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Serum copper and zinc levels in individuals with autism spectrum disorders
Abstract
Trace elements play a critical role in the pathogenesis of autism spectrum disorders (ASD). The aim of this study was to investigate the serum levels of zinc (Zn) and copper (Cu) in Chinese children with ASD. Sixty patients (48 males, 12 females) diagnosed with ASD and 60 healthy sex-matched and age-matched control participants were assessed for serum Zn and Cu content at admission. The severity of ASD was also evaluated using the Childhood Autism Rating Scale (CARS) score. The results indicated that the mean serum Zn levels and Zn/Cu ratio were significantly lower in children with ASD compared with normal cases (P<0.001, respectively), whereas serum Cu levels were significantly higher (P<0.001). There was a significant negative association between Zn/Cu and CARS scores (r=-0.345, P=0.007). On the basis of the receiver operating characteristic curve, the optimal cut-off value of serum levels of Zn/Cu as an indicator for an auxiliary diagnosis of autism was projected to be 0.665, which yielded a sensitivity of 90.0% and a specificity of 91.7%; the area under the curve was 0.968 (95% confidence interval, 0.943-0.993). In conclusion, these results suggested an association between serum levels of Zn and Cu and ASD among Chinese patients, and the Zn/Cu ratio could be considered a biomarker of ASD.
... Regarding the studies that evaluated Zn concentrations in relation to other conditions associated with ASD, Li et al. (2014) observed lower Zn concentrations in hair and serum for the ASD group with and without catatonia compared with the control group, although with no significant differences [42]. Skalny et al. (2020) observed significantly lower concentrations of Zn in the hair in a group with concomitant ASD and ADHD compared to the control group [25]. ...
... Regarding the studies that evaluated Zn concentrations in relation to other conditions associated with ASD, Li et al. (2014) observed lower Zn concentrations in hair and serum for the ASD group with and without catatonia compared with the control group, although with no significant differences [42]. Skalny et al. (2020) observed significantly lower concentrations of Zn in the hair in a group with concomitant ASD and ADHD compared to the control group [25]. ...
... Among the studies that evaluated Zn concentrations in relation to ASD severity, Li et al. (2014) associated the serum Zn/Cu ratio with the clinical severity of ASD (defined by the CARS score) [42]. Sehgal et al. (2019) associated Zn deficiency in whole blood with ASD in 55% of individuals with severe ASD, but with no significant difference between the groups with ASD severity degrees [41]. ...
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, the prevalence of which has increased in children and adolescents over the years. Studies point to deficiency of trace elements as one of the factors involved in the etiology of the disorder, with zinc being one of the main trace elements investigated in individuals with ASD. The aim of this review is to summarize scientific evidence about the relationship between zinc status and ASD in children and adolescents. This review has been registered in the International Prospective Register of Systematic Reviews (registration number CRD42020157907). The methodological guidelines adopted were in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were selected from an active investigation of the PubMed, Scopus, LILACS, and Google databases to search for observational studies. Fifty-two studies from twenty-two countries were included. The sample sizes ranged from 20 to 2635, and the participants ranged from 2 to 18 years old. Nine types of biological matrices were used, with hair, serum, and plasma being the most frequently used in the evaluation of zinc concentrations. Significant differences in zinc concentrations between the ASD and control groups were observed in 23 studies, of which 19 (36%) showed lower zinc concentrations in the ASD group. The classification of studies according to methodological quality resulted in high, moderate, and low quality in 10, 21, and 21 studies, respectively. In general, we did not observe a significant difference between zinc concentrations of children and adolescents with ASD compared to controls; however, studies point to an occurrence of lower concentrations of Zn in individuals with ASD. This review reveals that more prospective studies with greater methodological rigor should be conducted in order to further characterize this relation.
... Available literature suggests strong geographical variations of Zn and Cu levels among ASD children in different countries [8,19] and a close link with Zn/Cu ratio [3,20] and Cp levels [15,21]. Bangladesh is plagued by maternal and child Zn deficiency, as well as rising ASD incidence [5,22]. ...
... A total of 67 subjects were recruited based on effect size [20]. For this purpose, initially, 49 ASD children with an age range of 2-9 years were included from the Parents Forum for Differently Able Children, Mohakhali, Dhaka. ...
... In this particular investigation, the mean plasma Zn level of the study group was significantly lower than that of the control group in children who were between the ages of 2 and 9 years old. In various blood samples, researchers in Egypt [25], Turkey [26], the United Kingdom [9], China [20] and Romania [3] came to almost identical conclusions, which were in line with the findings of the current study. However, despite the fact that the mean Zn level in children with ASD was lower than in healthy children, this study did not identify any statistically significant differences in the mean Zn levels between the study group and the control group in any of the age groups ranging from 2 to 5 years or from 6 to 9 years. ...
Neural and cognitive processes require zinc and copper homeostasis and a normal zinc/copper ratio. Ceruloplasmin, an intrinsic antioxidant protein, maintains copper homeostasis, which might also influence autism spectrum disorder (ASD). ASD children are frequently reported with altered levels of these elements with wide geographical variations. This study evaluated any alteration in plasma zinc, copper, zinc/copper ratio and serum ceruloplasmin levels in Bangladeshi ASD children with respect to healthy controls. A cross-sectional study was conducted on 67 children aged 2 to 9 years of both sexes. Among them, 35 had ASD, while 32 were age, sex and body mass index (BMI) matched apparently healthy children. Plasma zinc and copper levels were estimated by the flame atomic absorption spectrophotometry method. Serum ceruloplasmin levels were estimated by the immunoturbidimetric method. Zinc and zinc/copper ratio in the 2–9 years old ASD children group were significantly lower (p=0.032 and p=0.002 respectively). On the other hand, copper (p=0.020) and ceruloplasmin (p = 0.045) levels were significantly higher than those of apparently healthy children. ASD was significantly associated with zinc deficiency (p=0.000) and copper toxicity (p=0.05). All children were again divided into 2–5 and 6–9 years age groups according to laboratory reference values for zinc and copper. Copper toxicity was significantly associated with ASD in the 2–5 years old age group (p=0.011), with a significant difference in plasma copper levels (p=0.009) and zinc/copper ratio (p=0.001) but not serum ceruloplasmin levels (p=0.110) compared to healthy controls. Serum ceruloplasmin was positively associated with plasma copper in ASD children of all age groups. This study shows that ASD in Bangladesh can be associated with low plasma zinc and high plasma copper and serum ceruloplasmin levels.
... Moreover, metal micronutrients may also have a role in the development of ASD. Cu and Zn are essential for cognitive development, appropriate brain function, and heavy metal detoxification, among other functions [11][12][13]. According to previous research, children with ASD are more likely to suffer from Zn lower, high Cu levels, and a low Zn/ Cu ratio [12][13][14][15]. ...
... Cu and Zn are essential for cognitive development, appropriate brain function, and heavy metal detoxification, among other functions [11][12][13]. According to previous research, children with ASD are more likely to suffer from Zn lower, high Cu levels, and a low Zn/ Cu ratio [12][13][14][15]. The Zn/Cu ratio has been proposed as a biomarker for ASD by certain authors [16,17]. ...
... Si ou Li et al. reported that the mean serum Zn levels and Zn/Cu ratio were significantly lower in children with ASD in Mudanjiang city compared with normal children, whereas their serum Cu levels were significantly higher. There was a significant negative association between the Zn/Cu ratio and CARS scores [13]. However, clinical evidence on VA, Zn, and Cu levels in ASD patients is currently lacking. ...
Background
This study evaluated vitamin A (VA), copper (Cu), and zinc (Zn) levels in the population with autism spectrum disorder (ASD) in Jilin Province, China. Furthermore, we examined their links to core symptoms and neurodevelopment, as well as gastrointestinal (GI) comorbidities and sleep disorders.
Methods
This study included 181 children with autism and 205 typically developing (TD) children. The participants had not taken vitamin/mineral supplements in the prior three months. High-performance liquid chromatography was used to measure serum VA levels. By using inductively coupled plasma–mass spectrometry, Zn and Cu concentrations in plasma were determined. Importantly, the Childhood Autism Rating Scale, the Social Responsiveness Scale, and the Autism Behavior Checklist were used to measure core ASD symptoms. However, the Griffith Mental Development Scales-Chinese were used to measure neurodevelopment. GI comorbidities and sleep abnormalities were assessed with the 6 Item-Gastrointestinal Severity Index and Children’s Sleep Habits Questionnaire, respectively. Children with ASD with GI issues were grouped according to severity (low GI severity and high GI severity groups).
Results
(i) The difference in VA, Zn, Cu levels and the Zn/Cu ratio between ASD and TD children is small. But children with ASD had lower VA levels and Zn/Cu ratio, higher Cu levels than TD children. Cu levels in children with ASD were associated with the severity of core symptoms. (ii) Children with ASD were much more likely than their TD counterparts to suffer from GI comorbidities or sleep problems. Furthermore, it was observed that high GI severity was associated with lower levels of VA, whereas low GI severity was associated with higher levels of VA. (iii) The children with ASD who had both lower VA and lower Zn/Cu ratio had more severe scores on the Autism Behavior Checklist, but not on other measures.
Conclusion
Children with ASD had lower VA and Zn/Cu ratio, and higher Cu levels. Cu levels in children with ASD were weakly correlated with one subscale on social or self-help. ASD children with lower VA levels may face more serious GI comorbidities. Children with ASD combined VA-Zn/Cu lower had more severe core symptoms.
Trial registration
Registration number: ChiCTR-OPC-17013502. Date of registration: 2017-11-23.
... Autism is a long-term disability and a developmental disorder de ned by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders (DSM V) [1]. Serum levels of Zinc have been associated with ASD, and the (Zinc/Copper) ratio can be a biomarker of ASD [2] being abnormally low in ASD individuals [3]. Thus, it is indispensable to avail simple, accurate, and reliable alternative analytical methods that conveniently and promptly assess trace element levels [4], especially, as screening quick tools in schools or rural and remote locations. ...
... De ned by APA in the (DSM V), ASD is a neurodevelopmental disorder with a group of long-term disabilities [1]. Many studies suggested an association between serum levels of Zn and ASD, and that the Zinc to copper (Zn/Cu) ratio, being low, can be a biomarker of ASD [2], [3]. Thus, it is indispensable to nd simple, accurate, selective, and reliable alternative analytical methods that can conveniently, and promptly assess trace elements' levels in the body [4]. ...
... Being an essential catalytic or structural element of many proteins and important for neural activity and the control of neuronal death, zinc may be an important trace element for the etiology and symptoms of subgroups of ASD [56]. However, since the results did not con rm a correlation with CARS score, they did not match the results of other studies reporting a signi cant negative association between the Zn/Cu ratio and CARS scores [2]. ...
Background: Autism is a long-term disability and a developmental disorder in which many studies suggested an association with serum low levels of zinc. In addition, the zinc to copper (Zn/Cu) ratio can be a biomarker of ASD as it is abnormally low in individuals with autism.
Aim: The present study aimed to determine the levels of Zn in the bodies of children with autism spectrum disorder (ASD). The assay is done using new technology, the quantum magnetic resonance analysis (QMRA) method, and comparing its results with a reference testing laboratory method to determine the validity, sensitivity, and specificity of the new measurement method.
Method: The study was performed in a group of children (M=19; F=11; age range=3-15 years) with ASD (n=30) and a control group of typically developing children (n=30) matched in terms of sex and age. The main variables in this study were the body values of Zn measured with a QMRA-998 8th Generation device and in patients’ sera by the reference direct colorimetric method.
Statistical Analysis: Results were compared across groups using descriptive statistics, Pearson and Spearman’s correlation coefficients, Chi-Square significance, analysis of variance (ANOVA), and linear regression. In addition, a sensitivity and specificity cross-tabulation test was performed to evaluate the QMRA method in measuring Zn levels.
Results: Both methods showed lower means for Zn levels in the ASD group than in the control group with a significant correlation between the two methods when measuring Zn levels. With the QMRA method, the sensitivity was 84% and specificity was 87%.
Conclusion: It is suggested to test blood levels of Zn in all autistic children and give them a Zn supplement if needed. Non-invasive health measurement devices such as QMRA can be used as a screening or adjunct tool for the measurement of Zn levels in humans.
... Autism is a long-term disability and a developmental disorder de ned by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders (DSM V) [1]. Serum levels of Zinc have been associated with ASD, and the (Zinc/Copper) ratio can be a biomarker of ASD [2] being abnormally low in ASD individuals [3]. Thus, it is indispensable to avail simple, accurate, and reliable alternative analytical methods that conveniently and promptly assess trace element levels [4], especially, as screening quick tools in schools or rural and remote locations. ...
... De ned by APA in the (DSM V), ASD is a neurodevelopmental disorder with a group of long-term disabilities [1]. Many studies suggested an association between serum levels of Zn and ASD, and that the Zinc to copper (Zn/Cu) ratio, being low, can be a biomarker of ASD [2], [3]. Thus, it is indispensable to nd simple, accurate, selective, and reliable alternative analytical methods that can conveniently, and promptly assess trace elements' levels in the body [4]. ...
... Being an essential catalytic or structural element of many proteins and important for neural activity and the control of neuronal death, zinc may be an important trace element for the etiology and symptoms of subgroups of ASD [56]. However, since the results did not con rm a correlation with CARS score, they did not match the results of other studies reporting a signi cant negative association between the Zn/Cu ratio and CARS scores [2]. ...
Background: Autism is a long-term disability and a developmental disorder in which many studies suggested an association with serum low levels of zinc. In addition, the zinc to copper (Zn/Cu) ratio can be a biomarker of ASD as it is abnormally low in individuals with autism.
Aim: The present study aimed to determine the levels of Zn in the bodies of children with autism spectrum disorder (ASD). The assay is done using new technology, the quantum magnetic resonance analysis (QMRA) method, and comparing its results with a reference testing laboratory method to determine the validity, sensitivity, and specificity of the new measurement method.
