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Objective: the aim of this study was to provide evidence that DMSA detoxification treatments cause a reduction of the heavy metal burden in the autistic, and that this reduction lessens neurological symptoms associated with ASD (Autistic Spectrum Disorder).
Method: The participants were 44 children, age 3 to 9 years of age, with Autistic Spectrum Disorder (ASD) according to Diagnostic and Statistical Manual of Mental Disorders 4t Edition, (DMS-IV). The severity of the autistics symptomatologiy had been measured by the Childhood Autism Rating Scale (SCARS). We collected urine samples before and after the DMSA challenge test, comparing urine metal output. We also compared the results of the DMSA detoxification(=the urine challenge test) with behavioral effects, typical for ASD.
Results: The DMSA challenge test increased the urine metal output for a number of potentially toxic metals. Statistically significant difference were noted between the baseline urine and DMSA challenge test regarding the level of cadmium, mercury, and lead (P=0.006, P=0.049, and P=0.008 respectively). We also noted that behavioral effects, typical for ASD (autism spectrum disorders) were reduced with this method of detoxification. A comparison between CARS Subscales and Total Score before and after a 6-month chelation program showed greatest improvements for Verbal and nonverbal communication (P <0.001), Taste, Smell and Touch (P 0.001) and Relating to People (P 0.005). Other improvements were noted for Adaptation to Change and Improvement.
Conclusion: DMSA chelation increased the urinary output of toxic and neurotoxic metals. Our data supports evidence that detoxification treatment with oral DMSA has beneficial effect on ASD patients.
Autism is a neuro-developmental disorder characterized by qualitative impairments in social interaction and communication, along with restricted activities and interests (1).
The pathophysiological etiologies which precipitate autism symptoms remain elusive and controversial in many cases, but both genetic and environmental factors (and their interactions) have been implicated. One environmental factor that has received significant attention is the body burden of mercury, lead, and other toxic metals (2).
The etiology of autism remains unclear; both environmental and genetic factors have been suggested. Because heavy metals disrupt enzyme functions and cellular signaling processes and generate oxidative stress leading to apoptosis, they could play either a fundamental or a modulating role in the etiology of autism (3).
Heavy metal toxicity can occur from either a high exposure or a decreased ability to excrete heavy metals, with the latter case seeming to be the primary issue in autism. The primary mechanism for excreting mercury and some other toxic metals from the body involves binding to glutathione and then being excreted in the bile (4). Infants are especially vulnerable to metal poisoning because they are poor excretors due to low production of glutathione (5).
The individual burden of toxic metals was assessed based on urinary excretion, both before and after taking oral dimercaptosuccinic acid (DMSA). DMSA is an approved medication, considered safe and effective for treating lead intoxication incases meeting toxic criteria.
In addition, DMSA is widely used off-label for other metal exposures, for example, mercury. It acts by forming sulfhydryl linkages to divalent metal cations, forming a chelated metal complex which is excreted in the urine (6). It is considered an efficient chelating agent, safe for children (7).
Soden et al. (8) asserted that DMSA provoked excretion tests fail to yield evidence of an excess body burden of arsenic (As), cadmium (Cd), and mercury (Hg) in children with autism and the study by Kern et al. (9) on toxicity biomarkers in autism spectrum disorder suggests that increased levels of urinary porphyrins are associated with mercury toxicity. In the Kern study, mercury (Hg) excretion rate was reported to be six-fold higher in children with ASD, compared to healthy controls. The study hypothesized that heavy metals play a role in the development of autism and that further studies on urinary metal excretion are warranted (9).
We used the oral chelator 2,3-dimercaptosuccinic acid (DMSA) to stimulate heavy metal mobilization in children with autistic spectrum disorders (ASD), and correlated urine excretion results to determine how behavioral symptoms are affected. We noticed that the severity of a child's autistic symptoms improves after treatment with this "metal-removing therapy". This is in support of previous studies by the authors which indicate that heavy metal exposure is prevalent in autistic children and related to autistic symptoms (10). ❑
This study examines whether dimercaptosuccinic acid DMSA, an oral chelating agent that removes lead, mercury and other metals from the body, is beneficial for children with autism. The study aimed to evaluate how DMSA therapy affects behavior.
The participants were 44 Autistic spectrum disorder (ASD) children: 37 boys and 7 girls between the age of 3 and 9 years. Of the total 44 patients, 39 were diagnosed as autistic; two children had been diagnosed with Asperger Syndrome, and three with pervasive developmental disorder (NOS).
The children were either diagnosed previously by other psychiatrists, psychologists, and developmental pediatricians or were suspected by their parents as being autistic. All children attended the child psychiatric clinic of the Erfan Psychiatric Hospital in Jeddah, KSA. Samples were collected during the period of June 2006 to September 2010. All parents signed written informed consent form.
The following entry criteria were applied:
They included refusal to participate, physically handicapped children and children with progressive neurological disorders and unstable epilepsy. We excluded children who were taking regular medications including stimulants, anticonvulsants, and atypical antipsychotic drug.
