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Sulphation deficit in "Low-Functioning" autistic children: A pilot study
Abstract
Parents of autistic children and autism support groups often report that autistic episodes are exacerbated when the children eat certain foodstuffs such as dairy products, chocolates, wheat, corn sugar, apples, and bananas. The hypothesis that autistic behavior might be related to metabolic dysfunctions has led us to investigate in a group of "low functioning" autistic children and in an age-matched control group each made up of 20 subjects, the sulphation capacity available.
Utilizing the biochemical characteristics of paracetamol we evaluated by high performance liquid chromatography, the urine paracetamol-sulfate/paracetamol-glucuronide (PS/PG) ratio in all subjects following administration of this drug.
The PS/PG ratio in the group of autistic subjects gave a significantly lower results than the control group with p < .00002.
The inability to effectively metabolize certain compounds particularly phenolic amines, toxic for the CNS, could exacerbate the wide spectrum of autistic behavior.
... Genetic and immune factors associated with an increased risk of ASD have a detrimental effect on the body's ability to metabolize APAP. 3,54,70) Prenatal and postnatal: evaluation of molecular mechanism 20. APAP is known to be highly toxic in the presence of oxidative stress. ...
... None of the four studies suggested that APAP might cause ASD. The initial study, by Alberti et al. 54) in Italy, showed profound impairment of APAP metabolism in children with ASD and was published in 1999, several years prior to the study of Schultz et al. 46) However, Alberti et al. 54) did not suggest that exposure to APAP causes ASD. Furthermore, the study of Alberti et al. 54) was cited in PubMed-indexed journals only 3 times prior to 2006, [55][56][57] all within the context of understanding the physiology of ASD, not the cause. ...
... Unfortunately, children with ASD tend to have an impaired ability to utilize the sulfate pathway. 54,65,66) Additionally, children with ASD tend to experience oxidative stress, 3,67) which depletes glutathione. 65) Furthermore, APAP exposure significantly de pletes glutathione, 68) suggesting that re peated exposure to the drug is potentially more hazardous than a single exposure. ...
Despite worldwide acceptance of acetaminophen as a necessary medicine in the field of pediatrics, evidence that early life exposure to acetaminophen causes neurodevelopmental injury in susceptible babies and children has mounted for more than a decade. Evidence is diverse, including extensive work with laboratory animals, otherwise unexplained associations, factors associated with the metabolism of acetaminophen, and some limited studies in humans. Although evidence has reached an overwhelming level and has been reviewed in detail recently, some controversy remains. In this narrative review, some of those controversies are evaluated. Evidence from the prepartum and the postpartum period is considered, avoiding controversies raised by considering only the limited evidence pointing exclusively toward risks during the prepartum period. Among other issues, the associations through time between acetaminophen use and the prevalence of neurodevelopmental disorders are considered. A systematic review reveals that the use of acetaminophen in the pediatric population was never tracked carefully, but historical events that affected use of the drug were documented and are sufficient to establish apparent correlations with changes in the prevalence of neurodevelopmental disorders. In addition, problems with exclusive reliance on results from meta-analyses of large datasets and from studies involving small time frames of drug exposure are reviewed. Further, evidence demonstrating why some children are susceptible to acetaminophen-induced neurodevelopmental injury is examined. It is concluded that, at least among the factors considered, there is no valid rationale for controversy regarding the conclusion that early life exposure to acetaminophen causes neurodevelopmental injury in susceptible babies and small children.
... 62, p. 153 They are distinguished from other cultural concepts of a more pernicious possession by the devil. 63 Evil spirits can sometimes act alone, but most of the time they are believed to be acting in accordance with God's orders. This can happen because the sick individual has sinned and, therefore, God sent the spirits to possess him as punishment. ...
... This is a grave offense in Arab Bedouin tradition. 63 Spirits can be healed by a "Darvish", a traditional healer versed in the holy text of the Koran, who is able to communicate with and overpower the evil spirits. There are several schools of thought when it comes to the training of a "Darvish", and the result is a mixture of different kinds of therapeutic approaches. ...
... Family presence is an important part of the ritual, and the healer will often engage with them during the healing ceremony. 63 However, the treatment is for not only the short term, but focusing more on the solution to the immediate problem. The "Darvish" is a religious authority and, just as Western physicians try to instill healthy lifestyles in their patients for the prevention of illness, the "Darvish" does the same from his perspective. ...
... Autistic children usually show abnormal sulfate capacity and a specific inability to sulfate paracetamol causing them to process acetaminophen differently. 35,36 Parents of autistic children may also exhibit abnormal trans sulfuration metabolism. 37 Actually it is possible that children predisposed to developing autism have a sulfation deficit which may lead to increased blood levels of acetaminophen after administration of therapeutic doses. 2 The American Academy of Pediatrics warned that clinical signs of liver diseasefever and abdominal painare often treated with acetaminophen. ...
... Parents and autism support groups commonly report that autistic episodes are triggered when these children eat wheat, corn, sugar, apples, bananas, chocolate, cheese, and other dairy products. 35 Because many of these "trigger" foods are high in phenolic amines (e.g., dopamine and serotonin) that depend on sulfate for excretion, sulfate metabolism in children with autism has been investigated. 51 The liver uses sulfate derived from the amino acid cysteine to make a variety of foreign and domestic substances soluble for excretion. ...
... 55 Reduced ability of autistic children to sulfate phenols and amines might lead to accumulations of un-metabolized catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine) in the brain, with neurotoxic effects. 35 www.ajptr.com ...
Autism Spectrum Disorder (ASD) represents a major public health concern as a prevalent neurodevelopmental disorder with pronounced risk for failure of adaptation across social, educational, and psychological outcomes. The exact etiology of autism is unclear. However there is a lot of research work giving some insights about the possible predisposing factors that enhance chance of autism. Several lines of evidence suggest that prenatal and/or early life acetaminophen exposure may adversely affect neurodevelopment increasing incidence of autism. Since 1980 acetaminophen greatly has replaced aspirin as an analgesic and anti-pyretic following reports indicating that aspirin use was associated with Reye‟s syndrome. Notably acetaminophen use has been associated with at least a 10-fold rise of autism epidemic since the early 1980s.Several mechanisms have been suggested to implicate the role of acetaminophen in pathogenesis of autism as altered immune function and impaired hepatic detoxification capacity resulting in
accumulation of potentially neurotoxic metabolites. In early life, maturational compromises to the glucuronidation pathway in combination with the compromises to the sulfation pathway that typify autistic children, may lead to utilization of the suboptimal secondary metabolic routes with the potential for adverse neurological effects in susceptible individuals. Acetaminophen use during pregnancy has also been associated with altered metabolism increasing autism rates in born infants. The use of acetaminophen may also trigger autism by activating the endocannabinoid system thereby interfering with normal development. Accumulating evidence linking significantly increased rates of autism with prenatal and early life acetaminophen exposure strongly suggests its cautious use during these critical times.