Method: The study was performed in a group of children (M=19; F=11; age range=3-15 years) with ASD (n=30) and a control group of typically developing children (n=30) matched in terms of sex and age. The main variables in this study were the body values of Zn measured with a QMRA-998 8th Generation device and in patients’ sera by the reference direct colorimetric method.
Statistical Analysis: Results were compared across groups using descriptive statistics, Pearson and Spearman’s correlation coefficients, Chi-Square significance, analysis of variance (ANOVA), and linear regression. In addition, a sensitivity and specificity cross-tabulation test was performed to evaluate the QMRA method in measuring Zn levels.
Results: Both methods showed lower means for Zn levels in the ASD group than in the control group with a significant correlation between the two methods when measuring Zn levels. With the QMRA method, the sensitivity was 84% and specificity was 87%.
Conclusion: It is suggested to test blood levels of Zn in all autistic children and give them a Zn supplement if needed. Non-invasive health measurement devices such as QMRA can be used as a screening or adjunct tool for the measurement of Zn levels in humans.
... Autism is a long-term disability and a developmental disorder defined by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders (DSM V) [1]. Serum levels of Zinc have been associated with ASD, and the (Zinc/Copper) ratio can be a biomarker of ASD [2] being abnormally low in ASD individuals [3]. Thus, it is indispensable to avail simple, accurate, and reliable alternative analytical methods that conveniently and promptly assess trace element levels [4], especially, as screening quick tools in schools or rural and remote locations. ...
... Defined by APA in the (DSM V), ASD is a neurodevelopmental disorder with a group of long-term disabilities [1]. Many studies suggested an association between serum levels of Zn and ASD, and that the Zinc to copper (Zn/Cu) ratio, being low, can be a biomarker of ASD [2], [3]. Thus, it is indispensable to find simple, accurate, selective, and reliable alternative analytical methods that can conveniently, and promptly assess trace elements' levels in the body [4]. ...
... Being an essential catalytic or structural element of many proteins and important for neural activity and the control of neuronal death, zinc may be an important trace element for the etiology and symptoms of subgroups of ASD [56]. However, since the results did not confirm a correlation with CARS score, they did not match the results of other studies reporting a significant negative association between the Zn/Cu ratio and CARS scores [2]. [14] The normal ranges mentioned in the literature for serum Zn is 60-90 µg/dl between the ages of 1-12 months, 80-110 µg/dl between the ages of 1-10 years, and 90-120 µg/dl between the ages of 10-15 years [5], [4]. ...
Method: The study was performed in a group of children (M=19; F=11; age range=3-15 years) with ASD (n=30) and a control group of typically developing children (n=30) matched in terms of sex and age. The main variables in this study were the body values of Zn measured with a QMRA-998 8th Generation device and in patients’ sera by the reference direct colorimetric method.
Statistical Analysis: Results were compared across groups using descriptive statistics, Pearson and Spearman’s correlation coefficients, Chi-Square significance, analysis of variance (ANOVA), and linear regression. In addition, a sensitivity and specificity cross-tabulation test was performed to evaluate the QMRA method in measuring Zn levels.
... Autism is a long-term disability and a developmental disorder de ned by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders (DSM V) [1]. Serum levels of Zinc have been associated with ASD, and the (Zinc/Copper) ratio can be a biomarker of ASD [2] being abnormally low in ASD individuals [3]. Thus, it is indispensable to avail simple, accurate, and reliable alternative analytical methods that conveniently and promptly assess trace element levels [4], especially, as screening quick tools in schools or rural and remote locations. ...
... De ned by APA in the (DSM V), ASD is a neurodevelopmental disorder with a group of long-term disabilities [1]. Many studies suggested an association between serum levels of Zn and ASD, and that the Zinc to copper (Zn/Cu) ratio, being low, can be a biomarker of ASD [2], [3]. Thus, it is indispensable to nd simple, accurate, selective, and reliable alternative analytical methods that can conveniently, and promptly assess trace elements' levels in the body [4]. ...
... Being an essential catalytic or structural element of many proteins and important for neural activity and the control of neuronal death, zinc may be an important trace element for the etiology and symptoms of subgroups of ASD [56]. However, since the results did not con rm a correlation with CARS score, they did not match the results of other studies reporting a signi cant negative association between the Zn/Cu ratio and CARS scores [2]. ...
Background: Autism is a long-term disability and a developmental disorder in which many studies suggested an association with serum low levels of zinc. In addition, the zinc to copper (Zn/Cu) ratio can be a biomarker of ASD as it is abnormally low in individuals with autism.
Aim: The present study aimed to determine the levels of Zn in the bodies of children with autism spectrum disorder (ASD). The assay is done using new technology, the quantum magnetic resonance analysis (QMRA) method, and comparing its results with a reference testing laboratory method to determine the validity, sensitivity, and specificity of the new measurement method.
Method: The study was performed in a group of children (M=19; F=11; age range=3-15 years) with ASD (n=30) and a control group of typically developing children (n=30) matched in terms of sex and age. The main variables in this study were the body values of Zn measured with a QMRA-998 8th Generation device and in patients’ sera by the reference direct colorimetric method.
Statistical Analysis: Results were compared across groups using descriptive statistics, Pearson and Spearman’s correlation coefficients, Chi-Square significance, analysis of variance (ANOVA), and linear regression. In addition, a sensitivity and specificity cross-tabulation test was performed to evaluate the QMRA method in measuring Zn levels.
Results: Both methods showed lower means for Zn levels in the ASD group than in the control group with a significant correlation between the two methods when measuring Zn levels. With the QMRA method, the sensitivity was 84% and specificity was 87%.
Conclusion: It is suggested to test blood levels of Zn in all autistic children and give them a Zn supplement if needed. Non-invasive health measurement devices such as QMRA can be used as a screening or adjunct tool for the measurement of Zn levels in humans.
... 31,36,40,43,44 However, very recent studies from USA and Jamaica found no significant/positive relations of male gender with ASD. 2,30,32,34,37,38,39,42,45 Socioeconomic status (SES): Only three studies out of six found a positive association between higher SES and increased ASD risk compared to controls, 30,41,32 in which opposite findings observed in other studies. 31,35,40 Parental education: Four out of eight studies found positive relation between advanced level of maternal education and ASD risk compared to controls, 2,41,32,39 where rest of the studies found opposite/mixed results. ...
... Zinc and Copper:Li et al. (2014) found significantly lower mean serum zinc levels in children with ASD (p<0.001)45 . However, Sehgal et al. found it was higher in ASD case (p=0.02)48 . ...
... Zinc and Copper:Li et al. (2014) found significantly lower mean serum zinc levels in children with ASD (p<0.001)45 . However, Sehgal et al. found it was higher in ASD case (p=0.02)48 . ...
Objective: Exposure to different environmental factors appears to be widespread, detrimental to human brain development and a potential risk factor for autism spectrum disorder (ASD). We conducted a systematic review on the relationship between environmental factors and ASD in Bangladesh.Methods: This paper reviews the evidence on modifiable environmental factors that have been associated, in some studies, with ASD, including socio-demographic and physical environmental factors exposures during prenatal and postnatal periods. Besides, this review is restricted to human studies with at least 50 cases of ASD, having a valid comparison group, conducted within the past two decades. Moreover, literatures searched using three electronic databases (PubMed, Google Scholar, and Biomed Central) from August 2020 to January 2021, based on the PRISMA guidelines. Literatures screened by two distinguished reviewers (Khan MS; Tareq SM), and resolved differences by consensus and further discussion with third reviewer based on requirements. Then selected the eligible 21 studies based on inclusion criteria’s. Two of the reviewers independently screened articles, extracted data for descriptive information and assessed risk of bias by using the Newcastle-Ottawa scale (NOS).Results: There is no article found with poor quality in NOS. The overall quality of the studies is high. There are strong association between ASD risk and some factors such as advanced maternal age, lead exposure during pregnancy and early childhood, blood Arsenic level of ASD children. Though few factors are related to increased risk of ASD; so far, no specific environmental factor has been found associated with increased risk of ASD with large power of study.Conclusion: There is appears to be a lack of such type of study in developing countries like Bangladesh. Therefore, nationwide widespread research needed to address the modifiable environmental risk factors for ASD.International Journal of Human and Health Sciences Vol. 06 No. 03 July’22 Page: 237-248
... This pattern, an increase in toxic metals, and a decrease in essential metals has been shown in a plethora of metallomics data. Many studies have shown that children with ASD display a higher body content of toxic metals such as Pb, Hg, and Cd compared to neurotypical controls (Cohen et al., 1982;Eppright et al., 1996;Filipek et al., 1999;Al-Ayadhi, 2005;Fido and Al-Saad, 2005;Nataf et al., 2006;Adams et al., 2007;Geier and Geier, 2007;Clark et al., 2010;Geier et al., 2010Geier et al., , 2012Blaurock-Busch et al., 2011;Elsheshtawy et al., 2011;Lakshmi Priya and Geetha, 2011;Al-Farsi et al., 2013;Yasuda et al., 2013;, and altered levels of essential metals, such as a decrease in Zn (Wecker et al., 1985;Blaurock-Busch et al., 2011;Elsheshtawy et al., 2011;Yasuda et al., 2011;Li et al., 2014;Tabatadze et al., 2015) and increase in Cu (Blaurock-Busch et al., 2011;Elsheshtawy et al., 2011;Lakshmi Priya and Geetha, 2011;Russo and deVito, 2011;Li et al., 2014;Tabatadze et al., 2015). In most studies, both a deficiency in Zn and an increase in Cu occur in the same samples. ...
... This pattern, an increase in toxic metals, and a decrease in essential metals has been shown in a plethora of metallomics data. Many studies have shown that children with ASD display a higher body content of toxic metals such as Pb, Hg, and Cd compared to neurotypical controls (Cohen et al., 1982;Eppright et al., 1996;Filipek et al., 1999;Al-Ayadhi, 2005;Fido and Al-Saad, 2005;Nataf et al., 2006;Adams et al., 2007;Geier and Geier, 2007;Clark et al., 2010;Geier et al., 2010Geier et al., , 2012Blaurock-Busch et al., 2011;Elsheshtawy et al., 2011;Lakshmi Priya and Geetha, 2011;Al-Farsi et al., 2013;Yasuda et al., 2013;, and altered levels of essential metals, such as a decrease in Zn (Wecker et al., 1985;Blaurock-Busch et al., 2011;Elsheshtawy et al., 2011;Yasuda et al., 2011;Li et al., 2014;Tabatadze et al., 2015) and increase in Cu (Blaurock-Busch et al., 2011;Elsheshtawy et al., 2011;Lakshmi Priya and Geetha, 2011;Russo and deVito, 2011;Li et al., 2014;Tabatadze et al., 2015). In most studies, both a deficiency in Zn and an increase in Cu occur in the same samples. ...
... The probably most extensive study to date that investigated 1,967 hair samples of individuals with ASD found a clear correlation between age and abnormal metal levels (Yasuda et al., 2011(Yasuda et al., , 2013. Intriguingly, in several studies, the severity of trace metal abnormalities was directly correlated to the severity of ASD symptoms (Elsheshtawy et al., 2011;Lakshmi Priya and Geetha, 2011;Li et al., 2014). ...
Metal dyshomeostasis plays a significant role in various neurological diseases such as Alzheimer’s disease, Parkinson’s disease, Autism Spectrum Disorders (ASD), and many more. Like studies investigating the proteome, transcriptome, epigenome, microbiome, etc., for years, metallomics studies have focused on data from their domain, i.e., trace metal composition, only. Still, few have considered the links between other “omes,” which may together result in an individual’s specific pathologies. In particular, ASD have been reported to have multitudes of possible causal effects. Metallomics data focusing on metal deficiencies and dyshomeostasis can be linked to functions of metalloenzymes, metal transporters, and transcription factors, thus affecting the proteome and transcriptome. Furthermore, recent studies in ASD have emphasized the gut-brain axis, with alterations in the microbiome being linked to changes in the metabolome and inflammatory processes. However, the microbiome and other “omes” are heavily influenced by the metallome. Thus, here, we will summarize the known implications of a changed metallome for other “omes” in the body in the context of “omics” studies in ASD. We will highlight possible connections and propose a model that may explain the so far independently reported pathologies in ASD.
... of Zn was found to be significantly associated with the higher risk of ASD, which is coincident with several similar studies based on blood or hair samples [24,35,47,48]. Deficiency in Zn is widely reported to associate with not only various pathological conditions, but also neurodegenerative diseases and neurodevelopment disorders. ...
... Several studies have suggested the association between the concentration of Cu and the risk of ASD [11,24,35]. There are even two studies which explored applying the Zn/Cu ratio as an indicator of ASD [11,24]. ...
... Several studies have suggested the association between the concentration of Cu and the risk of ASD [11,24,35]. There are even two studies which explored applying the Zn/Cu ratio as an indicator of ASD [11,24]. With the optimal cut-off value of 0.665, the area under the curve was 0.968 (95% confidence interval, 0.943-0.993), ...
Essential metal elements (EMEs) have essential roles in neurological development and maintenance of human homeostasis. We performed a case-control study to explore association between the risk of autism spectrum disorder (ASD) and the 11 EMEs [Calcium (Ca), potassium (K), magnesium (Mg), sodium (Na), manganese (Mn), selenium (Se), cobalt (Co), Molybdenum (Mo), copper (Cu), zinc (Zn), and iron (Fe)] in serum. Ninety-two autistic subjects (cases) and age-sex-matched healthy subjects (controls = 91) from Beijing, China were recruited. In addition, totally 109 mothers of recruited children participated in this study. ICP-AES and ICP-MS were applied to determine the concentration of 11 EMEs in serum. The concentrations of Ca, K, and Mg were significantly higher in the cases than in the controls (OR [95% CI]: 1.031 [1.006–1.058] for Ca; 1.081 [1.046–1.118] for K; 1.161 [1.012–1.331] for Mg), while the concentrations of Zn and Cu were significantly lower (0.997 [0.995–0.999] for Cu; 0.996 [0.992–1.000] for Zn). Clear dose-response relationships between EMEs concentrations and the risk of ASD, as well as the correlation between EME concentrations and the severity of ASD were observed for most of the above EMEs. Six and seven specific correlated pairs between mothers and children were found in the cases and controls separately. The overall profiles of the EMEs were changed in the cases as compared to the controls. This study suggested that the higher levels of Ca, K, and Mg and lower levels of Zn and Cu may be associated with an elevated risk of ASD.