All of the children admitted to the study received routine childhood vaccinations. All autistic children were subjected to a full clinical child psychiatric sheet for diagnosis of autism spectrum disorder and exclusion of other psychiatric disorder according to Diagnostic and Statistical Manual of Mental Disorders 4th Edition, (DSM-IV) (11).
The severity of autistic symptomatology was measured by the Childhood Autism Rating Scale (CARS), translated by El-Dafrawi. It consists of 15 categories, each rated on a four-point scale. The individual is considered non-autistic when his total score falls in the range of 15-29, mild-to-moderately autistic when his total score falls in the range of 30-36, and severely autistic when his total score falls in the range of 37-60 (12,13).
Reassessment of severity of autistic criteria had been done six months after treatment with the chelating substance DMSA using the Childhood Autism rating Scale CARS. ❑
To avoid nutritional inadequacies, the psychiatric clinic provided nutritional supplements, including a multimineral-vitamin-amino acid complex in powder form and zinc gluconate (15mg) previous to chelation. Clinic staff members were in charge of distributing these supplements on a daily basis for three months prior to chelation.
Before DMSA was administered, renal function and normal blood chemistry tests were performed at Erfan Hospital Clinical Laboratory. We also tested the toxic metal content in unchallenged urine samples (baseline urine) as follows:
Baseline urine (first morning urine):
Prior to the DMSA urine challenge, urine samples were collected from all children in the early morning. To avoid contamination, urine collection cups and tubes had been provided to the Centre by Micro Trace Minerals Laboratories of Germany At the laboratory, samples were acid-digested with certified metal-free acids involving closed vessel microwave digestion. For sample dilution ultrapure water was used. Testing was performed via inductively coupled plasma with mass spectrometry (ICP-MS), utilizing cell technique. Certified urine standards and in-house standards were used to validate result (14).
DMSA urine challenge test:
We prepared the children for the challenge test as follows:
Thereafter, according to the management plan, all children were advised to take one single dose of DMSA per month, specifically 10 mg/kg body weight for a total of 6 months.
Special data files were developed in the computer corresponding to the available data using Excel program 2010. These data were converted and manipulated by using SPSS software program version 17.0. Data were analyzed: characteristics of the sample was presented; mean and standard deviation was estimated as regarding age, developmental milestones in months and numbers and percentages were calculated in regards to sex distribution, type of diagnosis and classification of the test group as regarding CARS total score (mild, moderate and severe). We compared the pre- and post-DMSA results, t test and p value were calculated, and we also compared CARS subscales and total score before and after the 6-month regimen of monthly DMSA chelation treatment, using the same statistical tests to identify the statistically significant difference between groups. Correlation between urine toxic metal levels and subscales scores and total score of CARS was done among cases as a whole. Those correlations were done to test the positive and negative relations between the two variables. The Pearson test was done and the p value was calculated. The relations and correlations were considered statistically significant when p <0.05 and considered highly statistically significant if p <0.01. Tables were presented by using the same SPSS program (15). The level of significance was set at p <0.05. ❑
Table Table11 shows that 37 (84%) of the sample were boys in contrast to 7 (16%) girls. The mean age of the whole sample was 5.11±1.57. Thirty-nine children were diagnosed as autistic, 2 (4.5%) with Asperger Syndrome, and 3 (6.9%) were diagnosed PDD (NOS). The mean age of sitting was (6.77±0.96), crawling (10.41±1.65), walking (13.70±1.49), and talking (12.56± 4.03).
We need to point out that in nonexposed individuals, the urine metal excretion under non-challenged situations provides inconspicuous results. If food, drink and the environment are relatively metal-free, baseline urine values fall within the reference range as listed in Table Table11 and and2.2. The reference ranges employed and listed here are provided by environmental agencies such as the UBA (Umweltbundesamt) and WHO (World Health Organisation).
For this autistic group, the baseline urine concentration of all metals tested exceeded the given reference range. Significant deviations were noted for Aluminum, Arsenic, Chromium, Nickel and Lead. This indicates immediate exposure.
There were statistical significant difference between the Baseline urine and the DMSA challenge test regarding the level of cadmium, mercury, and lead. This indicates that DMSA stimulates binding and excretion of these metals. We could see no indication from our data that DMSA affects arsenic, chromium, antimony, nickel, uranium and vanadium. In fact, when comparing the mean and standard deviation (SD) of baseline vs challenge values, DMSA administration did not affect these metals (As, Cr, Sb, Ni, U, V). In fact, it slightly lowered urinary excretion.
This raises the question regarding exposure, strengthening the hypothesis that metal exposure in autistic groups is often immediate, possibly caused by metal-rich food, drink and the environment.
There was a significant positive correlation between Baseline urine Aluminum & body use, taste, smell, touch responses, and Total CARS. This indicates that a higher aluminum exposure is associated with increased impairment in these body functions and higher Total CARS.
