Advances in Autism Research
compiled by Teresa Binstock for ARI
Hormones & Toxic Metals in Autism
Boyd E. Haley, Ph.D., is chair of chemistry at the University of Kentucky. Dr. Haley has studied mercury and its effects for a long time, his curiosity prompted by thimerosal sensitivity he had while quite young. He has written extenstively on his findings that testosterone exacerbates mercury toxicity. Clinical ramifications have been published by Mark R. Geier, M.D., Ph.D., and his son and colleague David A. Geier, Ph.D., and others.
1. Biomarkers supporting mercury toxicity as the major exacerbator of neurological illness, recent evidence via the urinary porphyrin tests
Interview with Boyd E. Haley, Ph.D.
Chair of Chemistry Department, Univ of Kentucky
Medical Veritas 3 (2006) 921-934
2. Toxic Overload: Assessing the Role of Mercury in Autism
Boyd E. Haley, Ph.D.
Chair of Chemistry Department, Univ of Kentucky
Mothering Magazine; Issue 115, November/December 2002
3. Testimony Before the House Government Reform Committee
Boyd Haley, Ph.D.
Chair of Chemistry Department, Univ of Kentuck
November 14, 2002
4. Porphyrinuria in childhood autistic disorder: implications for environmental toxicity
Nataf R et al.
Toxicol Appl Pharmacol. 2006 Jul 15;214(2):99-108.
To address a possible environmental contribution to autism, we carried out a retrospective study on urinary porphyrin levels, a biomarker of environmental toxicity, in 269 children with neurodevelopmental and related disorders referred to a Paris clinic (2002-2004), including 106 with autistic disorder. Urinary porphyrin levels determined by high-performance liquid chromatography were compared between diagnostic groups including internal and external control groups. Coproporphyrin levels were elevated in children with autistic disorder relative to control groups. Elevation was maintained on normalization for age or to a control heme pathway metabolite (uroporphyrin) in the same samples. The elevation was significant (P < 0.001). Porphyrin levels were unchanged in Asperger's disorder, distinguishing it from autistic disorder. The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder (P < 0.001) but not significantly in Asperger's. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) with a view to heavy metal removal. Following DMSA there was a significant (P = 0.002) drop in urinary porphyrin excretion. These data implicate environmental toxicity in childhood autistic disorder.
5. A prospective assessment of porphyrins in autistic disorders: a potential marker for heavy metal exposure
Geier DA, Geier MR.
Neurotox Res. 2006 Aug;10(1):57-64.
Autism was recently associated with a urinary porphyrin pattern indicative of mercury toxicity in a large cohort of French children. The IRB of the Institute for Chronic Illnesses approved the present study. A total of 37 consecutive American patients (> or = 7 years-old) with autism spectrum disorders (ASDs) (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-DSM IV), born from 1983-1998, that presented to the Genetic Centers of America for outpatient genetic evaluations were prospectively examined for urinary prophryin levels (LabCorp, Inc.) from June 2005-June 2006. Imaging and laboratory testing were conducted on each patient to rule-out other causal factors for their ASDs. As controls, age-, sex-, and race-matched neurotypical ASD siblings were examined. An apparent dose-response effect was observed between autism severity and increased urinary coproporphyrins. Patients with non-chelated autism (2.25-fold, 83% had levels > 2 SD above the control mean) and non-chelated ASDs (2-fold, 58% had levels > 2 SD above the control mean), but not patients with non-chelated pervasive developmental delay-not otherwise specified (PDD-NOS) or Asperger's disorder (1.4-fold, 46% had levels > 2 SD above the control mean), had significantly increased median coproporphyrin levels versus controls. A significant increase (1.7-fold) in median coproporphyrin levels was observed among non-chelated ASD patients versus chelated ASD patients. Porphyrins should be routinely clinically measured in ASDs, and potential ASD treatments should consider monitoring porphyrin levels. Additional research should be conducted to evaluate the potential role for mercury exposure in some ASDs.
6. A prospective study of mercury toxicity biomarkers in autistic spectrum disorders
Geier DA, Geier MR.
J Toxicol Environ Health A. 2007 Oct;70(20):1723-30.