... There is considerable evidence for an association between zinc deficiency and ASD (Yasuda and Tsutsui, 2013;Li et al., 2014;Goyal et al., 2019). Zinc-binding genes associated with ASD are up-regulated in all neurodevelopmental stages (Supplementary Table S1). ...
... In 78 children with ASD, 15.4% had higher copper levels than the reference range, and 30.8% were in the highest 10% of the copper reference range (Faber et al., 2009). In another study, mean serum copper levels were significantly higher in ASD children than in healthy controls (Li et al., 2014). A third study of 79 autistic individuals found a similar pattern, in which autistic and Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) patients had significantly higher plasma levels of copper (Russo and Devito, 2011). ...
... Such differences are not known to be sex-dependent (Faber et al., 2009), though copper levels alone may differ by sex due to oral contraceptive use (Babic et al., 2013). One study found that the zinc/copper ratio could be used as a diagnostic biomarker (Li et al., 2014). Zinc/copper cycles may play a role in ASD occurrence, and the rhythmicity of these cycles can be used as a diagnostic tool to classify ASD (Curtin et al., 2018). ...
The aim of the present review is to summarize the prevalence of abnormal levels of various metal micronutrients including copper (Cu), iron (Fe), magnesium (Mg), zinc (Zn), and selenium (Se) in Autism Spectrum Disorder (ASD) using hair, nail and serum samples. A correlation of selected abnormal metal ions with known neurodevelopmental processes using Gene Ontology (GO) term was also conducted. Data included in this review are derived from ASD clinical studies performed globally. Metal ion disparity data is also analyzed and discussed based on gender (Male/Female) to establish any gender dependent correlation. Finally, a rational perspective and possible path to better understand the role of metal micronutrients in ASD is suggested.
... In particular, certain studies have demonstrated the absence of significant changes or a significant increase in serum Zn levels in ASD patients as compared to the controls [15,16]. Several studies have showed lower concentration of zinc from plasma samples of children with ASD [17,18]. Our study supports these findings by recording a significantly lower concentration of zinc in plasma of autistic children (635.7 ± 21 vs 1024.1 ± 15, p-value 0.001) compared to healthy control group. ...
... Zinc is involved in the gut-brain interaction, and many ASD patients also have gastrointestinal symptoms [19,20]. There are considerable evidences for an association between zinc deficiency and ASD [17,21]. Zinc levels may also be correlated to the severity of ASD [22]. ...
Trace elements are essential for the human body’s various physiological processes but if they are present in higher concentration, these elements turn to be toxic and cause adverse effect on physiological processes. Similarly, deficiency of these essential elements also affects physiological processes and leads to abnormal metabolic activities. There is a lot of interest in recent years to know the mystery behind the involvement of trace elements in the metabolic activities of autistic children suspecting that it may be a risk factor in the aetiology of autism. The present study aims to analyse the plasma trace elements in autistic children using the total reflection X-ray fluorescence (TXRF) technique. Plasma samples from 70 autistic children (mean age: 11.5 ± 3.1) were analysed with 70 age- and sex-matched healthy children as controls (mean age: 12 ± 2.5). TXRF analysis revealed the higher concentration of copper (1227.8 ± 17.8), chromium (7.1 ± 2.5), bromine (2695.1 ± 24) and arsenic (126.3 ± 10) and lower concentration of potassium (440.1 ± 25), iron (1039.6 ± 28), zinc (635.7 ± 21), selenium (52.3 ± 8.5), rubidium (1528.9 ± 28) and molybdenum (162,800.8 ± 14) elements in the plasma of autistic children in comparison to healthy controls. Findings of the first study from India suggest these altered concentrations in elements in autistic children over normal healthy children affect the physiological processes and metabolism. Further studies are needed to clarify the association between the altered element concentration and physiology of autism in the North Karnataka population in India.
... Data implicate metal dyshomeostasis and abnormalities of the "metallome" (i.e., binding, distribution and metabolic handling of trace metals) in the pathogenesis of ASD [1][2][3][4][5][6]. For example, elevated blood levels of copper and an increased ratio of copper to zinc have been reported in children with ASD and proposed as potential biomarkers of this disorder [1][2][3]5,6]. ...
... Data implicate metal dyshomeostasis and abnormalities of the "metallome" (i.e., binding, distribution and metabolic handling of trace metals) in the pathogenesis of ASD [1][2][3][4][5][6]. For example, elevated blood levels of copper and an increased ratio of copper to zinc have been reported in children with ASD and proposed as potential biomarkers of this disorder [1][2][3]5,6]. Copper is a redox-reactive metal that acts as a cofactor in many electron transfer reactions, whose free concentration must be maintained within a safe narrow range in order to prevent dysregulated oxidation of proteins and lipids due to elevated levels. ...
A 23 year old male diagnosed with autism spectrum disorder and treated with valproic acid presented with acute onset of hepatic failure; he died less than two months later. Laboratory studies led to a diagnosis of Wilson Disease. The case raised questions about a possible pathogenic role of disrupted copper homeostasis in ASD, and exacerbation of this disruption as a result of treatment with valproic acid. Screening for abnormalities of copper homeostasis may stimulate strategies for therapeutic targeting of a contributing etiological factor and avoidance of contraindicated medications.
... The importance of zinc in ASD is supported by multiple pieces of evidence, including a strong association between low levels of this metal and ASD risk as well as a causative role of zinc deficiency in neuronal defects and development of ASD-related symptoms and "therapeutic" effects of zinc supplementation. In fact, low hair and serum levels of zinc and/or altered Zn/Cu ratio have been detected in children with ASD [129][130][131]. The effects of zinc deficiency on ASD have been observed in animal models. ...
... Association studies [117][118][119][120][121] Maternal nutrition Association studies; meta-analyses; in vitro studies, animal studies [123][124][125][126][127][128][129][130][131][132][133][134][136][137][138][139][140][141][142] Fetal exposure to drugs, smoke, alcohol Association studies; meta-analyses [143][144][145][146][147][148][149][150][151] Maternal diseases Meta-analyses [152,153] Maternal infections Association studies; meta-analyses; animal studies [154][155][156][157][158][159][160][161] Fetal exposure to toxic xenobiotics Association studies; meta-analyses; in vitro studies; animal studies [166][167][168][169][170][171] ...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects social interaction and communication, with restricted interests, activity and behaviors. ASD is highly familial, indicating that genetic background strongly contributes to the development of this condition. However, only a fraction of the total number of genes thought to be associated with the condition have been discovered. Moreover, other factors may play an important role in ASD onset. In fact, it has been shown that parental conditions and in utero and perinatal factors may contribute to ASD etiology. More recently, epigenetic changes, including DNA methylation and micro RNA alterations, have been associated with ASD and proposed as potential biomarkers. This review aims to provide a summary of the literature regarding ASD candidate genes, mainly focusing on synapse formation and functionality and relevant epigenetic and environmental aspects acting in concert to determine ASD onset.
... Multiple out-of-pocket specialty lab tests, including buccal swabs for functional genomic profile (IntellxxDNA) [135], urine organic acid [136] tests and testing for organic compounds and metabolites (Mosaic Diagnostics and Genova Diagnostics), hair analysis [137] for metals and minerals (Mosaic Diagnostics), blood analysis for nutritional (vitamin and mineral) status (Genova Diagnostics) [138] and IgG-mediated food sensitivities [139] (Mosaic Diagnostics), stool studies [140] for pathogens and GI health (Mosaic Diagnostics), and urine analysis for mycotoxins [141] (Mosaic Diagnostics) were conducted in the first year after the twin's official autism diagnosis from March of 2022 with repeat testing in 2023. Findings of these tests in both twins included biomarkers [142][143][144][145][146][147][148][149][150][151][152][153][154][155] associated with mild gastrointestinal inflammation (one child with low elastase and the other with significant fat staining, though plentiful lactobacillus and bifidobacteria and unremarkable secretory IGAs), fa y acid imbalances (high omega 6:3 ratio), nutrient deficits (minerals tested below the 50th percentile, and both twins were relatively low in vitamins C, B12, and B3, alpha lipoic acid, glutathione) with signs of mold exposure (highly elevated urinary ochratoxin and citrinin), fungal issues (elevated arabinose for both girls, and elevated tartaric acid for L), signs of bacterial overgrowth (elevated hippuric acid for P and dihydroxyphenylpropionic acid for L), metal excretion (high aluminum in both girls), sensitivities to common foods, and urinary excretion of toxic compounds and their metabolites (some >100th percentile, glyphosate at or above 75th percentile for both twins). ...
The prevalence of autism has been increasing at an alarming rate. Even accounting for the expansion of autism spectrum disorder diagnostic (ASD) criteria throughout the 1990’s, there has been an over 300% increase in ASD prevalence since the year 2000. The often debilitating personal, familial, and societal sequelae of autism are generally believed to be lifelong. However, there have been several encouraging case reports demonstrating the reversal of autism diagnoses, with a therapeutic focus on addressing the environmental and modifiable lifestyle factors believed to be largely underlying the condition. This case report describes the reversal of autism symptoms among dizygotic, female twin toddlers and provides a review of related literature describing associations between modifiable lifestyle factors, environmental exposures, and various clinical approaches to treating autism. The twins were diagnosed with Level 3 severity ASD “requiring very substantial support” at approximately 20 months of age following concerns of limited verbal and non-verbal communication, repetitive behaviors, rigidity around transitions, and extensive gastrointestinal symptoms, among other common symptoms. A parent-driven, multidisciplinary, therapeutic intervention involving a variety of licensed clinicians focusing primarily on addressing environmental and modifiable lifestyle factors was personalized to each of the twin’s symptoms, labs, and other outcome measures. Dramatic improvements were noted within several months in most domains of the twins’ symptoms, which manifested in reductions of Autism Treatment Evaluation Checklist (ATEC) scores from 76 to 32 in one of the twins and from 43 to 4 in the other twin. The improvement in symptoms and ATEC scores has remained relatively stable for six months at last assessment. While prospective studies are required, this case offers further encouraging evidence of ASD reversal through a personalized, multidisciplinary approach focusing predominantly on addressing modifiable environmental and lifestyle risk factors.
... The study revealed significantly lower serum Zn levels and Zn/Cu ratios in children with ASD, suggesting a potential imbalance in these trace elements. Interestingly, we also observed higher serum Cu levels in the ASD group, and the Zn/Cu ratio showed a significant negative association with ASD severity measured by the Childhood Autism Rating Scale score (42). ...
This interview delves into the relationship between zinc (Zn) and copper (Cu) in autism spectrum disorder (ASD), featuring insights from Dr. Geir Bjørklund, MD, a Norwegian researcher. Collaborative studies conducted across diverse countries, including China, Slovenia, Romania, Russia, Brazil, and Egypt, consistently reveal altered Zn and Cu levels in individuals with ASD. These findings suggest a potential correlation between elevated Cu levels and increased severity of ASD symptoms. Dr. Bjørklund emphasizes the multifaceted dynamics of metallothioneins (MTs), essential proteins for metal binding and detoxification, and their potential association with Zn deficiency in ASD individuals. The interview illuminates the balance between Zn and Cu within the GABAergic system, implicating these trace elements in synaptic modulation and broader neurobiological functions. Future research directions proposed by Dr. Bjørklund encompass exploring multiple biological mediums for accurate trace element assessment, investigating interactions between different trace elements, and exploring factors influencing trace element levels in various tissues. The significance of Zn supplementation in treating ASD, the implications of MT dysfunction, and the importance of dual monitoring of Cu and Zn during therapy are thoroughly discussed. The conclusion expresses gratitude for Dr. Bjørklund’s invaluable contributions to comprehending the role of Zn and Cu in ASD, highlighting the global relevance of his research and the need for a comprehensive approach to understanding trace element dynamics in this complex neurodevelopmental disorder.
... Multiple out-of-pocket specialty lab tests, including buccal swabs for functional genomic profile (IntellxxDNA) [135], urine organic acid [136] tests and testing for organic compounds and metabolites (Mosaic Diagnostics and Genova Diagnostics), hair analysis [137] for metals and minerals (Mosaic Diagnostics), blood analysis for nutritional (vitamin and mineral) status (Genova Diagnostics) [138] and IgG-mediated food sensitivities [139] (Mosaic Diagnostics), stool studies[140] for pathogens and GI health (Mosaic Diagnostics), and urine analysis for mycotoxins [141] (Mosaic Diagnostics) were conducted in the first year after the twin's official autism diagnosis from March of 2022 with repeat testing in 2023. Findings of these tests in both twins included biomarkers [142][143][144][145][146][147][148][149][150][151][152][153][154][155] associated with mild gastrointestinal inflammation (one child with low elastase and the other with significant fat staining, though plentiful lactobacillus and bifidobacteria and unremarkable secretory IGAs),fatty acid imbalances (high omega 6:3 ratio), nutrient deficits (minerals tested below the 50 th percentile, and both twins were relatively low in vitamins C, B12, and B3, alpha lipoic acid, glutathione) with signs of mold exposure (highly elevated urinary ochratoxin and citrinin), fungal issues (elevated arabinose for both girls, and elevated tartaric acid for L), signs of bacterial overgrowth (elevated hippuric acid for P and dihydroxyphenylpropionic acid for L), metal excretion (high aluminum in both girls), sensitivities to common foods, and urinary excretion of toxic compounds and their metabolites (some >100 th percentile, glyphosate at or above 75 th percentile for both twins). ...
