male children by the enzyme-linked immunosorbent assay (ELISA) method. In addition, the SLC6A4 promoter region (5-HTTLPR) insertion/deletion (I/D) polymorphism was studied, using whole genomic DNA. Results: Plasma serotonin was significantly low in autistic children compared to control (P = 0.001), although correlation to severity of autism was not significant. The frequency of short (S) allele in autism cases was 10% and in the control group it was absent. Conclusion: Our study demonstrated an increased prevalence of 5-HTTLPR S allele in autism subjects. Significantly decreased plasma serotonin was detected in autism subjects, with no significant relationship between 5-HTTLPR genotype and plasma 5-HT being evident

Protective effect of ashwagandha (Withania somnifera) against neurotoxicity induced by aluminum chloride in rats

Objective: To evaluate the neuroprotective effect of ashwagandha extract against aluminum chloride-induced neurotoxicity in rats. Methods: Rats were divided into control, aluminum-intoxicated rats treated daily with aluminum trichloride (AlCl3) (100 mg/kg, orally) for 30 d and aluminum-intoxicated animals protected by receiving daily ashwagandha extract (200 mg/kg, orally) one hour before AlCl3 administration for 30 d. Levels of lipid peroxidation, nitric oxide, reduced glutathione and tumor necrosis factor-α were measured in the cortex, hippocampus and striatum. In addition, the activities of Na+, K+, ATPase and acetylcholinesterase were determined in the three studied brain regions. Results: Aluminum increased the levels of lipid peroxidation and nitric oxide in the cortex, hippocampus and striatum and decreased the reduced glutathione level in the hippocampus and striatum. In rats protected with ashwagandha extract, non significant changes were observed in lipid peroxidation, nitric oxide and reduced glutathione. In addition, ashwagandha extracts prevented the increased activity of acetylcholinesterase and Na+, K+, ATPase induced by AlCl3 in the cortex, hippocampus and striatum. The present findings also showed that the significant increase in tumor necrosis factor-α induced by AlCl3 in the cortex and hippocampus was prevented by ashwagandha extract. Conclusions: The present results suggest that ashwagandha extract possesses antioxidant and anti-inflammatory effects against aluminum neurotoxicity. In addition, ashwagandha extract could prevent the decline in cholinergic activity by maintaining normal acetylcholinesterase activity. The later effect could recommend the use of ashwagandha as a memory enhancer

MTHFR Genetic Polymorphism As a Risk Factor in Egyptian Mothers with Down Syndrome Children

Recent reports linking Down syndrome (DS) to maternal polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) gene locus have generated great interest among investigators in the field. The present study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in the MTHFR gene as maternal risk factors for DS. Forty two mothers of proven DS outcomes and forty eight control mothers with normal offspring were included. Complete medical and nutritional histories for all mothers were taken with special emphasis on folate intake. Folic acid intake from food or vitamin supplements was significantly low (below the Recommended Daily Allowance) in the group of case mothers compared to control mothers. Frequencies of MTHFR 677T and MTHFR 1298C alleles were significantly higher among case mothers (32.1% and 57.1%, respectively) compared to control mothers (18.7% and 32.3%, respectively). Heterozygous and homozygous genotype frequencies of MTHFR at position 677 (CT and TT) were higher among case mothers than controls (40.5% versus 25% and 11.9% versus 6.2%, respectively) with an odds ratio of 2.34 (95% confidence interval [CI] 0.93–5.89) and 2.75 (95% CI 0.95–12.77), respectively. Interestingly, the homozygous genotype frequency (CC) at position 1298 was significantly higher in case mothers than in controls (33.3% versus 2.1% respectively) with an odds ratio of 31.5 (95% CI 3.51 to 282.33) indicating that this polymorphism may have more genetic impact than 677 polymorphism. Heterozygous genotype (AC) did not show significant difference between the two groups. We here report on the first pilot study of the possible genetic association between DS and MTHFR 1298A/C genotypes among Egyptians. Further extended studies are recommended to confirm the present work

Gastrointestinal alterations in autism spectrum disorder: What do we know?