Porphyrins are derivatives formed in the heme synthesis pathway and porphyrins afford a measure of xenobiotic exposure. The steps in the heme pathway most vulnerable to heavy metal inhibition are uroporphyrin decarboxylase (UROD) and coproporphyrinogen oxidase (CPOX) reactions. Mercury toxicity was associated with elevations in urinary coproporphyrin (cP), pentacarboxyporphyrin (5cxP), and precoproporphyrin (prcP) (also known as keto-isocoproporphyrin) levels. Two cohorts of autistic patients in the United States and France had urine porphyrin levels associated with mercury toxicity. A prospective study of urinary porphyrin testing at LabCorp (United States) and the Laboratoire Philippe Auguste (France) involving 71 autism spectrum disorder (ASD) patients, neurotypical sibling controls, and general population controls was undertaken. ASD patients had significant elevations in urinary levels of cP, 5cxP, and prcP relative to controls, and > 50% of ASD patients had urinary cP levels more than 2 standard deviations above the mean values for neurotypical sibling controls. Significant reductions in urinary 5cxP and cP levels were observed in ASD patients following chelation. A significant correlation was found between urinary porphyrins measured at LabCorp and those measured at the Laboratoire Philippe Auguste on individual ASD patients. The established developmental neurotoxicity attributed to mercury and biochemical/genomic evidence for mercury susceptibility/toxicity in ASDs indicates a causal role for mercury. Urinary porphyrin testing is clinically available, relatively inexpensive, and noninvasive. Porphyrins need to be routinely measured in ASDs to establish if mercury toxicity is a causative factor and to evaluate the effectiveness of chelation therapy.
7. A clinical trial of combined anti-androgen and anti-heavy metal therapy in autistic disorders
Geier DA, Geier MR.
Neuro Endocrinol Lett. 2006 Dec;27(6):833-8.
BACKGROUND: A medical hypothesis has suggested that some autism spectrum disorders (ASDs) may result from interactions between the methionine cycle-transsulfuration and androgen pathways following exposure to mercury. METHODS: The IRB of the Institute for Chronic Illnesses approved the present study. A novel treatment was utilized combining LUPRON (leuprolide acetate, TAP Pharmaceuticals, Inc.) and CHEMET (meso-2, 3-dimercaptosuccinic acid--DMSA, McNeil Consumer Products Company) on 11 consecutive children with ASDs. RESULTS: A significant (p<0.01) overall improvement from the 70-79th percentile of severity (median baseline score=87) at baseline to the 40-49th percentile of severity (median end of study period score=63) at the end of the study was observed for patients treated for a median of approximately 4 months. Significant improvements in sociability, cognitive awareness, behavior, and clinical symptoms/behaviors of hyperandrogenemia were also observed. Significant decreases in blood androgens and increases in urinary heavy metal concentrations were observed. Minimal drug adverse effects were found. CONCLUSION: This study provides the first clinical evidence for the benefit that combined anti-androgen and anti-heavy metal therapy may have on some children with ASDs. Additional studies should examine androgen and heavy metal mechanisms of action in ASDs, and future ASD treatment protocols should consider androgens and heavy metals.
8. A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders
Geier DA, Geier MR.
Horm Res. 2006;66(4):182-8.
BACKGROUND/AIMS: The prevalence of autism spectrum disorders (ASDs) is 1 in 300 children in the US. ASDs are characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movement patterns, and sensory dysfunction. Pre-pubertal age children with ASDs were assessed for metabolites in the methionine cycle-transsulfuration and androgen pathways, and for present physical development/behaviors indicative of hyperandrogenicity. METHODS: The Institutional Review Board of the Institute for Chronic Illnesses (Office for Human Research Protections, US Department of Health and Human Services IRB number: IRB00005375) approved the present study. Sixteen consecutive pre-pubertal age children (</=11 years old; mean +/- SD: 5.9 +/- 2.1 years old) with previously diagnosed ASDs that presented to the Genetic Centers of America for outpatient care were evaluated. RESULTS: Significantly (p < 0.01) increased levels of serum/plasma dehydroepiandrosterone and serum total testosterone relative to the age- and sex-specific normal laboratory reference ranges were observed. Conversely, serum follicle-stimulating hormone levels were significantly (p < 0.01) decreased. Plasma-reduced glutathione (p < 0.01), plasma cysteine (p < 0.01), plasma methionine (p < 0.01), serum cystathionine (p < 0.05), and serum homocysteine (p < 0.01) were all significantly decreased. CONCLUSION: The results suggest a possible cyclical interaction between the methionine cycle-transsulfuration and androgen pathways in some children with ASDs. Copyright (c) 2006 S. Karger AG, Basel.
9: The potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity
Geier MR, Geier DA.
Med Hypotheses. 2005;64(5):946-54.