The prevalence of autism has been increasing at an alarming rate. Even accounting for the expansion of autism spectrum disorder diagnostic (ASD) criteria throughout the 1990’s, there has been an over 300% increase in ASD prevalence since the year 2000. The often debilitating personal, familial, and societal sequelae of autism are generally believed to be lifelong. However, there have been several encouraging case reports demonstrating reversal of autism diagnoses with a therapeutic focus on addressing the environmental and modifiable lifestyle factors believed to be largely underlying the condition. This case report describes the reversal of autism among dizygotic, female twin toddlers and provides a review of related literature describing associations between modifiable lifestyle factors, environmental exposures, and various clinical approaches to treating autism. The twins were diagnosed with Level 3 severity ASD “requiring very substantial support” at approximately 20 months of age following concerns of limited verbal and non-verbal communication, repetitive behaviors, rigidity around transitions, and extensive gastrointestinal symptoms, among other common symptoms. A parent-driven, multidisciplinary, therapeutic intervention involving a variety of licensed clinicians focusing primarily on addressing environmental and modifiable lifestyle factors was personalized to each of the twin’s symptoms, labs, and other outcome measures. Dramatic improvements were noted within several months in most domains of the twins’ symptoms, which was manifested in reductions of Autism Treatment Evaluation Checklist (ATEC) scores from 76 to 32 in one of the twins and from 43 to 4 in the other twin. The improvement in symptoms and ATEC scores has remained relatively stable for six months at last assessment. While prospective studies are required, this case offers further encouraging evidence of ASD reversal through a personalized, multidisciplinary approach focusing predominantly on addressing environmental and lifestyle risk factors.
... It usually presents later after 4-5 years old until the excessive copper deposition exists. Chinese study proved an association between serum levels of copper (Cu) and ASD, and they considered elevated Cu ratio as a biomarker of ASD [25]. No cases had NLD, and 8 cases (100%) had DLD. ...
Background
Children with various metabolic disorders are considered a high-risk group for different developmental delays. Delayed language development (DLD) and autism spectrum disorder (ASD) have a common incidence in children with metabolic disorders which negatively impact their social and academic life. So, early assessment of this high-risk group for the presence of DLD and/or ASD is of great significance and providing better prognosis through starting therapy as early as possible.
Aim of the work
It aims to detect the presence of DLD and ASD among children with metabolic disorders.
Methods
This is an analytical (observational) cross-sectional study. The subjects of this study comprised a convenient sample of 100 children diagnosed as having different metabolic disorders with age range between 24 and 48 months. The Modified Preschool Language Scale, Fourth Edition–Arabic version and the Childhood Autism Rating Scale were applied for all children, to detect the presence of DLD and ASD.
Results
Assessment of 100 children with unequal distribution of 13 types of metabolic disorders found that 86% of cases had DLD and 16% had ASD. Regarding different metabolic disorders, we found both DLD and ASD in nine types and only DLD in four types of metabolic disorders.
Conclusion
Children with metabolic disorders are at a high risk for DLD and ASD. Early detection of these cases provides early intervention and better outcome.
... The authors state that Zinc/Copper cycles may play a role in the onset of ASD and the rhythmicity between these cycles and can be used as a diagnostic tool for ASD classification [34]. ...
Autistic spectrum disorders are part of the category of neurodevelopmental disorders, characterized by: difficulties in communication and social interaction, restrictive and repetitive patterns of behaviours and activities, which are present throughout the developmental period, and can be diagnosed in the first five years of life. Due to the increase in the incidence of this disorder in recent years, it has become a topic of great interest both to specialists in child and adolescent psychiatry and to researchers in the field. Given the polymorphism of Autism Spectrum Disorder and the need to discover factors that better explain the etiology of this disorder, studies related to biomarkers are extremely varied. One of the areas of study that have exercised particular interest is related to the involvement of metals in the pathology of autism spectrum disorder. Apart from the controversies related to heavy metals that according to studies affect the developmental process, there are studies that suggest that some micronutrients such as zinc, copper, selenium, iron, magnesium, may be involved in the etiology of autism spectrum disorder. Starting from these studies, we set out to investigate to what extent these essential metals for the body are involved in the etiology of autism spectrum disorder and how they influence the severity of symptoms.
... 57 It has been suggested that zinc may be an important mineral in the treatment of ASD because metallothionein regulates gene expression and reduces heavy metal toxicity. 58 Mousain-Bosc, Roche, et al. examined the effects of magnesium and B6 supplementation in pervasive developmental disorders (PDD) and found that 70% of children with PDD aged 1-10 years improved social interaction, communication, abnormal/delayed functioning, and limited stereotyped behaviors. 59 Although vitamin and mineral supplementation is a recommended intervention for ASD, the number of studies on this subject is small. ...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that occurs in the early stages of development, characterized by limitations in social communication and interaction behaviors, repetitive limiting behaviors and limited interests. Nutritional problems and gastrointestinal complaints seen in ASD have been known since the first diagnosis of the disease and are considered as a feature of the disease. It is known that children with ASD have feeding problems five times more often than children with normal development. The most common nutritional problems seen in children with ASD are food selectivity, difficulty in eating skills, selective, strange and unusual eating behavior, sensitivity to a certain presentation of food, avoidance of new foods, excessive and persistent intake of one type of food and meal time behavioral problems. Dietary approaches such as gluten-free casein-free diet, ketogenic diet, special carbohydrate diet, feingold diet, Candida body ecology diet, eliminated allergy diets are applied. However, the evidence for these practices is limited. It is recommended to monitor children with ASD in terms of inadequate and unbalanced nutrition and to consider feeding problems and malnutrition in applying restrictive and special diets.
... For example, a study of 230 children with ASD, pervasive developmental disorder and Asperger's syndrome found that 15.4% of children with ASD had higher copper plasma levels than the reference range (Faber et al., 2009). A study by Li et al., that included 60 patients with ASD and 60 age and sex-matched controls, also showed that children with ASD had elevated copper serum levels when compared to healthy sex matched and age matched controls (Li et al., 2014). However, a study by our group, that included 64 children with ASD and 65 non-ASD controls, did not find significant differences in copper concentrations in serum or hair of North American children with ASD when compared to healthy controls (Mehta et al., 2021). ...
To better understand zinc and copper regulation and their involvement in various biochemical pathways as it relates to autism spectrum disorder (ASD), isotopic composition of serum zinc and copper were evaluated in both healthy children and children with ASD in North America. No significant difference in isotopic composition of serum zinc or copper with respect to healthy controls and ASD children were identified. However, the isotopic composition of serum copper in boys was found to be enriched in ⁶⁵ Cu in comparison to previously published healthy adult copper isotopic composition. Furthermore, in both boys and girls, the average isotopic composition of serum zinc is heavier than previously published healthy adult isotopic zinc composition. There was also a negative association between total zinc concentrations in serum and the zinc isotopic composition of serum in boys. Finally, children with heavier isotopic composition of copper also showed a high degree of variability in their zinc isotopic composition. While numerous studies have measured the isotopic composition of serum zinc and copper in adults, this is one of the first studies which measured the isotopic composition of serum copper and zinc in children, specifically those diagnosed with ASD. The results of this study showed that age and gender specific normal ranges of isotopic composition must be established to effectively use isotopic composition analysis in studying various diseases including ASD.
... A key ASD therapeutic agent that has shown its effectiveness in treating ASDs through NMDAR modulation is zinc [344][345][346][347]. The hypothesis of zinc supplementation as a potent treatment strategy for ASDs has stemmed from reports that reduced serum zinc levels have been identified in autistic individuals (discussed further in Section 4) [348][349][350][351][352]. To date, a limited number of studies have examined the therapeutic outcome of zinc supplementation in animal models. ...
NMDA-type glutamate receptors are critical for synaptic plasticity in the central nervous system. Their unique properties and age-dependent arrangement of subunit types underpin their role as a coincidence detector of pre- and postsynaptic activity during brain development and maturation. NMDAR function is highly modulated by zinc, which is co-released with glutamate and concentrates in postsynaptic spines. Both NMDARs and zinc have been strongly linked to autism spectrum disorders (ASDs), suggesting that NMDARs are an important player in the beneficial effects observed with zinc in both animal models and children with ASDs. Significant evidence is emerging that these beneficial effects occur via zinc-dependent regulation of SHANK proteins, which form the backbone of the postsynaptic density. For example, dietary zinc supplementation enhances SHANK2 or SHANK3 synaptic recruitment and rescues NMDAR deficits and hypofunction in Shank3ex13–16−/− and Tbr1+/− ASD mice. Across multiple studies, synaptic changes occur in parallel with a reversal of ASD-associated behaviours, highlighting the zinc-dependent regulation of NMDARs and glutamatergic synapses as therapeutic targets for severe forms of ASDs, either pre- or postnatally. The data from rodent models set a strong foundation for future translational studies in human cells and people affected by ASDs.
... The inter-daily variation of zinc, magnesium, calcium, aluminum, cadmium, lead, mercury, and arsenic determination was 2.2, 9.6, 6.3, 8.2, 6.9, 11.1, 9.4, and 6.9%, respectively. The control geometric mean value and reference range for each trace element were obtained from the data for 436 male healthy subjects aged [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] year old, as previously reported. 6 , 7 , 19 , 20 The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of La Belle Vie Research Laboratory. ...
The children today are in the midst of the epidemic of neurodevelopmental disorders. In this metallomics study for the scalp hair samples of total 2550 children with autistic disorders (2108 males and 442 females aged 0-15 year), it was demonstrated that near one half of the infantile individuals aged 0-3 year are suffering from zinc deficiency and toxic metal burdens. Zinc level correlated closely to the index of zinc/iron ratio more than zinc/copper ratio. Furthermore, there were significant relationships between zinc deficiency and toxic metal burdens such as lead and aluminum which were inversely associated with not only zinc level but also zinc/iron ratio with higher regression coefficients of r = −0.486 and −0.551 (p < 0.00001), respectively. High-significant inverse association was detected between zinc and molybdenum concentration (r = −0.509) and also between zinc/iron ratio and molybdenum (r = −0.548). These findings suggest that infantile zinc deficiency relates to the high burdens of not only toxic but also some essential metals such as molybdenum, iron and manganese and that these various mineral imbalances play principal roles to the etiology of neurodevelopmental disorders. We expect that the early assessment and intervention of the mineral imbalances (or dis-homeostasis) in individual child open an avenue for evidence-based individualized treatment of neurodevelopmental disorders and also of the comorbid immune disorders, in near future.
... Zinc is an essential element in humans and one of the most prevalent metal ions in the brain (Vela et al. 2015). Among the six studies comparing blood zinc levels between children with autism and healthy controls, one reported a decreased level (Li et al. 2014), one reported an increased level (Bjorklund 2013), and four found no difference (Jackson et al. 1978;Macedoni-Lukšič et al. 2015;Russo et al. 2011;Wu et al. 2018). These inconsistent findings could have resulted from racial and regional differences and the fasting status of the subjects. ...
This case-control study explored the associations between autism spectrum disorder (ASD) and the serum concentration of nine chemical elements in children. The study recruited 92 Chinese children with ASD and 103 typically developing individuals. Serum concentrations of nine chemical elements (calcium, iodine, iron, lithium, magnesium, potassium, selenium, strontium, and zinc) were determined by inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectrometry (ICP-AES). An unconditional logistic regression model was used to analyze the associations between the serum concentrations of the elements and the risk of ASD. After adjusting for confounders, the multivariate analysis results showed that zinc ≤ 837.70 ng/mL, potassium > 170.06 μg/mL, and strontium ≤ 52.46 ng/mL were associated with an increased risk of ASD, while selenium > 159.80 ng/mL was associated with a decreased risk of ASD. Furthermore, the degree of lithium and zinc deficiency was associated with ASD severity. The results indicated that metallomic profiles of some specific elements might play important roles in the development of ASD, a finding of scientific significance for understanding the etiology, and providing dietary guidance for certain ASD types.
... [14] Low levels of zinc have been measured in the infant hair of individuals with ASD; [15] disruptions in fetal copper homeostasis during brain development might contribute to ASD risk with both elevated and decreased copper levels linked with autism. [16] Vaccines Wakefield et al. [17] claimed that MMR vaccination results in inflammatory bowel syndrome leading to autism. This study attracted worldwide attention and contributed to harmful drops in vaccination and resulted in measles outbreaks in several countries. ...
... Another place for its crucial effect on development is the nervous system [165]. According to many studies, zinc supplement has been considered for ASD and ADHD [166,167]. ...
The effects of a sufficient amounts of vitamins and nutrients on the proper function of the nervous system have always been regarded by scientists. In recent years, there are many studies have been done on controling or improving the symptoms of neurological and behavioral disorders which is created by changes in the level of vitamins and other nutrition, such as omega-3 and iron supplements. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that causes disruption individual communication, especially in social interactions. Its symptoms include anxiety, violence, depression, self-injury, trouble with social contact and pervasive, stereotyped, and repetitive behavior. ASD is most noticeable in early childhood. Attention Deficit Hyperactivity Disorder (ADHD) is a lasting pattern of inattention with or without hyperactivity that makes functional disrupt in daily life. ADHD symptoms included; impulsivity, hyperactivity, inattention, restlessness, talkativeness, excessive fidgeting in situations as sitting, meetings, lectures, or at the movies, boredom, inability to make decisions, and procrastination. The exact etiology of ADHD has not yet been found, but several observations have been assumed the reduced function of the brain lead to deficits in motor planning and cognitive processing. It has been shown that Pro-inflammatory cytokines and oxidative stress biomarkers could be increased in both ASD and ADHD. Several studies have been done to illustrate if vitamins and other dietary supplements are effective in treatment and prevention of ASD and ADHD. In this review, we aim to evaluate the effects of vitamins and other dietary supplements (e.g., melatonin, zinc supplements, magnesium supplements) on ASD and ADHD.