There is an emerging body of evidence associating children having autism spectrum disorder (ASD) with gastrointestinal (GI) symptoms, such as abdominal pain, chronic diarrhea, constipation, vomiting, gastroesophageal reflux, intestinal infections, and increased intestinal permeability. Moreover, in many studies, large differences in the composition of intestinal microbiota and metabolic products between ASD patients and controls were reported. Deepening the role and the biology of the gut microbiome may be fundamental to elucidate the onset of GI symptoms in ASD individuals and their etiopathogenetic causes. The gut-brain axis may affect brain development and behaviors through the neuroendocrine, neuroimmune, and autonomic nervous systems

Dietary adequacy of Egyptian children with autism spectrum disorder compared to healthy developing children

Although the etiology and pathology of autism spectrum disorder (ASD) is still poorly understood, a number of environmental, anthropological, neurobiological and genetic factors have been related to the pathophysiology of ASD, even the impact of oxidative stress response related to the environment and nutrition intake. Usual recommended dietary habits are based on the combination of behavioral and dietary or nutraceutical interventions together with pharmacotherapy. Investigations about a reliable relationship between diet and ASD are still lacking. The present study aimed at comparing dietary regimens and habits of normally developing apparently healthy children, without diagnosed ASD, with a pediatric population of individuals affected by autistic disorder. Assessments of nutritional and anthropometric data, in addition to biochemical evaluation for nutrient deficiencies, were performed. A total of 80 children with autistic disorder and 80 healthy, normally developing pediatric individuals were enrolled in the study. Parents were asked to complete the standardized questionnaire regarding the different types of food and the proportion of a serving for their children. Biochemical analysis of micro- and macronutrients were also done. Plotting on the Egyptian sex-specific anthropometric growth (auximetric) chart, absolute weights as well as weight-related for age classes, were significantly higher in cases than healthy controls. No differences between groups were observed in regard to total kilocalories (kcal), carbohydrates, and fat intake. A total of 23.8% of children with autistic disorder vs. 11.3% in the healthy control group had a nutrient intake with features below the Recommended Dietary Allowance (RDA) of protein. Children with autistic disorder showed low dietary intake of some micronutrients; calcium (Ca), magnesium (Mg), iron (Fe), selenium (Se) and sodium (Na), also they had significantly high intake of potassium (K) and vitamin C compared to healthy controls. Serum Mg, Fe, Ca, folate and vitamin B12 in children with autistic disorder were significantly low compared with healthy children. Significant positive correlations between serum Mg, Fe, Ca, vitamin B12 and folate and their levels in food were present. These results confirmed that different nutritional inadequacy was observed in Egyptian children with autistic disorder. The evidence reported in the present study should recommend screening of the nutritional status of ASD children for nutrient adequacy to reduce these deficiencies by dietary means or by administering appropriate vitamin and mineral supplements. Nutritional intervention plan should be tailored to address specific needs

MTHFR genetic polymorphism as a risk factor in Egyptian mothers with Down syndrome children. Dis

Abstract. Recent reports linking Down syndrome (DS) to maternal polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) gene locus have generated great interest among investigators in the field. The present study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in the MTHFR gene as maternal risk factors for DS. Forty two mothers of proven DS outcomes and forty eight control mothers with normal offspring were included. Complete medical and nutritional histories for all mothers were taken with special emphasis on folate intake. Folic acid intake from food or vitamin supplements was significantly low (below the Recommended Daily Allowance) in the group of case mothers compared to control mothers. Frequencies of MTHFR 677T and MTHFR 1298C alleles were significantly higher among case mothers (32.1% and 57.1%, respectively) compared to control mothers (18.7% and 32.3%, respectively). Heterozygous and homozygous genotype frequencies of MTHFR at position 677 (CT and TT) were higher among case mothers than controls (40.5% versus 25% and 11.9% versus 6.2%, respectively) with an odds ratio of 2.34 (95% confidence interval [CI] 0.93-5.89) and 2.75 (95% CI 0.95-12.77), respectively. Interestingly, the homozygous genotype frequency (CC) at position 1298 was significantly higher in case mothers than in controls (33.3% versus 2.1% respectively) with an odds ratio of 31.5 (95% CI 3.51 to 282.33) indicating that this polymorphism may have more genetic impact than 677 polymorphism. Heterozygous genotype (AC) did not show significant difference between the two groups. We here report on the first pilot study of the possible genetic association between DS and MTHFR 1298A/C genotypes among Egyptians. Further extended studies are recommended to confirm the present work