... Salicylates are phenolic compounds, and phenols are catalyzed through sulfation by the phenol sulfotransferase (PST) enzyme requiring adequate sulfate [63]. Children with ASD are very low in sulfate and lack the ability to sulfate [16,63], so it is likely that this is a mechanism of action that makes this diet particularly beneficial. ...
... Salicylates are phenolic compounds, and phenols are catalyzed through sulfation by the phenol sulfotransferase (PST) enzyme requiring adequate sulfate [63]. Children with ASD are very low in sulfate and lack the ability to sulfate [16,63], so it is likely that this is a mechanism of action that makes this diet particularly beneficial. ...
This study presents the results of the effectiveness of 13 therapeutic diets for autism spectrum disorder from 818 participants of a national survey, including benefits, adverse effects, and symptom improvements. The average Overall Benefit of diets was 2.36 (0 = no benefit, 4 = great benefit), which was substantially higher than for nutraceuticals (1.59/4.0) and psychiatric/seizure medications (1.39/4.0), p < 0.001. The average Overall Adverse Effects of diets was significantly lower than psychiatric/seizure medications (0.10 vs. 0.93, p < 0.001) and similar to nutraceuticals (0.16). Autism severity decreased slightly over time in participants who used diet vs. increasing slightly in those that did not (p < 0.001). Healthy and Feingold diets were the two top-rated diets by Overall Benefit; the ketogenic diet was the highest for nine symptoms (though had fewer respondents); and the gluten-free/casein-free diet was among the top for overall symptom improvements. Different diets were reported to affect different symptoms, suggesting that an individual’s symptoms could be used to guide which diet(s) may be the most effective. The results suggest that therapeutic diets can be safe and effective interventions for improving some ASD-related symptoms with few adverse effects. We recommend therapeutic diets that include healthy foods and exclude problematic foods. Therapeutic diets are inexpensive treatments that we recommend for consideration by most people with ASD.
... None of the 4 papers suggested that acetaminophen might cause ASD. For example, the initial study by Antonino Alberti's group in Italy showing profound impairment of acetaminophen metabolism in children with ASD (45) had been published in 1999, several years prior to the Schultz study. However, Alberti's study did not in any way suggest that exposure to acetaminophen might cause ASD. ...
... Fortunately, in healthy individuals, NAPQI is rapidly neutralized by glutathione (Figure 4). Unfortunately, children with ASD tend to have an impaired ability to utilize the sulfate pathway (45,56,57). In addition, children with ASD tend to have oxidative stress (2, 58), a factor that depletes glutathione (56). ...
Evidence that early life exposure to acetaminophen causes neurodevelopmental injury in susceptible children has mounted for more than a decade. Evidence is diverse, including extensive work with laboratory animals, otherwise unexplained associations, factors associated with the metabolism of acetaminophen, and some limited studies in humans. Although evidence has reached an overwhelming level and has been reviewed in detail recently, some controversy remains. In this narrative review, some of those controversies are evaluated. First, the associations through time between acetaminophen use and the prevalence of neurodevelopmental disorders are considered. A systematic review reveals that the use of acetaminophen in the pediatric population was never tracked carefully, but historical events that affected use of the drug were documented and are sufficient to establish apparent correlations with changes in the prevalence of neurodevelopmental disorders. Second, problems with exclusive reliance on results from meta-analyses of large datasets and from studies involving small time frames of drug exposure are reviewed. Third, the potential bias in a study designed to separate the role of vaccines and acetaminophen in the induction of autism spectrum disorder (Autism 2008;12:293-307) is carefully evaluated. Finally, evidence demonstrating why some children are susceptible to acetaminophen-induced neurodevelopmental injury is examined. It is concluded that, at least among the factors considered, there is no valid rationale for controversy regarding the conclusion that early life exposure to acetaminophen causes neurodevelopmental injury in susceptible babies and small children.
... Table IV, a number of additional factors are consistent with the view that early childhood exposure to paracetamol in the presence of oxidative stress can induce ASD. For example, genetic and autoimmune factors associated with ASD have an influence on paracetamol metabolism [70]. In addition, excessive, population-wide exposure to children's paracetamol in the Korean population [71] is associated with exceedingly high levels of ASD [72,73], (see Table IV). ...
... Genetic and immune factors associated with an increased risk of ASD have a detrimental effect on the body's ability to metabolize paracetamol. [5,70,93] The genetic and immune factors connected with ASD do not exert their effects via altered paracetamol metabolism, but rather through other, unknown mechanisms. ...
Paracetamol (acetaminophen) use during pregnancy and early childhood was accepted as safe in the 1970s, but is now a subject of considerable concern. Careful analysis shows that initial acceptance of the drug was based on the false assumption that drug interactions in babies and adults are the same, and on a complete absence of knowledge regarding the impact of the drug on brain development. At least fourteen epidemiological studies now indicate that prenatal exposure to paracetamol is associated with neurodevelopmental problems. Based on these studies, it can be concluded that prenatal exposure to paracetamol causes statistically significant risks of developmental delays, attention deficit hyperactivity disorder, and a subtype of autism spectrum disorder (ASD) associated with hyperkinetic behavior. In contrast, data regarding postnatal exposure to paracetamol are limited, and several factors impede a classic multivariate analysis of epidemiologic data to resolve the issue. However, circumstantial evidence regarding postnatal exposure to the drug is abundant, and includes at least three otherwise unexplained temporal relationships, data from laboratory animal studies, several miscellaneous and otherwise unexplained correlations, and a lack of alternative suspects that fit the evidence-derived profile. Based on this evidence, it can be concluded without any reasonable doubt that oxidative stress puts some babies and children at risk of paracetamol-induced neurodevelopmental injury, and that postnatal exposure to paracetamol in those susceptible babies and children is responsible for many if not most cases of ASD.