... Cu overload may cause synaptic damage detected in ASD children (Baj et al. 2021). It may also block dopamine beta-hydroxylase function that is known to alter the noradrenaline synthesis mechanism (Li et al. 2014) and reduce the production of serotonin (Priya and Geetha 2011). ...
Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder characterized mainly by qualitative deficiencies in social communication skills, accompanied by repetitive and restricted behavior patterns. This study was conducted to investigate the associations between the risk of ASD development in children and exposure to trace elements (arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), lead (Pb), nickel (Ni), and zinc (Zn)). Two groups of children, including 44 ASD and 35 typically developing (TD) children, were selected, and their fasting urine samples were obtained. The concentration levels of trace elements were assayed using ICP-MS. The results showed that as compared to the TD group, the concentration levels of As (p = 0.002) and Pb (p < 0.001) and also Cr (p < 0.001), Cu (p = 0.001), and Ni (p < 0.001) were significantly higher among ASD children. In terms of gender, boys with ASD showed elevated levels of Cr, Cu, Ni, and Pb, whereas the urine levels of As, Cr, Cu, Ni, and Pb were markedly higher among girls when compared to the non-ASD children. Under the logistic regression model, the risk difference for As, Co, Cr, Cu, Ni, Pb, and Zn remained significant when adjustment was applied for age and gender confounders.
... The concept of zinc supplementation as a potential ASD treatment has been based on observations that (1) reduced serum zinc levels have been identified in individuals with ASD [53][54][55][56][57], and (2) prenatal zinc-deficient animals display ASD-like behaviours including increased anxiety, social interaction deficits and altered ultrasonic vocalisation [58,59]. The efficacy and mechanistic underpinnings of zinc supplementation as a treatment strategy have so far been primarily examined in rodent models carrying ASD-associated SHANK2 or SHANK3 mutations, but also in the maternal immune activation model of ASD [37,41,44,45,[59][60][61][62]. ...
Background
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by a dyad of behavioural symptoms—social and communication deficits and repetitive behaviours. Multiple aetiological genetic and environmental factors have been identified as causing or increasing the likelihood of ASD, including serum zinc deficiency. Our previous studies revealed that dietary zinc supplementation can normalise impaired social behaviours, excessive grooming, and heightened anxiety in a Shank3 mouse model of ASD, as well as the amelioration of synapse dysfunction. Here, we have examined the efficacy and breadth of dietary zinc supplementation as an effective therapeutic strategy utilising a non- Shank -related mouse model of ASD—mice with Tbr1 haploinsufficiency.
Methods
We performed behavioural assays, amygdalar slice whole-cell patch-clamp electrophysiology, and immunohistochemistry to characterise the synaptic mechanisms underlying the ASD-associated behavioural deficits observed in Tbr1 +/− mice and the therapeutic potential of dietary zinc supplementation. Two-way analysis of variance (ANOVA) with Šídák's post hoc test and one-way ANOVA with Tukey’s post hoc multiple comparisons were performed for statistical analysis.
Results
Our data show that dietary zinc supplementation prevents impairments in auditory fear memory and social interaction, but not social novelty, in the Tbr1 +/− mice. Tbr1 haploinsufficiency did not induce excessive grooming nor elevate anxiety in mice. At the synaptic level, dietary zinc supplementation reversed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N -methyl- d -aspartate receptor (NMDAR) hypofunction and normalised presynaptic function at thalamic-lateral amygdala (LA) synapses that are crucial for auditory fear memory. In addition, the zinc supplemented diet significantly restored the synaptic puncta density of the GluN1 subunit essential for functional NMDARs as well as SHANK3 expression in both the basal and lateral amygdala (BLA) of Tbr1 +/− mice.
Limitations
The therapeutic effect of dietary zinc supplementation observed in rodent models may not reproduce the same effects in human patients. The effect of dietary zinc supplementation on synaptic function in other brain structures affected by Tbr1 haploinsufficiency including olfactory bulb and anterior commissure will also need to be examined.
Conclusions
Our data further the understanding of the molecular mechanisms underlying the effect of dietary zinc supplementation and verify the efficacy and breadth of its application as a potential treatment strategy for ASD.
... Zinc deficiency, when combined with copper toxicity, may result in dysregulated neurotransmitter system function, decreased Zinc finger protein activity, and decreased zinc-dependent gastrointestinal enzymatic activity. Zinc deficiency can result in oxidative stress, which can affect Zinc finger patterns important in cell signalling as transcription factors [29]. Additionally, zinc deficiency is associated with synaptic dysregulation, and the majority of candidate genes for autism have been discovered in excitatory post-synapses. ...
Background
Attention deficit hyperactivity disorder (ADHD) is a neuro-developmental ailment diagnosed with inattention and hyperactivity-impulsivity. It is one of the most prevalent neurodevelopmental disorders and has complex aetiology, both genetic and environmental. There is a perceived decrease in skill acquirement, leading to insufficient income and job opportunities as adults, which drives them towards poor physical and mental outcomes compared to their contemporaries without ADHD. The impact of heavy metals on ADHD is a topic of interest but is much less studied. Copper has been implicated as a pro-oxidant and in the metal accelerated production of free radicals that may affect oxidative stress. Zinc also serves as an antioxidant, and changes in its concentrations may impact the homeostasis of oxidative stress.
Methods
Twenty-four children diagnosed with ADHD were taken as cases and matched with 24 healthy controls. Hair and urine samples were collected from all the study participants. The samples were collected in sterile containers according to established protocols. Acid digestion of hair samples was done using 65% nitric acid and 30% hydrogen peroxide. Urine samples were extracted by a solution of 0.1% Triton-X-100 and 1% ultrapure nitric acid. The levels of zinc and copper were determined in both samples by inductively coupled plasma optical emission spectrometry (ICP-OES). The copper/zinc ratio (Cu/Zn) was calculated from these values. Mann Whitney U Test and receiver operating characteristic (ROC) analysis were done to estimate statistical significance.
Results
The median age of the study population was eight years. Overall, 34 male and 14 female subjects participated. There was no significant difference in height, weight and BMI between the cases and controls. Hair zinc levels in the ADHD group (198.49 µg g-1 of hair) was significantly lower than the control group (527.05 µg g-1 of hair). However, hair copper levels were increased significantly in the ADHD children (14.01 µg g-1 of hair) compared to the controls (7.43 µg g-1 of hair). Urine zinc levels were significantly lower in cases than controls (525.7 µg g-1 of spot urine creatinine vs 1374.09 µg g-1 of spot urine creatinine). However, copper levels in urine were higher in the ADHD children (17.01 µg g-1 of spot urine creatinine compared to 7.26 µg g-1 of spot urine creatinine in controls). Both hair and urine copper to zinc ratio was significantly higher in the ADHD group. On ROC analysis, the hair Cu/Zn ratio had an area under the curve (AUC) of 0.920 (p-value <0.001), and the urine Cu/Zn ratio had an AUC of 0.967 (p-value <0.001). When used as a diagnostic classifier for ADHD based on the cut-off value determined by ROC, both hair and urine Cu/Zn ratio had high sensitivity and specificity.
Conclusion
Low zinc levels in the urine and hair of children and higher levels of copper may impact the aetiology of ADHD in these children. At an early stage, the Cu/Zn ratio in both hair and urine samples may be used as a precise biomarker to identify and monitor such children.
... Several studies have investigate the potential association of copper levels and a potential biomarker of low zinc/copper ratios in children with ASD [66][67][68]. Plasma levels of copper were reported to be significantly increased in samples of 79 children (68 males; mean age = 11.7 years ± 5.62 [SD]) with autistic disorder and 52 children (47 males; mean age = 9.9 years ± 7.6 [SD]) with pervasive developmental disorder-not otherwise specified (PDD-NOS), diagnosed according to DSM-IV criteria, compared to 18 age and gender similar neurotypical controls [67]. Interestingly, in this study, plasma copper levels did not distinguish the sample of 21 children (19 males; mean age = 14.87 ± 7.87 [SD]) diagnosed with Asperger's syndrome from the controls. ...
Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local concentrations. For example, synaptic release of free copper acts locally to modulate NMDA receptor-mediated neurotransmission. Moreover, within the developing brain, iron is critical to hippocampal maturation and the differentiation of parvalbumin-expressing neurons, whose soma and dendrites are surrounded by perineuronal nets (PNNs). The PNNs are a specialized component of brain extracellular matrix, whose polyanionic character supports the fast-spiking electrophysiological properties of these parvalbumin-expressing GABAergic interneurons. In addition to binding cations and creation of the Donnan equilibrium that support the fast-spiking properties of this subset of interneurons, the complex architecture of PNNs also binds metal cations, which may serve a protective function against oxidative damage, especially of these fast-spiking neurons. Data suggest that pathological disturbance of the population of fast-spiking, parvalbumin-expressing GABAergic inhibitory interneurons occur in at least some clinical presentations, which leads to disruption of the synchronous oscillatory output of assemblies of pyramidal neurons. Increased expression of the GluN2A NMDA receptor subunit on parvalbumin-expressing interneurons is linked to functional maturation of both these neurons and the perineuronal nets that surround them. Disruption of GluN2A expression shows increased susceptibility to oxidative stress, reflected in redox dysregulation and delayed maturation of PNNs. This may be especially relevant to neurodevelopmental disorders, including autism spectrum disorder. Conceivably, binding of metal redox reactive cations by the perineuronal net helps to maintain safe local concentrations, and also serves as a reservoir buffering against second-to-second fluctuations in their concentrations outside of a narrow physiological range.
... Cu excess overload is the causative agent of synaptic pathology discovered in ASD. Copper can effectively block dopamine beta-hydroxylase function at the coeruleus locus, which, in turn, leads to alteration of noradrenaline synthesis mechanisms (Li et al., 2014a). ...
The identification of biomarkers as diagnostic tools and predictors of response to treatment of neurological developmental disorders (NDD) such as schizophrenia (SZ), attention deficit hyperactivity disorder (ADHD), or autism spectrum disorder (ASD), still remains an important challenge for clinical medicine. Metallomic profiles of ASD patients cover, besides essential elements such as cobalt, chromium, copper, iron, manganese, molyb-denum, zinc, selenium, also toxic metals burden of: aluminum, arsenic, mercury, lead, beryllium, nickel, cad-mium. Performed studies indicate that children with ASD present a reduced ability of eliminating toxic metals, which leads to these metals' accumulation and aggravation of autistic symptoms. Extensive metallomic studies allow a better understanding of the importance of trace elements as environmental factors in the pathogenesis of ASD. Even though a mineral imbalance is a fact in ASD, we are still expecting relevant tests and the elaboration of reference levels of trace elements as potential biomarkers useful in diagnosis, prevention, and treatment of ASD.
... As known, insufficient intake of Zinc (hypozincosis) is typical for the population of many countries in the world (Cheboi et al., 2021;Knoell et al., 2019), such as Portugal, Turkey, Panama, Iran, Egypt and others (Palanog et al., 2019), where such clinically pronounced symptoms of hypozincosis as infantilism, hypoasmia, and hypogeisia are registered (Li et al., 2014;Pfaender et al., 2017;Yasuda et al., 2011). Ackland and Michalczyk (2016) claim that Zinc deficiency is the cause of death in more than half a million infants and children under the age of 5 years annually. ...
To solve the problem of insufficient intake of essential macro - and micronutrients into the human body, particularly in the case of the essential trace element Zinc, the possibility of enriching a socially significant product (milk) with various forms of Zinc is considered. The influence of Zinc-containing compounds on the colloidal milk system's dispersed composition and stability, photon correlation spectroscopy methods, acoustic and electroacoustic spectroscopy was established in this research. It has been shown that Zinc lysinatoriboflavinate, is a colloidal and chelated organic form of the essential trace element Zinc, having the most negligible effects on the composition and stability of the dispersed phase particles. This increases the average hydrodynamic radius of the dispersed phase by 5% and the ζ-potential by 10%.
A quantum-chemical simulation of the interaction of milk κ-casein sites with various forms of the essential trace element Zinc in the QChem program was performed using the IQmol molecular editor. The mechanism of action of various forms of Zinc on the components of the dispersed system of milk, in particular milk protein (casein), is suggested.
... Furthermore, a number of studies considered this decreased ratio as a chemical marker for ASD. Additionally, our data stated a significant fair negative correlation between this ratio and the scoring of ASD (r = − 0.333 & p = 0.001) which agreed with a number of previous studies [50][51][52] . ...
Autism Spectrum Disorder (ASD) and learning disabilities are neurodevelopmental disabilities characterized by dramatically increasing incidence rates, yet the exact etiology for these disabilities is not identified. Impairment in tryptophan metabolism has been suggested to participate in the pathogenesis of ASD, however, further validation of its involvement is required. Additionally, its role in learning disabilities is still uninvestigated. Our objective was to evaluate some aspects of tryptophan metabolism in ASD children (N = 45) compared to children with learning disabilities (N = 44) and healthy controls (N = 40) by measuring the expression levels of the MAOA, HAAO and AADAT genes using real-time RT-qPCR. We also aimed to correlate the expression patterns of these genes with parental ages at the time of childbirth, levels of serum iron, and vitamin D3 and zinc/copper ratio, as possible risk factors for ASD. Results demonstrated a significant decrease in the expression of the selected genes within ASD children (p < 0.001) relative to children with learning disabilities and healthy controls, which significantly associated with the levels of our targeted risk factors (p < 0.05) and negatively correlated to ASD scoring (p < 0.001). In conclusion, this study suggests that the expression of the MAOA, HAAO and AADAT genes may underpin the pathophysiology of ASD.
... As [141]. Saghazadeh et al. reported a significant effect size of −0.361 (z-value = 2.31, p = 0.021), indicating that the ASD patients (n = 513) had lower blood Zn levels than controls (n = 333), after excluding two outlier studies. ...