Autism is a neurodevelopmental disorder that according to the Centers for Disease Control and Prevention (CDC) affects 1 in 150 children in the United States. Autism is characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recently emerging evidence suggests that mercury, especially from childhood vaccines, appears to be a factor in the development of the autistic disorders, and that autistic children have higher than normal body-burdens of mercury. In considering mercury toxicity, it has previously been shown that testosterone significantly potentates mercury toxicity, whereas estrogen is protective. Examination of autistic children has shown that the severity of autistic disorders correlates with the amount of testosterone present in the amniotic fluid, and an examination of a case-series of autistic children has shown that some have plasma testosterone levels that were significantly elevated in comparison neurotypical control children. A review of some of the current biomedical therapies for autistics, such as glutathione and cysteine, chelation, secretin, and growth hormone, suggests that they may in fact lower testosterone levels. We put forward the medical hypothesis that autistic disorders, in fact, represents a form of testosterone mercury toxicity, and based upon this observation, one can design novel treatments for autistics directed towards higher testosterone levels in autistic children. We suggest a series of experiments that need to be conducted in order to evaluate the exact mechanisms for mercury-testosterone toxicity, and various types of clinical manipulations that may be employed to control testosterone levels. It is hoped by devising therapies that address the steroid hormone pathways, in addition to the current treatments that successful lower heavy metal body-burdens of mercury, will work synergistically to improve clinical outcomes. In light of the fact that there are a number of other diseases that may have a chronic mercury toxicity component, such as Alzheimer's disease, heart disease, obesity, ALS, asthma, and other various forms of autoimmune disorders, it is imperative that further research should be conducted to understand mercury-testosterone toxicity.
10: A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies
Geier DA, Geier MR.
Neuro Endocrinol Lett. 2007 Oct;28(5):565-73.
Impairments in social relatedness and communication, repetitive behaviors, abnormal movement patterns, and sensory dysfunction characterize autism spectrum disorders (ASDs). Seventy consecutive patients with an ASD diagnosis (DSM-IV criteria, >/= 6 years-old) who presented to the Genetic Centers of America for outpatient genetic/developmental evaluations from 2005-2007 were examined. Patients were evaluated using CLIA-approved Laboratory Cooperation of America (LabCorp) testing for: serum testosterone, serum free testosterone, % free testosterone, serum/plasma dehydroepiandrosterone (DHEA), androstendione, and follicle-stimulating hormone (FSH). Morning blood samples collected following an overnight fast, compared to the pertinent reference means, showed significantly increased relative mean levels for: serum testosterone (158%), serum free testosterone (214%), percent free testosterone (121%), DHEA (192%), and androstenedione (173%). By contrast, compared to the pertinent reference mean, the relative mean level of FSH (51%) was significantly decreased. Additionally, at least one of the androgen attributes examined exceeded its recognized laboratory age- and sex-specific reference range in 81.4% (57 of 70) of the patients examined. With respect to their age- and sex-specific reference ranges, females had significantly higher overall mean relative testosterone and relative free testosterone levels than males. Increased androgens in patients diagnosed with ASDs may involve cyclical interactions between the androgen and the transsulfuration pathways, particularly following mercury exposure. A review of therapies that have significantly improved clinical outcomes in ASD patients indicates they share commonality in helping lower androgens. Thus, androgens should be routinely clinically measured in patients with an ASD diagnosis and appropriate androgen-lowering therapies considered for those who have significantly elevated levels.
11: A case series of children with apparent mercury toxic encephalopathies manifesting with clinical symptoms of regressive autistic disorders
Geier DA, Geier MR.
J Toxicol Environ Health A. 2007 May 15;70(10):837-51.
Impairments in social relatedness and communication, repetitive behaviors, and stereotypic abnormal movement patterns characterize autism spectrum disorders (ASDs). It is clear that while genetic factors are important to the pathogenesis of ASDs, mercury exposure can induce immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with ASDs. The Institutional Review Board of the Institute for Chronic Illnesses (Office for Human Research Protections, U.S. Department of Health and Human Services, IRB number IRB00005375) approved the present study. A case series of nine patients who presented to the Genetic Centers of America for a genetic/developmental evaluation are discussed. Eight of nine patients (one patient was found to have an ASD due to Rett's syndrome) (a) had regressive ASDs; (b) had elevated levels of androgens; (c) excreted significant amounts of mercury post chelation challenge; (d) had biochemical evidence of decreased function in their glutathione pathways; (e) had no known significant mercury exposure except from Thimerosal-containing vaccines/Rho(D)-immune globulin preparations; and (f) had alternate causes for their regressive ASDs ruled out. There was a significant dose-response relationship between the severity of the regressive ASDs observed and the total mercury dose children received from Thimerosal-containing vaccines/Rho (D)-immune globulin preparations. Based upon differential diagnoses, 8 of 9 patients examined were exposed to significant mercury from Thimerosal-containing biologic/vaccine preparations during their fetal/infant developmental periods, and subsequently, between 12 and 24 mo of age, these previously normally developing children suffered mercury toxic encephalopathies that manifested with clinical symptoms consistent with regressive ASDs. Evidence for mercury intoxication should be considered in the differential diagnosis as contributing to some regressive ASDs.