... Three times is enemy action" Ian Fleming, in "Goldfinger" As shown in Table 3, a number of additional factors are consistent with the view that early childhood exposure to acetaminophen in the presence of oxidative stress can induce ASD. For example, genetic and autoimmune factors associated with ASD have an influence on acetaminophen metabolism [51]. In addition, excessive, population-wide exposure to childhood acetaminophen in the Korean population [52] is associated with exceedingly high levels of ASD [53,54], (See Table 3). ...
... 10. Genetic and immune factors associated with an increased risk of ASD have a detrimental effect on the body's ability to metabolize acetaminophen. [46,51,71] The genetic and immune factors connected with ASD do not exert their effects via altered acetaminophen metabolism, but rather through other, unknown mechanisms. ...
Acetaminophen use during pregnancy and early childhood was accepted in the 1970s, but is now a subject of considerable concern. Careful analysis shows that initial acceptance of the drug was based on false assumptions and ignorance of the impact of the drug on brain development. Fourteen studies now indicate that prenatal exposure to acetaminophen is associated with neurodevelopmental problems. Based on corrections for confounding factors applied to the analyses of available data, it can be concluded that prenatal exposure to acetaminophen causes statistically significant risks of one subtype of autism spectrum disorder (ASD), developmental delays, and attention deficit hyperactivity disorder. In contrast, data regarding postnatal exposure to acetaminophen are limited, and several factors impede a classic multivariate analysis of data to resolve the issue. However, circumstantial evidence regarding postnatal exposure to the drug is abundant, and it can be concluded beyond a reasonable doubt that postnatal exposure to acetaminophen in susceptible children is responsible for many if not most cases of ASD. Circumstantial evidence includes at least three otherwise unexplained temporal relationships, data from laboratory animal studies, several miscellaneous and otherwise unexplained correlations, and the lack of alternative suspects that fit the evidence-derived profile.
... These data are hampered by relevant interspecies differences in SULT expression and the technical difficulties in maintaining the activity of cytosolic enzymes in vitro 2,15 . Clinical evidence on SULT activity derives mostly from Rosemary Waring's clinical studies on sulphur biotransformation pathways in specific chronic diseases, which introduced paracetamol as a probe drug to estimate sulfation capacity [17][18][19][20][21][22] . Occasional epidemiological studies have focused on the associations between SULT genotype and cancer risk and treatment response 23 . ...
... In the same decade, Bonham-Carter used a similar design to test the correlation between SULT activity measured with different substrates and the in vivo conjugation of paracetamol and salicylamide in man, but came to a different conclusion: they found no significant relationship between the in vivo pattern of sulfoconjugation of either drug and the activity of platelet SULT assayed with tyramine 45 . Throughout de 90s, Waring et al. produced vast literature devoted to studying variations in sulphur xenobiochemistry in pregnancy, circadian rhythm and several chronic diseases, including autism, migraine, inflammatory arthritis, biliary cirrhosis and chronic neurological diseases [17][18][19][20][21][22]46,47 . This team used paracetamol sulfate and the ratio PS/PG as an estimate of sulfation capacity, leading to breakthroughs such as scientific evidence suggestive of abnormal sulfur metabolism affecting people with autism spectrum disorders. ...
... While these studies are small, collectively analyzing just over 100 ASD individuals, together they show a consistent observation of reduced serum sulfate levels in ASD children. Moreover, a study of 232 ASD children, and 68 age-matched controls, found significantly higher (N50%) sulfate excretion in the urine of ASD children [45], while others have observed a reduced sulfonation capacity when compared to typically developing children [2,21,22,29,46]. Interestingly, a potential connection between altered heparan sulfate biology and autism has also been posited [33]. ...
... Of the neurodevelopmental disorders, the strongest potential link with abnormal sulfate chemistry is autism; children diagnosed with ASD have lower serum sulfate levels [1,6,19,46], higher sulfate excretion [45], and reduced sulfonation capacity [2,21,22,29,46]. Additionally, the BTBR T + tf/J mouse strain also exhibits significantly lower serum sulfate levels [13]. ...
Background:
Sulfate availability is crucial for the sulfonation of brain extracellular matrix constituents, membrane phospholipids, neurosteroids, and neurotransmitters. Observations from humans and mouse models suggest dysregulated sulfate levels may be associated with neurodevelopmental disorders, such as autism. However, the cellular mechanisms governing sulfate homeostasis within the developing or adult brain are not fully understood.
Methods:
We utilized a mouse model with a conditional allele for the sulfate transporter Slc13a4, and a battery of behavioral tests, to assess the effects of disrupted sulfate transport on maternal behaviors, social interactions, memory, olfaction, exploratory behavior, anxiety, stress, and metabolism. Immunohistochemistry examined neurogenesis within the stem cells niches.
Findings:
The sulfate transporter Slc13a4 plays a critical role in postnatal brain development. Slc13a4 haploinsufficiency results in significant behavioral phenotypes in adult mice, notably impairments in social interaction and long-term memory, as well as increased neurogenesis in the subventricular stem cell niche. Conditional gene deletion shows these phenotypes have a developmental origin, and that full biallelic expression of Slc13a4 is required only in postnatal development. Furthermore, administration of N-acetylcysteine (NAC) within postnatal window P14-P30 prevents the onset of phenotypes in adult Slc13a4+/- mice.
Interpretation:
Slc13a4 haploinsufficient mice highlight a requirement for adequate sulfate supply in postnatal development for the maturation of important social interaction and memory pathways. With evidence suggesting dysregulated sulfate biology may be a feature of some neurodevelopmental disorders, the utility of sulfate levels as a biomarker of disease and NAC administration as an early preventative measure should be further explored.
... Наиболее частые проявления со стороны пищеварительного канала (ПК) у детей с аутизмом следующие: -дисбиоз кишечника; -панкреатопатия; -ферментопатия; -хронический воспалительный процесс, в ряде случаев вирусной этиологии [7]; -аутоиммунные реакции; -несбалансированное питание; -контаминация паразитов; -снижение функции металлотионеина в кишечнике; -нарушение регенерации слизистой оболочки кишечника вследствие истощения запасов сульфатов [5]. Цель исследования -изучение состояния ПК при аутизме для выработки индивидуальной схемы коррекции в комплексном лечении больного. ...