Lead (Pb) is a heavy metal which is abundant in the environment and known to cause neurotoxicity in children even at minute concentration. However, the trace elements calcium (Ca), magnesium (Mg), zinc (Zn) and iron (Fe) are essential to children due to its protective effect on neurodevelopment. The primary objective of this study was to assess the role of Pb and trace elements in the development of autism spectrum disorder (ASD) among preschool children. A total of 81 ASD children and 74 typically developed (TD) children aged between 3 and 6 years participated in the study. Self-administered online questionnaires were completed by the parents. A first-morning urine sample was collected in a sterile polyethene urine container and assayed for Pb, Ca, Mg, Zn and Fe using an inductively coupled plasma mass spectrometry (ICP-MS). Comparisons between groups revealed that the urinary Pb, Mg, Zn and Fe levels in ASD children were significantly lower than TD children. The odds of ASD reduced significantly by 5.0% and 23.0% with an increment of every 1.0 μg/dL urinary Zn and Fe, respectively. Post interaction analysis showed that the odds of ASD reduced significantly by 11.0% and 0.1% with an increment of every 1.0 μg/dL urinary Zn and Pb, respectively. A significantly lower urinary Pb level in ASD children than TD children may be due to their poor detoxifying mechanism. Also, the significantly lower urinary Zn and Fe levels in ASD children may augment the neurotoxic effect of Pb.
Autism spectrum disorder (ASD) is becoming an increasingly common disorder of the development of the nervous system in the modern world. The diagnosis is made based on observation of the patient's behavior, which significantly complicates the diagnosis and treatment of the disorder. The subjectivity of behavioral diagnostics dictates the need for the study of biomarkers of ASD. Over the past two decades, researchers have focused on identifying specific biological abnormalities in ASD that will help in the diagnosis of the disease. This review discusses the state of research on various biomarkers currently being developed for ASD.
Introduction
Autism spectrum disorder (ASD) is a multifaceted developmental condition that commonly appears during early childhood. The etiology of ASD remains multifactorial and not yet fully understood. The identification of biomarkers may provide insights into the underlying mechanisms and pathophysiology of the disorder. The present study aimed to explore the causes of ASD by investigating the key biomedical markers, trace elements, and microbiota factors between children with autism spectrum disorder (ASD) and control subjects.
Methods
Medline, PubMed, ProQuest, EMBASE, Cochrane Library, PsycINFO, Web of Science, and EMBSCO databases have been searched for publications from 2012 to 2023 with no language restrictions using the population, intervention, control, and outcome (PICO) approach. Keywords including “autism spectrum disorder,” “oxytocin,” “GABA,” “Serotonin,” “CRP,” “IL-6,” “Fe,” “Zn,” “Cu,” and “gut microbiota” were used for the search. The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the article quality, and a random model was used to assess the mean difference and standardized difference between ASD and the control group in all biomedical markers, trace elements, and microbiota factors.
Results
From 76,217 records, 43 studies met the inclusion and exclusion criteria and were included in this meta-analysis. The pooled analyses showed that children with ASD had significantly lower levels of oxytocin (mean differences, MD = −45.691, 95% confidence interval, CI: −61.667, −29.717), iron (MD = −3.203, 95% CI: −4.891, −1.514), and zinc (MD = −6.707, 95% CI: −12.691, −0.722), lower relative abundance of Bifidobacterium (MD = −1.321, 95% CI: −2.403, −0.238) and Parabacteroides (MD = −0.081, 95% CI: −0.148, −0.013), higher levels of c-reactive protein, CRP (MD = 0.401, 95% CI: 0.036, 0.772), and GABA (MD = 0.115, 95% CI: 0.045, 0.186), and higher relative abundance of Bacteroides (MD = 1.386, 95% CI: 0.717, 2.055) and Clostridium (MD = 0.281, 95% CI: 0.035, 0.526) when compared with controls. The results of the overall analyses were stable after performing the sensitivity analyses. Additionally, no substantial publication bias was observed among the studies.
Interpretation
Children with ASD have significantly higher levels of CRP and GABA, lower levels of oxytocin, iron, and zinc, lower relative abundance of Bifidobacterium and Parabacteroides, and higher relative abundance of Faecalibacterium, Bacteroides, and Clostridium when compared with controls. These results suggest that these indicators may be a potential biomarker panel for the diagnosis or determining therapeutic targets of ASD. Furthermore, large, sample-based, and randomized controlled trials are needed to confirm these results.
Objectives:
The association between copper levels and autism spectrum disorder (ASD) has been a controversial topic. This study investigated relationship between copper levels and ASD.
Content:
The following databases are searched until April 2022: PubMed, EMBASE and Web of Science. Combined effect size standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated with Stata 12.0. In this meta-analysis, 29 case-control studies were included, which included 2,504 children with ASD and 2,419 healthy controls. The copper levels in hair (SMD: -1.16, 95% CI: -1.73 to -0.58) was significantly lower in ASD children than healthy controls. The copper levels in blood (SMD: 0.10, 95% CI: -0.12 to 0.32) not significantly compare ASD with controls.
Summary and outlook:
Copper may be associated with the development of ASD in children.
Background
The global prevalence of autism spectrum disorder (ASD) is on the rise, and high levels of exposure to toxic heavy metals may be associated with this increase. Urine analysis is a noninvasive method for investigating the accumulation and excretion of heavy metals. The aim of this study was to identify ASD-associated urinary metal markers.
Methods
Overall, 70 children with ASD and 71 children with typical development (TD) were enrolled in this retrospective case—control study. In this metallomics investigation, inductively coupled plasma mass spectrometry was performed to obtain the urine profile of 27 metals.
Results
Children with ASD could be distinguished from children with TD based on the urine metal profile, with ASD children showing an increased urine metal Shannon diversity. A metallome-wide association analysis was used to identify seven ASD-related metals in urine, with cobalt, aluminum, selenium, and lithium significantly higher, and manganese, mercury, and titanium significantly lower in the urine of children with ASD than in children with TD. The least absolute shrinkage and selection operator (LASSO) machine learning method was used to rank the seven urine metals in terms of their effect on ASD. On the basis of these seven urine metals, we constructed a LASSO regression model for ASD classification and found an area under the receiver operating characteristic curve of 0.913. We also constructed a clinical prediction model for ASD based on the seven metals that were different in the urine of children with ASD and found that the model would be useful for the clinical prediction of ASD risk.
Conclusions
The study findings suggest that altered urine metal concentrations may be an important risk factor for ASD, and we recommend further exploration of the mechanisms and clinical treatment measures for such alterations.
Background
Changes of toxic metals and essential elements during childhood may be the risk factor of autism spectrum disorder (ASD). This research established an accurate personalized predictive model of ASD behaviors among children by using the blood element detection index of children in Xinjiang, China.
Methods
A total of 1537 children (240 ASD behavior children and 1297 non-ASD behavior children) aged 0–7 were collected from September 2018 to September 2019 in Urumqi Children's Hospital and the health management institute of Xinjiang Medical University. For measuring the copper (Cu), zinc (Zn), magnesium (Mg), iron (Fe), calcium (Ca), lead (Pb), and cadmium (Cd), 80 μL of blood was taken from each participant's ring finger. Univariate logistic regression analysis was used to select predictors, then the multivariate logistic regression was used to establish the predictive model. The discriminability, calibration and clinical validity of the model were evaluated by the receiver operating characteristic (ROC) curve, Hosmer-Lemeshow test and decision curve analysis (DCA).
Results
Gender, concentrations of Pb, Ca and Zn in children's blood specimens were found to be the independent risk factors of ASD behaviors and were used to develop the nomogram model. The area under the ROC curve (AUC) in the development group (AUC = 0.778) and the validation group (AUC = 0.775) showed the model had discrimination ability. The calibration curve indicated the model was accurate, and the DCA proved its clinical application value.
Conclusion
The nomogram model can be used as a reliable tool to predict the risk of ASD behaviors among children.
Background: Nutrition is important in autism spectrum disorder (ASD). Because nutritional problems of children with ASD can lead to nutritional deficiencies and this can also directly or indirectly affect symptoms related to autism. We investigated the effect of diet and supplementation treatments on gastrointestinal, behavioral or sleep problems based on the results of literature review.
Methods: We generated four questions based on literature. We carried out title and abstract-based search using the Web of Science database. Of 4580 abstracts were identified, 192 papers were reviewed and 55 papers precisely meeting the inclusion criteria.
Results: The studies examining the effects of vitamins, minerals, probiotics, and other supplements on ASD symptoms had different dosages, different treatment durations, small sample sizes and used different scales for evaluation. The results of the studies of the effectiveness of GFCF and ketogenic diet to reduce gastrointestinal, behavioral and sleeping problems in children and adolescents were contradictory.
Conclusions: It is not possible to suggest the GFCF and/or ketogenic diet, vitamins, minerals and probiotics to individual with ASD based on the available evidence. By planning a sufficient and balanced diet, it should be aimed to prevent nutrient deficiency and to ensure growth in accordance with the age in children with ASD.
Recent advances in gut microbiota researches are establishing the association between food, gut microbiota, and brain health. Previously unknown communication networks between inhabiting microbes within the gut linings and the brain are being uncovered. The nature of the interaction between gut microbiota and the brain is a new frontier of research exploration. Diet plays an important role in modulating microbiota-gut-brain axis and exerts a profound influence on brain functioning. This review focuses on the effect of plant food bioactives or phytochemicals in modulating gut microbiota profile in Autistic individuals, for improving brain health and functioning. Autism Spectrum Disorder (ASD) is a neurodevelopmental disease marked by issues with speech, memory, and social behavior. Currently, an alarming rise in ASD cases among the children across the globe is being recorded. ASD has no known cure or causes; genetic or environmental factor possibly plays an important role in the development of ASD. Since dietary intervention is one of the most important solutions that might bring a positive change in the overall brain functioning of the ASD individuals. In this review, important plant food bioactives and gut microbes associated with better brain health and functioning in ASD individuals with its mode of action have been explained. Specifically plant food bioactives having influence over brain functions like memory, behavior, and cognition through balancing beneficial gut microbiota to reduce the symptoms associated with ASD are presented.
Otizm Spektrum Bozukluğu (OSB) dünya çapında gittikçe artan bir prevalans gösteren nöro-gelişimsel bir bozukluktur. OSB genellikle genetik ve çevresel faktöre bağlı olarak oluşabilmektedir. Vakaların büyük kısmı çocukluk çağında, anormal sosyal iletişim ve davranış değişiklikleri ile tanı almaktadır. Otizm, uyku problemleri, psikolojik problemleri, beslenme ve sindirim problemlerini de beraberinde getirmektedir. Beslenme problemleri sonucunda besin ögesi eksiklikleri ve malabsorpsiyona bağlı olarak çeşitli hastalıklar ortaya çıkabilmektedir. Otizmli bireylerin bakımında etkin olan kişilerin gözlem ve tespitlerine dayalı olarak değişen şekillerde beslenme tutumları gelişmektedir. OSB doğru tedavi ve yönlendirme ile pozitif yönde gelişim gösterebilen, belirtilerin azaltılabildiği bir hastalıktır. Bu çalışmada, OSB’nin ne olduğu ve OSB’li çocukların ebeveynlerinin gözlemleri ile otizmlilerde görülen beslenme problemlerine karşı ailelerin gösterdiği tutumların araştırıldığı literatürden örnekler verilmiş ve detaylı bir literatür derlemesi yapılmıştır. Çalışmada, ebeveynlerin otizmli bireylerin beslenmelerine olan yaklaşımlarının ve tutumlarının tespiti ve değerlendirilmesi mevcuttur. Çalışmamın amacı, ebeveynlerin otizmli bireylerin beslenmesi ile ilgili tutumlarının doğru şekilde yönlendirilmesi amacıyla gerçekleştirilebilecek eğitimlere ve literatüre katkı sağlayabilmektir.
Background:
In recent years, trace elements (TEs) have gained considerable attention in the course of treatment and diagnosis of ischemic stroke. The purpose of the conducted research was to determine the trace mineral status (Se, Cu, Zn, Cu/Zn ratio, and Cu/Se ratio) in patients with acute ischemic stroke compared to the population of healthy people in the northeastern region of Poland.
Materials and methods:
141 patients with acute ischemic stroke (AIS) and 69 healthy control subjects were examined. The serum concentrations of mineral components were assessed by the atomic absorption spectrometry method. Clinical parameters were updated based on medical records.
Results:
The serum Se and Zn concentrations were significantly decreased (p < 0.0001; p < 0.0001) in patients with AIS compared with healthy control subjects. However, no significant differences were revealed in terms of the serum Cu concentration (p = 0.283). As expected, we found that the serum Cu/Zn and Cu/Se molar ratios were significantly higher (p = 0.001; p < 0.0001) in patients with AIS compared with healthy control subjects.
Conclusions:
Disturbed metal homeostasis is a significant contributor to AIS pathogenesis. Furthermore, marked disruption of the serum Cu/Zn and Cu/Se molar ratios could serve as a valuable indicator of AIS patients' nutritional status and oxidative stress levels.
Autism spectrum disorder (ASD) is a common childhood neurodevelopmental disorder that may be related to trace elements. However, reports on the relationship between them are still inconsistent. In this article, we conducted a meta-analysis on this issue. We searched the PubMed, EMBASE, and Cochrane databases as of November 15, 2019. A random-effects model was used, and subgroups of studies were analyzed using samples of different measurements. Twenty-two original articles were identified (18 trace elements, including a total of 1014 children with ASD and 999 healthy controls). In autistic children, the overall levels of barium (Ba), mercury (Hg), lithium (Li), and lead (Pb) were higher. There were significant differences in the levels of copper (Cu) in the hair and serum between autistic children and the control group. The levels of Hg, Li, Pb and selenium (Se) in the hair of autistic children were higher than those of healthy children, while the levels of zinc (Zn) in the blood were lower. Excessive exposure to toxic heavy metals and inadequate intake of essential metal elements may be associated with ASD. Preventing excessive exposure to toxic metals and correcting poor dietary behaviors may be beneficial for the prevention and treatment of the disease.