There was a significant positive correlation between Baseline urine Arsenic & Verbal communication. This means that a higher arsenic exposure is associated with impairment in verbal communication.
There was a significant positive correlation between Baseline urine Cadmium & taste, smell and touch responses. This indicates that cadmium exposure impairs taste, smell, and touch responses.
There was a significant positive correlation between Baseline urine Chromium & body use, auditory response, and taste, smell, touch responses. This means that the higher chromium exposure is associated with impairment in body use, auditory responses, and taste, smell, touch responses.
There was a significant positive correlation between Baseline urine Mercury & taste, smell & touch responses. Mercury exposure is thus associated with impairment in taste, smell, and touch responses.
There was a significant positive correlation between Baseline urine Uranium & taste, smell & touch responses. This means that uranium exposure is associated with taste, smell, and touch response impairment.
There was a significant positive correlation between Baseline urine Vanadium & body use, auditory response, taste, smell, touch responses, and Total CARS. This could indicate that vanadium exposure is associated with more impairment in body use, auditory response, taste, smell, touch responses and higher Total CARS.
There were statistical significant difference (Table (Table4),4), indicating that DMSA chelation treatment is beneficial in the reduction of different symptoms of autism such as:
The majority of patients in this study were boys (84%) as outlined in Table Table1.1. This was in line with Whiteley et al (2010) (16) who noticed a greater preponderance of males over females (approximating 4:1) among autistic children.
Thirty-nine children were diagnosed as autistic, 2 (4.5%) as Asperger Syndrome, and 3 (6.9%) were diagnosed as PDD (NOS) (Table (Table1).1). This was consistent with Fombonne who claimed that autism is the most common of the Pervasive Developmental Disorders and is increasingly referred to as one of the Autism Spectrum Disorders (18).
In our group, the mean age of sitting was (6.77±0.96), crawling (10.41±1.65), walking (13.70±1.49), and talking (12.56±4.03) (Table (Table1).1). Filipek et al stated that in some cases autistic infants appear to develop normally until age 1 to 3 years. Then, sudden changes may occur that indicate the presence of ASD (19).
There were statistically significant difference between the baseline urine and DMSA challenge test regarding the level of cadmium, mercury, and lead (p=0.006, p=0.049, and p= 0.008 respectively). Levels of cadmium, mercury, and lead were higher during the DMSA challenge test (mean=0.97±0.01, 16.12± 36.57, 41.48±12.43 respectively) than the baseline urine level (mean=0.86±0.04, 3.35± 3.81, 31.48±11.52 respectively) (Table (Table2).2). This was in line with Adams et al who stated that the severity of autism significantly correlated with the body burden of toxic metals as assessed through pre challenge tests (20).
Urine measurements before taking DMSA provide an indication of an immediate environmental exposure. Urine tests performed after the DMSA challenge reflect the accumulated or relative body burden (14,21,22).
DMSA therapy appears to be generally safe and effective in reducing specific symptoms of autism in some children (7). Bradstreet et al. investigated the body burden of toxic metals by giving DMSA and found that the urinary mercury excretion of children with autism was 3.1 times higher after the DMSA challenge (21). Lonsdale's findings indicate that detoxification treatment may have beneficial effects on some autistic children (25). Our data supports this.
In 2010, Yorbik et al linked Chromium, Cadmium and Lead levels in urine of children with autism (26). Bernard et al reported about mercury intoxication and its relation to autism (28). From our data we observed that the metals Aluminum, Cadmium, Chromium, Mercury, Uranium and Vanadium caused the most noticeably impairement with Taste, Smell and Touch Response being affected the most. In summary:
The results of this study support previous research, suggesting that toxic metals contribute to the severity of autism. Geier et al speculated that Autism may be "a combination of genetic/biochemical susceptibilities in the form of a reduced ability to excrete mercury and/or increased environmental exposure at key developmental times" (27). Bernard et al. hypothesized that postnatally exposed children develop articulation problems and show an inability to generate meaningful speech (28).
Our evaluation confirmed specific metals as neuro-developmental toxins, and we observed that a reduction in toxic metals is helpful in reducing some symptoms typically associated with autism. Through detoxification methods such as DMSA chelation, we reduced the severity of symptoms among our autistic group. ❑
Specific toxic metals affect the severity of symptoms typically seen in autism spectrum disorder, and we recommend that a larger study assesses the severity of autism symptoms, both before and after DMSA treatment. Such a study should include genetic tests such as the Glutathion S-transferases, because missing or nonfunctioning enzyme systems affect the body's natural detoxification mechanism. Research into the genetic make-up of the autistic population would enhance present knowledge about the far-reaching influence of toxins. Such a comprehensive study would provide much needed information on why toxins affect populations differently. It would also lend credibility to the notion that toxic metals influence autism severity and that detoxification therapy along with nutritional therapy provide a novel form of treatment to alleviate toxicity and autistic symptoms (29-31).