У статті розглянуто особливості ураження травного каналу (ТК) у дітей з аутизмом. Наведено алгоритм обстеження дітей з аутизмом в ХСМГЦ, а також статистичні дані про частоту ураження ТК. Відмічено основні напрями корекції розладів травлення та її результати.
... One study using the Fisher Discriminant Analysis found that these biomarkers could discriminate between ASD and typically developing individuals with a 97% accuracy with a follow-up study showing up to a 96% accuracy for the training dataset and 88-95% accuracy for the validation dataset [90,91]. Functional variations of trans-sulfation deficits have been developed but remain rather preliminary [92]. ...
Autism spectrum disorder is an increasingly prevalent neurodevelopmental disorder in the world today, with an estimated 2% of the population being affected in the USA. A major complicating factor in diagnosing, treating, and understanding autism spectrum disorder is that defining the disorder is solely based on the observation of behavior. Thus, recent research has focused on identifying specific biological abnormalities in autism spectrum disorder that can provide clues to diagnosis and treatment. Biomarkers are an objective way to identify and measure biological abnormalities for diagnostic purposes as well as to measure changes resulting from treatment. This current opinion paper discusses the state of research of various biomarkers currently in development for autism spectrum disorder. The types of biomarkers identified include prenatal history, genetics, neurological including neuroimaging, neurophysiologic, and visual attention, metabolic including abnormalities in mitochondrial, folate, trans-methylation, and trans-sulfuration pathways, immune including autoantibodies and cytokine dysregulation, autonomic nervous system, and nutritional. Many of these biomarkers have promising preliminary evidence for prenatal and post-natal pre-symptomatic risk assessment, confirmation of diagnosis, subtyping, and treatment response. However, most biomarkers have not undergone validation studies and most studies do not investigate biomarkers with clinically relevant comparison groups. Although the field of biomarker research in autism spectrum disorder is promising, it appears that it is currently in the early stages of development.
... Sulfur metabolism has also been investigated for its role in the emergence of diverging metabolomic profiles. In two studies, it was observed that children with ASD have a significantly lower ability to sulfate (detoxify) acetaminophen [34,35]. Lower concentrations of sulfate in the blood of children with ASD have been consistently observed [36,37]. ...
There have been promising results regarding the capability of statistical and machine-learning techniques to offer insight into unique metabolomic patterns observed in ASD. This work re-examines a comparative study contrasting metabolomic and nutrient measurements of children with ASD (n = 55) against their typically developing (TD) peers (n = 44) through a multivariate statistical lens. Hypothesis testing, receiver characteristic curve assessment, and correlation analysis were consistent with prior work and served to underscore prominent areas where metabolomic and nutritional profiles between the groups diverged. Improved univariate analysis revealed 46 nutritional/metabolic differences that were significantly different between ASD and TD groups, with individual areas under the receiver operator curve (AUROC) scores of 0.6–0.9. Many of the significant measurements had correlations with many others, forming two integrated networks of interrelated metabolic differences in ASD. The TD group had 189 significant correlation pairs between metabolites, vs. only 106 for the ASD group, calling attention to underlying differences in metabolic processes. Furthermore, multivariate techniques identified potential biomarker panels with up to six metabolites that were able to attain a predictive accuracy of up to 98% for discriminating between ASD and TD, following cross-validation. Assessing all optimized multivariate models demonstrated concordance with prior physiological pathways identified in the literature, with some of the most important metabolites for discriminating ASD and TD being sulfate, the transsulfuration pathway, uridine (methylation biomarker), and beta-amino isobutyrate (regulator of carbohydrate and lipid metabolism).
... Another common problem in individuals with ASD is the loss of effectively detoxifying compounds via sulfonation in the liver. Some of these compounds comprise hormones, neurotransmitters and bacterial-derived metabolites such as p-cresol which can influence the CNS [120,121]. These are some proposed mechanisms of how microbiota-derived metabolites may influence ASD pathogenesis. ...
Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders characterised by behavioural impairment and deficiencies in social interaction and communication. A recent study estimated that 1 in 89 children have developed some form of ASD in European countries. Moreover, there is no specific treatment and since ASD is not a single clinical entity, the identification of molecular biomarkers for diagnosis remains challenging. Besides behavioural deficiencies, individuals with ASD often develop comorbid medical conditions including intestinal problems, which may reflect aberrations in the bidirectional communication between the brain and the gut. The impact of faecal microbial composition in brain development and behavioural functions has been repeatedly linked to ASD, as well as changes in the metabolic profile of individuals affected by ASD. Since metabolism is one of the major drivers of microbiome–host interactions, this review aims to report emerging literature showing shifts in gut microbiota metabolic function in ASD. Additionally, we discuss how these changes may be involved in and/or perpetuate ASD pathology. These valuable insights can help us to better comprehend ASD pathogenesis and may provide relevant biomarkers for improving diagnosis and identifying new therapeutic targets.
... Since GSH is produced from homocysteine (and cysteine), GSH depletion may lead to the depletion of homocysteine by consuming it as a precursor. Impaired methylation can also weaken sulphation pathways; lower blood and higher urinary sulfate concentrations have been reported in ASD as early as 1997 [27][28][29]. ...
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder affecting 2% of children in the United States. Biochemical abnormalities associated with ASD include impaired methylation and sulphation capacities along with low glutathione (GSH) redox capacity. Potential treatments for these abnormalities include cobalamin (B12). This systematic review collates the studies using B12 as a treatment in ASD. A total of 17 studies were identified; 4 were double-blind, placebo-controlled studies (2 examined B12 injections alone and 2 used B12 in an oral multivitamin); 1 was a prospective controlled study; 6 were prospective, uncontrolled studies, and 6 were retrospective (case series and reports). Most studies (83%) used oral or injected methylcobalamin (mB12), while the remaining studies did not specify the type of B12 used. Studies using subcutaneous mB12 injections (including 2 placebo-controlled studies) used a 64.5-75 µg/kg/dose. One study reported anemia in 2 ASD children with injected cyanocobalamin that resolved with switching to injected mB12. Two studies reported improvements in markers of mitochondrial metabolism. A meta-analysis of methylation metabolites demonstrated decreased S-adenosylhomocysteine (SAH), and increased methionine, S-adenosylmethionine (SAM), SAM/SAH ratio, and homocysteine (with small effect sizes) with mB12. Meta-analysis of the transsulfuration and redox metabolism metabolites demonstrated significant improvements with mB12 in oxidized glutathione (GSSG), cysteine, total glutathione (GSH), and total GSH/GSSG redox ratio with medium to large effect sizes. Improvements in methylation capacity and GSH redox ratio were significantly associated with clinical improvements (with a mean moderate effect size of 0.59) in core and associated ASD symptoms, including expressive communication, personal and domestic daily living skills, and interpersonal, play-leisure, and coping social skills, suggesting these biomarkers may predict response to B12. Other clinical improvements observed with B12 included sleep, gastrointestinal symptoms, hyperactivity, tantrums, nonverbal intellectual quotient, vision, eye contact, echolalia, stereotypy, anemia, and nocturnal enuresis. Adverse events identified by meta-analysis included hyperactivity (11.9%), irritability (3.4%), trouble sleeping (7.6%), aggression (1.8%), and worsening behaviors (7.7%) but were generally few, mild, not serious, and not significantly different compared to placebo. In one study, 78% of parents desired to continue mB12 injections after the study conclusion. Preliminary clinical evidence suggests that B12, particularly subcutaneously injected mB12, improves metabolic abnormalities in ASD along with clinical symptoms. Further large multicenter placebo-controlled studies are needed to confirm these data. B12 is a promising treatment for ASD.