Zinc is an essential micronutrient for cellular proliferation and subsequent body and brain development. Zinc deficiency is becoming a major public health issue equally in under-developed and developed countries. The lack of sufficient zinc, whether related to environmental or internal factors, is an important environmental stressor that is eligible to become elucidated as a contributing factor for the pathogenesis of autism spectrum disorder (ASD). The aim of this manuscript is to briefly overview available data regarding the relationship of zinc deficiency with the development of ASD and to relate these data with currently known pathogenetic mechanisms of this disorder namely brain growth disturbances and neuropeptides secretion. Zinc deficiency impacts brain connectivity and growth and alters adequate neurotransmission. In addition, zinc deficiency may indirectly act on the brain by disturbing the immune system and by altering the normal gut-brain connection. Zinc seems to be important for the social effect of neuropeptides. Zinc supplementation in pregnant women and newborn children with the aim of preventing ASD needs further consideration.
Background
Disproportional heavy metals and essential elements were reported in children with autism spectrum disorder (ASD) that is obscure in etiology. Inevitably, the association is biased by diet and environmental factors.
Methods
50 pairs, one with ASD and the other living together from the same special school with cerebral palsy (CP), were recruited in Hangzhou (China), aged from 2-11 years old (74.0% male). All samples were divided into two subgroups: preschool-aged (2–5 years old) and school-aged (6–10 years old). Heavy metals (As, Hg, Pb) and essential elements (Al, Ca, Cu, Mg, Mn, Zn) in hair were quantified by inductively coupled plasma mass spectrometry analysis and flame atomic absorption spectroscopy.
Results
The children with ASD generally had lower hair levels of Mn (ASD 0.124 μg/g, CP 0.332 μg/g, P = 0.001) compared to the children with CP. After stratification for age, there were no significant differences detected in preschool-aged group. In school-aged group, the results exhibited the children with ASD had higher hair Pb (1.485 µg/g, 0.690 µg/g, P = 0.007) and Cu/Zn ratio (0.092, 0.060, P = 0.003), while hair Hg (0.254 µg/g, 0.353 µg/g, P = 0.016)、Mn (0.089 µg/g, 0.385 µg/g, P = 0.002)、Mg (17.81 µg/g, 24.53 µg/g, P = 0.014) and Zn (100.15 µg/g, 135.83 µg/g, P = 0.007) showed an opposite pattern.
Conclusions
These results suggest an imbalance of Mn in Chinese children with ASD.
The aim of this study was to determine the plasma selenium (Se), copper (Cu), and zinc (Zn) levels and to evaluate their possible association with metabolic syndrome (MetS) components in patients with schizophrenia. The study group consisted of 60 patients with schizophrenia and 60 sex- and age-matched healthy controls. Anthropometric measurements, blood pressure, and biochemical analysis of fasting blood were performed in all subjects. Patients with schizophrenia had significantly higher plasma Cu concentrations compared with controls (0.97 ± 0.31 vs. 0.77 ± 0.32 mg/L, p = 0.001). The plasma Cu concentration showed a positive correlation with plasma glucose and diastolic blood pressure in the patient groups (r s = 0.263, p < 0.05 and r s = 0.272, p < 0.05, respectively). The plasma Se level correlated positive with MetS score (r s = 0.385, p < 0.01), waist circumference (r s = 0.344, p < 0.05), plasma glucose (r s = 0.319, p < 0.05), and triglyceride concentrations (r s = 0.462, p < 0.001) in patients with schizophrenia. Plasma Zn did not correlate with any of the MetS components. These results suggest that alterations in plasma Cu and Se levels in medicated patients with schizophrenia could be associated with metabolic risk factors.
In recent years, increasing evidence has shown that children with autism spectrum disorders (ASDs) have lower levels of 25-hydroxyvitamin D [25(OH) D] relative to healthy controls. The purpose of this study was to evaluate the serum 25(OH) D levels in Chinese children with ASD. From January 2012 to December 2012, consecutive patients with ASD admitted to the Department of Neurology were identified. Clinical information was collected. Serum levels of 25(OH) D were measured at baseline. ASD severity was assessed at admission using the Childhood Autism Rating Scale total score. The results indicated that the mean serum 25(OH) D levels were significantly lower in autistic children as compared with normal cases (P=0.002). There was a significant negative relationship between circulating serum 25(OH) D levels and the severity of autism evaluated according to Childhood Autism Rating Scale Scores (P=0.000), after adjustment for the possible covariates such as age, sex, BMI, serum levels of calcium, phosphate, and magnesium, and seasons. After adjusting for all other possible covariates, 25(OH) D levels that remained can be seen as an independent predictor of ASD with an adjusted odds ratio of 1.23 (95% confidence interval, 1.10-1.37). These results indicate that lower 25(OH) D levels may be independently associated with severity of ASD among Chinese patients, and lower serum 25(OH) D levels could be considered as an independent risk factor for ASD.
To assess plasma zinc and copper concentration in individuals with autism and correlate these levels with symptom severity.
Plasma from 102 autistic individuals, and 18 neurotypical controls, were tested for plasma zinc and copper using inductively-coupled plasma-mass spectrometry. Copper and zinc levels and Cu/Zn were analyzed for possible correlation with severity of 19 symptoms.
Autistic individuals had elevated plasma levels of copper and Cu/Zn and lower, but not significantly lower, plasma Zn compared to neurotypical controls. There was a correlation between Cu/Zn and expressive language, receptive language, focus attention, hyperactivity, fine motor skills, gross motor skills and Tip Toeing. There was a negative correlation between plasma zinc concentration and hyperactivity, and fine motor skills severity.
These results suggest an association between plasma Cu/Zn and severity of symptoms associated with autism.
Autism spectrum disorders (ASDs) are a group of developmental disabilities that can cause significant social, communication and behavioral challenges. Several studies have suggested a disturbance in the copper (Cu) and zinc (Zn) metabolism in ASDs. Zinc deficiency, excess Cu levels, and low Zn/Cu ratio are common in children diagnosed with an ASD. The literature also suggests that mercury accumulation may occur as a cause or consequence of metallothionein (MT) dysfunction in children diagnosed with an ASD, which may be one of the causes of Zn deficiency. MTs are proteins with important functions in metal metabolism and protection. Zinc and Cu bind to and participate in the control of the synthesis of MT proteins. Studies indicate that the GABAergic system may be involved in ASDs, and that Zn and Cu may play a role in this system.
Amyotrophic lateral sclerosis is the most common motor neuron disease and is still incurable. The mechanisms leading to the selective motor neuron vulnerability are still not known. The interplay between motor neurons and astrocytes is crucial in the outcome of the disease. We show that mutant copper-zinc superoxide dismutase (SOD1) overexpression in primary astrocyte cultures is associated with decreased levels of proteins involved in secretory pathways. This is linked to a general reduction of total secreted proteins, except for specific enrichment in a number of proteins in the media, such as mutant SOD1 and valosin-containing protein (VCP)/p97. Because there was also an increase in exosome release, we can deduce that astrocytes expressing mutant SOD1 activate unconventional secretory pathways, possibly as a protective mechanism. This may help limit the formation of intracellular aggregates and overcome mutant SOD1 toxicity. We also found that astrocyte-derived exosomes efficiently transfer mutant SOD1 to spinal neurons and induce selective motor neuron death. We conclude that the expression of mutant SOD1 has a substantial impact on astrocyte protein secretion pathways, contributing to motor neuron pathology and disease spread.
Background: The mechanism by which astrocytes contribute to disease progression in mutant SOD1 mouse models of ALS is not known.
Results: Mutant SOD1 astrocytes release mutant SOD1-containing exosomes that are toxic for motor neurons.
Conclusion: Astrocyte-derived exosomes may have a role in disease spreading and motor neuron pathology.
Significance: New therapeutic approaches should target exosomes to contain disease progression.
This study investigates both the level of toxic metals in children with autism and the possible association of those toxic metals with autism severity. This study involved 55 children with autism ages 5–16 years compared to 44 controls with similar age and gender. The study included measurements of toxic metals in whole blood, red blood cells (RBC), and urine. The autism group had higher levels of lead in RBC (+41 %, p = 0.002) and higher urinary levels of lead (+74 %, p = 0.02), thallium (+77 %, p = 0.0001), tin (+115 %, p = 0.01), and tungsten (+44 %, p = 0.00005). However, the autism group had slightly lower levels of cadmium in whole blood (−19 %, p = 0.003). A stepwise, multiple linear regression analysis found a strong association of levels of toxic metals with variation in the degree of severity of autism for all the severity scales (adjusted R
2 of 0.38–0.47, p < 0.0003). Cadmium (whole blood) and mercury (whole blood and RBC) were the most consistently significant variables. Overall, children with autism have higher average levels of several toxic metals, and levels of several toxic metals are strongly associated with variations in the severity of autism for all three of the autism severity scales investigated.
Objective:
The objective of this study was to assess the levels of ten toxic metals and essential elements in hair samples of children with autism, and to correlate the level of these elements with the severity of autism.
Method:
The participants were 44 children, age 3 to 9 years, with Autistic Spectrum Disorder (ASD) according to Diagnostic and Statistical Manual of Mental Disorders 4th Edition, (DSM-IV). The severity of autistic symptomatology was measured by the Childhood Autism Rating Scale (CARS). Hair analysis was performed to evaluate the long term metal exposure and mineral level.
Results:
By comparing hair concentration of autistic vs nonautistic children, elevated hair concentrations were noted for aluminum, arsenic, cadmium, mercury, antimony, nickel, lead, and vanadium. Hair levels of calcium, iron, iodine, magnesium, manganese, molybdenum, zinc, and selenium were considered deficient. There was a significant positive correlation between lead & verbal communication (p = 0.020) and general impression (p = 0.008). In addition, there was a significant negative correlation between zinc & fear and nervousness (p = 0.022).
Conclusion:
Our data supports the historic evidence that heavy metals play a role in the development of ASD. In combination with an inadequate nutritional status the toxic effect of metals increase along with the severity of symptoms.
To assess plasma zinc and copper concentration in individuals with Asperger's Syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) and autistic disorder, and to analyze the efficacy of zinc therapy on the normalization of zinc and copper levels and symptom severity in these disorders.
Plasma from 79 autistic individuals, 52 individuals with PDD-NOS, 21 individuals with Asperger's Syndrome (all meeting DSM-IV diagnostic criteria), and 18 age and gender similar neurotypical controls, were tested for plasma zinc and copper using inductively-coupled plasma-mass spectrometry.
Autistic and PDD-NOS individuals had significantly elevated plasma levels of copper. None of the groups (autism, Asperger's or PDD-NOS) had significantly lower plasma zinc concentrations. Post zinc and B-6 therapy, individuals with autism and PDD-NOS had significantly lower levels of copper, but individuals with Asperger's did not have significantly lower copper. Individuals with autism, PDD-NOS and Asperger's all had significantly higher zinc levels. Severity of symptoms decreased in autistic individuals following zinc and B-6 therapy with respect to awareness, receptive language, focus and attention, hyperactivity, tip toeing, eye contact, sound sensitivity, tactile sensitivity and seizures. None of the measured symptoms worsened after therapy. None of the symptoms in the Asperger's patients improved after therapy.
These results suggest an association between copper and zinc plasma levels and individuals with autism, PDD-NOS and Asperger's Syndrome. The data also indicates that copper levels normalize (decrease to levels of controls) in individuals with autism and PDD-NOS, but not in individuals with Asperger's. These same Asperger's patients do not improve with respect to symptoms after therapy, whereas many symptoms improved in the autism group. This may indicate an association between copper levels and symptom severity.
Mitochondria contain two enzymes, Cu,Zn superoxide dismutase (Sod1) and cytochrome c oxidase (CcO), that require copper as a cofactor for their biological activity. The copper used for their metallation originates from a conserved, bioactive pool contained within the mitochondrial matrix, the size of which changes in response to either genetic or pharmacological manipulation of cellular copper status. Its dynamic nature implies molecular mechanisms exist that functionally couple mitochondrial copper handling with other, extramitochondrial copper trafficking pathways. The recent finding that mitochondrial proteins with established roles in CcO assembly can also effect changes in cellular copper levels by modulating copper efflux from the cell supports a mechanistic link between organellar and cellular copper metabolism. However, the proteins and molecular mechanisms that link trafficking of copper to and from the organelle with other cellular copper trafficking pathways are unknown. This review documents our current understanding of copper trafficking to, and within, the mitochondrion for metallation of CcO and Sod1; the pathways by which the two copper centers in CcO are formed; and, the interconnections between mitochondrial function and the regulation of cellular copper homeostasis.
Twin and family studies in autistic disorders (AD) have elucidated a high heritability of AD. In this literature review, we will present an overview on molecular genetic studies in AD and highlight the most recent findings of an increased rate of copy number variations in AD. An extensive literature search in the PubMed database was performed to obtain English published articles on genetic findings in autism. Results of linkage, (genome wide) association and cytogenetic studies are presented, and putative aetiopathological pathways are discussed. Implications of the different genetic findings for genetic counselling and genetic testing at present will be described. The article ends with a prospectus on future directions.
There is mounting evidence indicating that reactive free radical species are involved in initiation and development of many different forms of human pathologies including psychiatric disorders. In the present study, we aimed to determine whether serum selenium (Se), antioxidant enzyme (glutathione peroxidase, GSH-Px, superoxide dismutase, SOD, and catalase, CAT) activities, and plasma malondialdehyde (MDA) levels, a product of lipid peroxidation, were associated with obsessive-compulsive disorder (OCD). The participants were 28 patients with OCD that were drug-free at least for a month and a control group (n=28) of healthy subjects, matched with respect to age and sex. In both groups, the levels of the erythrocyte MDA, GSH-Px, SOD, Se, and the CAT were measured. The levels of MDA and SOD were statistically significantly higher (p<0.01, p<0.05 respectively) in patients than controls. The activities of CAT, GSH-Px, and serum Se levels were statistically significantly lower (p<0.0001, p<0.001, and p<0.001 respectively) in patients than controls. There was a positive correlation in patients between plasma GSH-Px activity and Se concentration (r=52, p=0.001). However, in patients with OCD, CAT and SOD activities were significantly and negatively correlated with MDA levels (r=-0.45, p=0.017 for CAT and r=-0.54, p=0.020 for SOD). The study shows the presence of a significant relationship of OCD and oxidative stress, and consequently, an involvement of free radicals and of the antioxidant defence.
Disbalance of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer's disease, and Parkinson's disease. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn2+ and Cu2+ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn2+ and Cu2+ with amyloid precursor protein (APP), β-amyloid (Abeta), tau-protein, metallothioneins, and GSK3β are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn2+ and Cu2+.
The trace metal zinc is a biofactor that plays essential roles in the central nervous system across the lifespan from early neonatal brain development through the maintenance of brain function in adults. At the molecular level, zinc regulates gene expression through transcription factor activity and is responsible for the activity of dozens of key enzymes in neuronal metabolism. At the cellular level, zinc is a modulator of synaptic activity and neuronal plasticity in both development and adulthood. Given these key roles, it is not surprising that alterations in brain zinc status have been implicated in a wide array of neurological disorders including impaired brain development, neurodegenerative disorders such as Alzheimer's disease, and mood disorders including depression. Zinc has also been implicated in neuronal damage associated with traumatic brain injury, stroke, and seizure. Understanding the mechanisms that control brain zinc homeostasis is thus critical to the development of preventive and treatment strategies for these and other neurological disorders.
Infections can cause mortality when the immune system is damaged. The catalytic, structural (in zinc-finger proteins) and regulatory roles of zinc mean that this ion is involved in the maintenance of an effective immune response. Both zinc deficiency and impaired cell-mediated immunity combine during aging to result in increased susceptibility to infection. Dietary supplementation with the recommended daily allowance of zinc for between one and two months decreases the incidence of infection and increases the survival rate following infection in the elderly. This article reviews the biochemical pathways through which zinc might act to increase immunoresistance to infection in the elderly.
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by social and language deficits, stereotypic behavior, and abnormalities in motor functions. The particular set of behavioral impairments expressed in any given individual is variable across the spectrum. These behavioral abnormalities are consistent with our current understanding of the neuropathology of ASD which suggests abnormalities in the amygdala, temporal and frontal cortexes, hippocampus, and cerebellum. However, regions unrelated to these behavioral deficits appear largely intact. Both genetic predisposition and environmental toxins and toxicants have been implicated in the etiology of autism; the impact of these environmental triggers is associated with increases in oxidative stress, and is further exacerbated when combined with genetic susceptibility. We have previously reported increased levels of 3-nitrotyrosine (3-NT), a marker of oxidative stress, in ASD cerebella. We have also shown that this increase was associated with an elevation in neurotrophin-3 (NT-3) levels. The objectives of the current study were to determine whether the increase in oxidative stress in ASD is brain region-specific, to identify the specific brain regions affected by oxidative stress, and to compare brain region-specific NT-3 expression between ASD and control cases. The levels of 3-NT and NT-3 were measured with specific ELISAs in individual brain regions of two autistic and age- and postmortem interval (PMI)--matched control donors. In the control brain, the levels of 3-NT were uniformly low in all brain regions examined ranging from 1.6 to 12.0 pmol/g. On the other hand, there was a great variation in 3-NT levels between individual brain regions of the autistic brains ranging from 1.7 to 281.2 pmol/g. The particular brain regions with the increased 3-NT and the magnitude of the increase were both different in the two autistic cases. In the older autistic case, the brain regions with highest levels of 3-NT included the orbitofrontal cortex (214.5 pmol/g), Wernicke's area (171.7 pmol/g), cerebellar vermis (81.2 pmol/g), cerebellar hemisphere (37.2 pmol/g), and pons (13.6 pmol/g); these brain areas are associated with the speech processing, sensory and motor coordination, emotional and social behavior, and memory. Brain regions that showed 3-NT increase in both autistic cases included the cerebellar hemispheres and putamen. Consistent with our earlier report, we found an increase in NT-3 levels in the cerebellar hemisphere in both autistic cases. We also detected an increase in NT-3 level in the dorsolateral prefrontal cortex (BA46) in the older autistic case and in the Wernicke's area and cingulate gyrus in the younger case. These preliminary results reveal, for the first time, brain region-specific changes in oxidative stress marker 3-NT and neurotrophin-3 levels in ASD.
The frequency of zinc deficiency, copper toxicity and low zinc/copper in children with autism spectrum disorders (ASDs) may indicate decrement in metallothionein system functioning. A retrospective review of plasma zinc, serum copper and zinc/copper was performed on data from 230 children with autistic disorder, pervasive developmental disorder-NOS and Asperger's syndrome. The entire cohort's mean zinc level was 77.2 microg dl(-1), mean copper level was 131.5 microg dl(-1), and mean Zn/Cu was 0.608, which was below the 0.7 cut-off of the lowest 2.5% of healthy children. The plasma zinc/serum copper ratio may be a biomarker of heavy metal, particularly mercury, toxicity in children with ASDs.
Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency. Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation.
Copper is an essential element in all living organisms, serving as a cofactor for many important proteins and enzymes. Metallochaperone proteins deliver copper ions to specific physiological partners by direct protein-protein interactions. The Atx1-like chaperones transfer copper to intracellular copper transporters, and the CCS chaperones shuttle copper to copper,zinc superoxide dismutase. Crystallographic studies of these two copper chaperone families have provided insights into metal binding and target recognition by metallochaperones and have led to detailed molecular models for the copper transfer mechanism.
Copper (Cu2+) is a physiologically important cation and is released from nerve terminals. Cu2+ modulates GABAA receptor currents in an α subunit subtype-dependent manner; α1βp3γ2L receptors are more sensitive to Cu2+ than α6β3γ2L receptors. We compared the effect of Cu2+ on αβ3γ2L receptors containing each of the six α subtypes and generated α1/α6 chimeras and mutants to determine the functional domain(s) and specific residues responsible for α subtype-dependent differences in Cu2+ sensitivity. Whole-cell GABAA receptor currents were obtained from L929 fibroblasts coexpressing wildtype, chimeric and mutant α subunits with β3 and γ2L subunits. Maximal Cu2+ inhibition of α1β3γ 2L and α2β3γ2L receptor currents was larger (52.2 ± 3.0 and 59.0 ± 2.5%, respectively) than maximal inhibition of α3β3γ2L, α4β3γ2L, α5β3γ2L, and α6β3γ2L receptor currents (22.6 ± 3.1, 19.2 ± 3.4, 20.2 ± 4.8, and 21.2 ± 3.6%, respectively). Receptors containing chimeric constructs with α1 subtype N-terminal sequence between residues 127 and 232 were inhibited by Cu2+ to an extent similar to those with α1 subtypes, suggesting that this N-terminal region (127-232) contains a major determinant for high Cu2+ sensitivity. α1 subtype residues V134, R135, and H141 in a VRAECPMH motif (VQAECPMH in the α2 subtype) conferred higher Cu2+ sensitivity, and the H141 residue was the major determinant in the motif. The β3 subtype M2 domain residue H267, which is a major determinant of Zn2+ inhibition, and α6 subtype M2-M3 loop residue H273, which is responsible for the increased Zn2+ sensitivity of the α6 subtype, also seemed to contribute to Cu2+ inhibition. These data suggest that the N-terminal VR(Q)AECPMH motif in α1 and α2 subtypes is the major determinant of increased subtype-dependent inhibition by Cu2+, that residue H141 is the major determinant in that motif, and that Cu2+ may also interact with GABAA receptors at sites similar to or overlapping Zn2+ sites.
Zinc is an essential micronutrient for human growth, development, and immune function. Zinc deficiency impairs overall immune function and resistance to infection. Mild to moderate zinc deficiency can be best detected through a positive response to supplementation trials. Zinc supplementation has been shown to have a positive effect on the incidence of diarrhea (18% reduction, 95% CI: 7-28%) and pneumonia (41% reduction, 95% CI: 17-59%), and might lead to a decrease in the incidence of malaria. Zinc has also proven to decrease the duration of diarrhea by 15% (95% CI: 5-24%). Maternal zinc supplementation may lead to a decrease in infant infections. Studies assessing the role of zinc supplementation among persons with HIV, tuberculosis, and the common cold have not been conclusive. Two studies have shown zinc supplementation to decrease child mortality by more than 50%. Zinc clearly has an important role in infant and childhood infectious diseases; programs to increase the intake of zinc among deficient populations are needed.
In Wilson disease, mutations in the ATP7B-gene lead to hepatic accumulation of copper that becomes toxic when the hepatic binding capacity is exceeded, leading to oxidative stress and acute liver failure. Several proteins are probably involved in dealing with the excess copper and oxidative stress. As a first step towards biomarker discovery and analyzes of copper metabolism in Wilson disease patients we characterized copper-induced changes in protein expression in cell lysates and culture media from an in vitro copper-overload model using surface enhanced laser desorption/ionization (SELDI) proteomics technology. HepG2 cells were cultured for 48 h with a physiological (0.5 microM) or a pathological (100 microM) copper concentration. Samples were applied to weak cation exchange (WCX) proteinchip arrays and chips were analyzed by time of flight (TOF)-mass spectrometry. Copper-coated IMAC chips were used to detect copper-binding proteins in cell lysate of copper depleted cells using buffers with increasing imidazole concentrations. Data from the 2 to 50 kDa range indicate that high extra-cellular copper substantially altered both intra-cellular protein expression as well as the composition of the secretome. In the lysate 15 proteins were found up-regulated, while 6 proteins were down-regulated. In culture media 21 proteins were increased while 4 proteins were decreased in abundance. Copper-coated protein chips revealed the presence of 18 high-affinity copper-binding proteins. Further identification is necessary to determine the exact cellular roles of the discovered proteins.
On the basis of the evidence that the excitability of hippocampal glutamatergic neurotransmitter system is enhanced by dietary zinc deficiency, the response of amygdalar neurotransmitter system was checked in young rats fed a zinc-deficient diet for 4 weeks. Extracellular zinc concentration in the amygdala, which was measured by the in vivo microdialysis, was almost the same as that in the hippocampus and decreased by zinc deficiency. Extracellular zinc concentration in the amygdala was increased both in the control and zinc-deficient rats by stimulation with 100mM KCl, suggesting that the increase in extracellular zinc in the amygdala, as well as that in the hippocampus, is linked with neuronal depolarization. In amygdalar extracellular fluid, the basal glutamate concentration was not significantly different between the control and zinc-deficient rats and was increased to almost the same extent between them by stimulation with 100mM KCl, unlike more increase in extracellular glutamate concentration in the hippocampus in zinc deficiency. On the other hand, the basal GABA concentration in the amygdalar extracellular fluid was significantly lower in zinc-deficient rats and was not increased both in the control and zinc-deficient rats by stimulation with 100mM KCl. These results suggest that GABAergic neurotransmitter system is critically impaired in the amygdala of young rats after 4-week zinc deprivation.
Zinc (Zn) deficiency, a frequent condition in human population especially in aged persons, induces oxidative stress and subsequently activates/inhibits oxidant-sensitive transcription factors that can affect cell function, proliferation and survival leading to disease. Zn deficiency-triggered oxidative stress could affect cell signalling, including transcription factors containing Zn finger motifs and other oxidant-sensitive transcription factors such as nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1). AP-1 can be activated in Zn deficiency that can occur secondary to an increase in cellular H(2)O(2), followed by activation of MAPKs p38 and JNK. Similarly, the cytosolic steps of the NF-kappaB cascade are activated by oxidants in Zn deficiency. However, an impaired nuclear transport of the active transcription factor leads to a low expression of NF-kappaB-dependent genes that could be involved in multiple steps of Zn deficiency associated pathology. We present here evidence that, following experimental depletion of Zn, both NF-kappaB and AP-1 signallings are altered in primary T cells isolated from young and elderly healthy individuals under CD3/CD28 costimulation. A supplementation of Zn restored both NF-kappaB and AP-1 activation in CD3/CD28 costimulated T cells from young, but not from elderly, healthy individuals, indicating that the Zn deficiency is only one component of a more complex mechanism involved in immunosenescence. In this review we summarize our present knowledge on NF-kappaB and AP-1 activation and underline the role of Zn in this process, especially in the context of Zn deficiency observed in aged persons leading to immunosenescence.
The objective of the study was to investigate the possible role of manganese and copper (Mn/Cu) imbalance of the food chain in the focally increased occurrence of Creutzfeldt-Jakob disease (CJD). Mn and Cu concentrations in soil, drinking water and foodstuffs collected from households in the region of focal accumulation of CJD patients and the control region were measured by FAAS. Considerably higher Mn/Cu ratios in the studied region than those in the control region were found for soil (49.3 vs. 21.1), honey (8.05 vs. 4.86), and for the main local food items: potatoes (2.09 vs. 1.07) and bread (5.85 vs. 5.35), however, only soil and potatoes were of statistical significance. The results could indicate a rare coincidence of the verified endogenous CJD risk (genetic) with a very probable exogenous CJD risk factor (Mn/Cu dietary/environmental imbalance), but whether and how this coincidence may contribute to the unique, continual temporo-spatial clustering of genetic CJD should be investigated in further studies.
Disordered metal metabolism in a large autism population. Presented at the American Psychiatric Association Annual Meeting
- Wj Walsh
- A Usman
- J Tarpey
Walsh WJ, Usman A, Tarpey J. Disordered metal metabolism in a large autism
population. Presented at the American Psychiatric Association Annual
Meeting. May, 2001, New Orleans. Available at: http://www.safeminds.
org/research/library/20010501.pdf.
Disordered metal metabolism in a large autism population
- W J Walsh
- A Usman
- J Tarpey
Walsh WJ, Usman A, Tarpey J. Disordered metal metabolism in a large autism
population. Presented at the American Psychiatric Association Annual
Meeting. May, 2001, New Orleans. Available at: http://www.safeminds.
org/research/library/20010501.pdf.