... DHEA is available for conversion to downstream substrates in the androgen synthesis pathway [4]. Among persons diagnosed with an ASD, one of the most consistent, significant biochemical findings (detected in >90% of persons diagnosed with an ASD) is decreased sulfate and sulfation processes [5][6][7]. As a result, there may be significant increases in sex hormone production among persons diagnosed with an ASD. ...
b> Introduction: Autism spectrum disorder (ASD) is defined by persistent deficits in communication, socialization, and stereotypic behaviors. It was previously hypothesized that hormone dysfunction is a frequent occurrence among children diagnosed with an ASD. Objectives: A hypothesis-testing epidemiological study examined the relationship between precocious puberty (PP) (a known disorder of childhood sex hormone dysfunction) and ASD diagnoses. Methods: The Independent Healthcare Research Database is composed of de-identified linked eligibility and claims health-care records prospectively generated from the Florida Medicaid system. A cohort of 101,736 children eligible for Florida Medicaid from 1990 to 2009 and continuously eligible with ≥10 outpatient office visits during the 120-month period following birth were examined using SAS and StatsDirect software. There were 1,593 children (15,738 person-years) in the ASD diagnosed cohort utilizing the Diagnostic and Statistical Manual of Mental Disorders, 4th revision criteria (the International Code for Disease, 9th revision [ICD-9] codes: 299.00 or 299.80) and 100,143 children (996,835 person-years) in the undiagnosed cohort. Results: The incidence rate of PP (ICD-9 code: 259.1) was examined using Cox proportional hazards ratio (HR) and frequency models. PP per 10,000 person-years in the ASD cohort (43.2) relative to the undiagnosed cohort (13.7) was significantly increased in frequency modeling (risk ratio = 3.15, p < 0.0001) and Cox proportional HR modeling (adjusted HR = 4.64, p < 0.0001). Further analyses revealed the incidence rate of PP diagnosed after 3 years of age was significantly increased (adjusted HR = 5.16, p < 0.0001) in the ASD cohort relative to the undiagnosed cohort but not for the incidence rate of PP diagnosed before 3 years (adjusted HR = 1.57, p = 0.44). Conclusion: This hypothesis-testing study provides strong evidence of an increased incidence rate of PP among children diagnosed with an ASD.
... A few studies already reported a sulfation deficit in autistic children, mainly in vivo through the metabolism of paracetamol 68 . The authors stated that the PST enzyme itself does not appear to be lacking or genetically weakened (our present genetic findings are in complete agreement with this statement), but that it is lacking a sufficient supply of sulfate to attach the phenolic molecules. ...
Hyperserotonemia is the most replicated biochemical abnormality associated with autism spectrum disorders (ASD). However, previous studies of serotonin synthesis, catabolism, and transport have not elucidated the mechanisms underlying this hyperserotonemia. Here we investigated serotonin sulfation by phenol sulfotransferases (PST) in blood samples from 97 individuals with ASD and their first-degree relatives (138 parents and 56 siblings), compared with 106 controls. We report a deficient activity of both PST isoforms (M and P) in platelets from individuals with ASD (35% and 78% of patients, respectively), confirmed in autoptic tissues (9 pineal gland samples from individuals with ASD—an important source of serotonin). Platelet PST-M deficiency was strongly associated with hyperserotonemia in individuals with ASD. We then explore genetic or pharmacologic modulation of PST activities in mice: variations of PST activities were associated with marked variations of blood serotonin, demonstrating the influence of the sulfation pathway on serotonemia. We also conducted in 1645 individuals an extensive study of SULT1A genes, encoding PST and mapping at highly polymorphic 16p11.2 locus, which did not reveal an association between copy number or single nucleotide variations and PST activity, blood serotonin or the risk of ASD. In contrast, our broader assessment of sulfation metabolism in ASD showed impairments of other sulfation-related markers, including inorganic sulfate, heparan-sulfate, and heparin sulfate-sulfotransferase. Our study proposes for the first time a compelling mechanism for hyperserotonemia, in a context of global impairment of sulfation metabolism in ASD.
... Is it the higher exposure to acetaminophen and its metabolites that "causes" ASD/ADHD or is the fact that you are going to develop ASD/ADHD the reason why you have a different clearance of acetaminophen? There is some evidence that supports the fact that kids with ASD/ADHD indeed have a different metabolism of acetaminophen and perhaps, as a consequence, have an elevated risk of adverse events if exposed to acetaminophen [15]. Furthermore, this design is also hampered because it was confounded by indication (maternal pain or fever during labor). ...
In his commentary Dr. Ola Saugstad tries to convince the readers of the journal that the replacement of acetylsalicylic acid with acetaminophen in the early 1980s has resulted in a sharp increase in autism spectrum disorder in the USA. As a consequence, he warns against the use of prenatal and postnatal acetaminophen in pregnant women and their fetuses/neonates until we know more about a possible time period during the fetal/neonatal development where the developing brain might be more sensitive to potential side effects of acetaminophen and its metabolites. He furthermore states that more care is needed when administering this “potentially toxic substance to individuals with developing brains”. He finishes his commentary by advocating for proper follow-up if using acetaminophen in newborns and infants to detect potential long term adverse effects.
We like to discuss in this commentary the arguments Dr. Saugstad has used to reach the aforementioned conclusions and warnings, and at the end we like to share with you our overall thoughts on this important topic.
... In children with ASD, a low sulphation capacity is observed. Scientists suggested that ASD children were unable to effectively metabolise phenolic amines functioning as neurotransmitters, such as dopamine, serotonin, and tyramine [53]. The research conducted by James et al. (2009) indicated that pretreatment with B12 and folinic acid caused a change in metabolite concentration in ASD individuals compared with the control group. ...
In this study, the levels of concentration of homocysteine thiolactone (HTL), cysteine (Cys), and cysteinylglycine (CysGly) in the urine of autistic and non-autistic children were investigated and compared. HTL has never been analyzed in autistic children. The levels of low molecular weight sulfur compounds in the urine of both groups were determined by validated methods based on high-performance liquid chromatography with spectrofluorometric and diode-array detectors. The statistical data show a significant difference between the examined groups. Children with autism were characterized by a significantly higher level of HTL (p = 5.86 × 10−8), Cys (p = 1.49 × 10−10) and CysGly (p = 1.06 × 10−8) in urine compared with the control group. A difference in the p-value of <0.05 is statistically significant. Higher levels of HTL, Cys, and CysGly in the urine of 41 children with autism, aged 3 to 17, were observed. The obtained results may indicate disturbances in the metabolism of methionine, Cys, and glutathione in some autistic patients. These preliminary results suggest that further research with more rigorous designs and a large number of subjects is needed.
... Associated functional GI abnormalities in children with ASD include low activities of disaccharidase enzymes [15], defective sulfation of ingested phenolic amines [16], bacterial overgrowth with greater diversity and number of clostridial species [17], and increased intestinal permeability [18]. Dietary restrictions and problem feeding behavior, nutrient malabsorption, and increased intestinal losses in children with ASD can compromise dietary intake and cause nutritional depletion. ...
Autism Spectrum Disorder (ASD) is a developmental disorder characterized by impaired communication and social interaction. Children with ASD are frequently diagnosed with gastrointestinal (GI) issues, including inflammatory bowel disease (IBD), gastroesophageal reflux, abdominal pain, diarrhea, and constipation, although the association between ASD and GI conditions is unclear. Underlying nutritional deficiencies are more common in children with ASD, and increase the risk of them developing medical conditions secondary to the behavioral diagnosis. This objective of this study was to examine the use of an elemental diet (ED) in the treatment of gastrointestinal disease in 5 children with ASD ages 2-21 years of age. In the study participants, the ED was well-tolerated with improvements in anthropometric measures, nutritional markers, and/or GI functioning reported after 12 weeks of intervention. Further research to advance the development of specific evidence-based guidelines in the management and treatment of gastrointestinal concerns in the ASD population is warranted.
... Specifically, in children with ASD, the levels of free sulfate [20,21], reduced glutathione [20][21][22][23], cysteine [20][21][22][23], and S-adenosyl methionine [20][21][22][23] in plasma are significantly lower than in controls. Animal studies have found that decreased availability of each of these same compounds is associated with inefficient metabolism of acetaminophen, and as a result, increased risk of acetaminophen toxicity [24][25][26][27][28]. Indeed, a case-control study of acetaminophen metabolism in children with ASD and unaffected controls found abnormalities in acetaminophen metabolism in those with ASD that suggest those with ASD in aggregate metabolize acetaminophen less efficiently than controls [29]. ...
Some evidence from the literature suggests that postnatal acetaminophen exposure may be associated with increased risk of autism spectrum disorder (ASD). Using a data set obtained from a previous study that was derived from an Internet-based survey among parents on 1515 children from the US, an adjusted odds ratio (aOR) and gender-specific aORs for doses of postnatal acetaminophen provided before age two were calculated against the outcome of ASD. Separately, parental uncertainty on the number of doses of acetaminophen provided was analyzed. A population attributable fraction (PAF) associated with postnatal acetaminophen exposure before age two for ASD among males was also estimated. Postnatal acetaminophen exposure, measured in doses before age two, was found to be associated with ASD among male children (aOR 1.023, CI 1.005–1.043, p = 0.020*), and parental uncertainty on the number of doses of acetaminophen provided before age two was also found to be associated with ASD. Using this data set, the PAF associated with postnatal acetaminophen was estimated to be about 40% of the risk of ASD among male children in the US. These results suggest the possibility that postnatal acetaminophen may be a significant contributor to the risk of ASD among males in the US.
... Thus, the previously mentioned HPHPA which depletes brain catecholamines and causes symptoms of ASD, such as stereotypical behavior, hyperactivity, and hyper-reactivity in experimental animals, appears in higher concentrations in the urine of children with ASD and is produced by Clostridium species [81]. The bacterially mediated p-cresol found in urine samples of autistic patients indicates a reduced capacity to sulfonate certain phenolic amines, toxic for the CNS, that are potentially exacerbating the autistic behavior [82]. The 4-ethylphenylsulfate, which is produced by several gut bacteria, induces autistic features and anxiety-like behavior when injected in mice, and, furthermore, was found to be 46-fold increased in autistic maternal immune activated mice [52,83]. ...
Background and Objectives: Gastrointestinal disturbances have been frequently, but not unanimously, reported in autism spectrum disorder (ASD) individuals. Thus, digestive symptoms, such as constipation, diarrhea, abdominal bloating, and pain have been reported to correlate to the various maladaptive behaviors in ASD children, such as irritability, social withdrawal, stereotypy, hyperactivity, and even language regression. In this context, the present study provides an overview on the prevalence of the gastrointestinal (GI) disorders in ASD and the correlation between these and ASD symptoms and comorbidities and subsequently discusses the metabolic and microbiome factors underlying the effects of GI disorders in ASD. Materials and Methods: For our analysis of GI symptoms in children with ASD, we have searched peer-reviewed journals from 2005 to 2017 in PubMed databases that addressed the specificity of GI symptoms in ASD and included correlations of GI and ASD symptoms. The criteria for inclusion were clear quantitative mentioning of GI modifications, GI symptoms correlation with specific ASD symptoms or comorbidities, an appropriate methodology for defining ASD, and larger size samples. For this topic, only studies on human patients and original research were considered. A subsequent search in PubMed databases in journals from 2000 to 2017 we analyzed 13 articles on the mechanisms underlying the impact of GI dysfunctions in ASD, including gut microbial dysbiosis, immune reactivity, genetics, and altered neurotransmitters on the gut–brain axis. Results: In the 18 original research studies that we selected out of an initial 327 studies, despite the different methodology, a predominant 83% highlighted the increased prevalence of GI symptoms in ASD patients. Constipation was most frequently cited, appearing in 12 of the studies (80%), followed by diarrhea reports in eight studies (53%). The association between cognitive and behavioral deficits and GI disorders was suggested in certain groups of ASD individuals. Conclusion: The evidence presented so far by numerous studies seems to indicate that GI dysfunctions are of particular relevance in ASD, underlined by various abnormalities along the nervous connections between the central nervous system and the gut, such as impaired parasympathetic activity and increased endocrine stress response. Sufficiently large size samples and standardized methodology are required for future studies to clarify the complex interactions between GI disturbances and ASD symptoms.
... Overgrowth of C. diicile can be linked to the etiology of autism through the inhibitory efect of p-cresol on dopamine β-hydroxylase as a rate-limiting enzyme of dopamine metabolism [63]. Moreover, C. diicile-induced production of p-cresol can inhibit sulfonation as a detoxiication mechanism of special importance when considering neonatal inactive glucuronida- tion as an alternative detoxiication reaction for xenobiotic excretion [64,65]. Based on this information, p-cresol may be linked to autism through impaired gut microbiota and the overgrowth of C. diicile [66]. ...
... In both rats and humans administered APAP, the endogenous quantities of p-cresol sulfate in the urine were cor-related with liver effects (rat) 37 and the APAP-sulfate/APAP-glucuronide ratio (humans), 38 directly leading to the concept of pharmacometabonomics. 37,38 Similarly, urinary concentrations of p-cresol and p-cresol sulfate have been found to be elevated in children with autism 39 and when the urinary APAP-sulfate/ APAP-glucuronide ratio was determined for 20 "low functioning" autistic children receiving the drug it was found to be significantly lower than for the controls. 40 The prediction of acute APAP-induced liver injury in humans, and consequent treatment needs or patient outcomes during hepatotoxicity remains difficult. A lack of sensitivity and specificity of currently used biomarkers of organ injury coupled with a poor understanding of the mechanistic basis of hepatotoxicity remain contributory factors. ...
After over 60 years of therapeutic use in the UK, paracetamol (acetaminophen, N-acetyl-p-aminophenol, APAP) remains the subject of considerable research into both its mode of action and toxicity. The pharmacological properties of APAP are the focus of some activity, with the role of the metabolite N-arachidonoylaminophenol (AM404) still a topic of debate. However, that the hepatotoxicity of APAP results from the production of the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI/NABQI) that can deplete glutathione, react with cellular macromolecules, and initiate cell death, is now beyond dispute. The disruption of cellular pathways that results from the production of NAPQI provides a source of potential biomarkers of the severity of the damage. Research in this area has provided new diagnostic markers such as the microRNA miR-122 as well as mechanistic biomarkers associated with apoptosis, mitochondrial dysfunction, inflammation and tissue regeneration. Additionally, biomarkers of, and systems biology models for, glutathione depletion have been developed. Furthermore, there have been significant advances in determining the role of both the innate immune system and genetic factors that might predispose individuals to APAP-mediated toxicity. This perspective highlights some of the progress in current APAP-related research.
... Two major pieces of evidence led to that hypothesis. First, it was observed that at least some patients with ASD exhibit defective xenobiotic sulfation [167]. In fact, when APAP was used as a probe drug to assess sulfation capacity, the ratio of APAP-sulfate to APAP-glucuronide was lower in severely autistic subjects compared to healthy controls [176]. ...
Research on acetaminophen (APAP) toxicity over the last several decades has focused on the pathophysiology of liver injury, but increasingly attention is paid to other known and possible adverse effects. It has been known for decades that APAP causes acute kidney injury, but confusion exists regarding prevalence, and the mechanisms have not been well investigated. More recently, evidence for pulmonary, endocrine, neurological, and neurodevelopmental toxicity has been reported in a number of published experimental, clinical, and epidemiological studies, but the quality of those studies has varied. It is important to view those data critically due to implications for regulation and clinical practice. Here, we review evidence and proposed mechanisms for extrahepatic adverse effects of APAP and weigh weaknesses and strengths in the available data.
Relevance for patients
APAP is one of the most commonly used drugs in the West. Although it is generally considered safe when used according to manufacturer recommendations, it has been known for decades that overdose can cause liver injury. Recent studies have suggested that APAP can damage cells in other organs as well, leading to calls for more and stricter regulations, which would limit use of this otherwise effective drug. It is especially important to view claims of developmental effects of antenatal APAP exposure with a critical eye because APAP is currently the only over-the-counter medication recommended for pregnant women to self-treat pain and fever.
... 18 In this paper we show a significant statistical correlation between mothers and their autistic children (table 1) 47.6 % of autistic patients present allergies, mainly skin and food allergies. 19,20 Changes in the gut barrier, microorganisms, foods, environment (hygiene hypothesis), autoimmunity, etc., need to be considered in the physiopathology of allergies and autism. ...
Introduction: Allergies are frequently found among patients with autism and autism shows an increased frequency among the allergic patients. Objective: To demonstrate that allergies and autism share some similar immunological patterns. Methods: The autoserum skin test (ASST) was used to demonstrate the presence of anti-IgE and/or anti-IgE receptor antibodies (FcεRIα). Results: The ASST demonstrated similar frequency, positives/positives and negatives/negatives, considering allergic and autistic patients. These similarities didn't exist when comparing with the control group. A positive correlation had been found with the results of autistic patients and their mothers. Conclusions: Autistic and allergic patients share some immunological similarities. Both differ from normal controls. It is not uncommon autistics with allergic symptoms and allergic patients with autism. If the immunological findings represent a clinical bridge between both processes, it is under discussion. Also it was demonstrated a possible genetic correlation between the patients with autism and their mothers.
... Autistic children can be sensitive to chemical exposure (Ashwood et al. 2009 ;Geier et al. 2009a , b ;James et al. 2009 ). ASD is associated with diminished activity of phenolsulfotransferase (PST) , which plays a role in phenol detoxifi cation and excretion (Alberti et al. 1999 ;McFadden 1996 ). Statistical associations between chemical exposures and autism susceptibility can be diffi cult with enzymes like PST, because its activity is also sensitive to variations in natural chemicals found in vegetables (Chi-Tai and Gow-Chin 2003 ;Yeh and Yen 2005 ), so children likely have different risks that vary with a multitude of dietary factors. ...
Autism spectrum disorder (ASD) is characterized by deficits in social interaction, delays and impairments in communication, and restricted interests and repetitive behaviors. ASD is highly heritable, indicating genetic causal factors, but its rising prevalence also suggests environmental changes, such as expanding numbers of chemical pollutants. Putative risk factors for ASD include various environmental factors and mutations in any one of over 19,000 human genes.
To identify risk factors, scientists apply statistical approaches to identify factors associated with ASD, then employ laboratory animals, commonly rodents, to ascertain whether the association indicates a causal relationship. If a mouse strain with a targeted mutation or chemical exposure expresses autistic-like phenotypes, it can be used as a “mouse model of autism” to elucidate causal mechanisms and develop drug treatments. Such approaches were successfully employed to understand Retts and Fragile-X syndromes, disabilities sharing features with autism. This review describes the social features of ASD and their behavioral analogues in laboratory rodents. It also describes the genetic and chemical risk factors associated with ASD and the underlying epigenetic processes mediating their influence on brain development and social behavior.
Epigenetic processes are powerfully affected by life experience. Natural environments offer rodents a complex array of choices, contingencies, rewards, and punishments. By contrast, standard laboratory cages and so-called “enriched” cages offer rodents sparse spatial and temporal variation, precluding variety of affective experience or opportunity to exercise their naturally evolved capacities for decision-making. Paucity of life experience can irreversibly obstruct development and run at cross-purposes with efforts to identify risk factors and treatments for ASD. Alternatives to standard laboratory animal caging will be explored.
... Autistic children can be sensitive to chemical exposure (Ashwood et al. 2009 ;Geier et al. 2009a , b ;James et al. 2009 ). ASD is associated with diminished activity of phenolsulfotransferase (PST) , which plays a role in phenol detoxifi cation and excretion (Alberti et al. 1999 ;McFadden 1996 ). Statistical associations between chemical exposures and autism susceptibility can be diffi cult with enzymes like PST, because its activity is also sensitive to variations in natural chemicals found in vegetables (Chi-Tai and Gow-Chin 2003 ;Yeh and Yen 2005 ), so children likely have different risks that vary with a multitude of dietary factors. ...
Autism spectrum disorder (ASD) is characterized by deficits in social interaction, delays and impairments in communication, and restricted interests and repetitive behaviors. ASD is highly heritable, indicating genetic causal factors, but its rising prevalence also suggests environmental changes, such as expanding numbers of chemical pollutants. Putative risk factors for ASD include various environmental factors and mutations in any one of over 19,000 human genes.
To identify risk factors, scientists apply statistical approaches to identify factors associated with ASD, then employ laboratory animals, commonly rodents, to ascertain whether the association indicates a causal relationship. If a mouse strain with a targeted mutation or chemical exposure expresses autistic-like phenotypes, it can be used as a “mouse model of autism” to elucidate causal mechanisms and develop drug treatments. Such approaches were successfully employed to understand Retts and Fragile-X syndromes, disabilities sharing features with autism. This review describes the social features of ASD and their behavioral analogues in laboratory rodents. It also describes the genetic and chemical risk factors associated with ASD and the underlying epigenetic processes mediating their influence on brain development and social behavior.
Epigenetic processes are powerfully affected by life experience. Natural environments offer rodents a complex array of choices, contingencies, rewards, and punishments. By contrast, standard laboratory cages and so-called “enriched” cages offer rodents sparse spatial and temporal variation, precluding variety of affective experience or opportunity to exercise their naturally evolved capacities for decision-making. Paucity of life experience can irreversibly obstruct development and run at cross-purposes with efforts to identify risk factors and treatments for ASD. Alternatives to standard laboratory animal caging will be explored.
... In particular, p-cresol may inhibit the dopamine β-hydrolase activity [103] and subsequently lead to increases in dopamine and homovanillic acid [103]. Autism has been linked to impaired sulfonation and altered dopamine and homo vanillic metabolic status [104,105], which further illustrates the potential influence of gut microbial metabolism in the aetiology of brain disorder. ...
This chapter presents a non-exhaustive overview on metabolic and nutritional implications of host-microbial metabolic pathways related to aromatic amino acid metabolism. Gut microbiota-derived metabolites modulate host metabolism and immunity involving different types of molecules such as short-chain fatty acids (SCFAs) and bile acids, and by metabolizing tryptophan, phenylalanine and tyrosine metabolism. The gut microbiota plays a key role in the aetiology, development and maintenance of many multifactorial disorders and may be a target for nutraceutical and/or medical therapies. Dietary modulation of the bacterial production of SCFAs has been the goal of extensive research with the aim of addressing specific metabolic deregulations in the context of metabolic and gastrointestinal disorders. The chapter shows that beyond SCFAs and bile acids, extensive gut microbiota modulation of host systemic metabolism involves aromatic amino acid metabolism, polyamines and possibly a compensatory mechanism of indole melatonin production.
... Des anomalies ont également été rapportées dans des pathologies psychiatriques : augmentation chez les patients présentant des TOC ou des épisodes maniaques, diminution associée à la dépression (Marazziti et al., 1996). Bien que les PST ne semblent pas avoir été spécifiquement étudiées dans les TSA jusqu'à présent, des anomalies de la sulfoconjugaison du paracétamol (également de structure phénolique) ont été rapportées (Alberti et al., 1999 (Hanley et al., 1977, Launay et al., 1988. On ne peut exclure que l'absence d'élévation des concentrations de 5-HIAA résulte de la compartimentation du métabolisme de la sérotonine : l'hypersérotoninémie des TSA semble localisée aux plaquettes sanguines, qui n'expriment pas la MAO-A, enzyme prépondérante dans le catabolisme des monoamines endogènes. ...
Autism Spectrum Disorders (ASD) are defined by three core symptoms: social interaction impairments, language impairments, and stereotyped behavior and restricted interests. Beyond this definition lie extremely diverse clinical situations, in terms of symptoms severity as well as comorbidities and associated features. The aetiology of ASD is considered to be mostly genetic, but the molecular mechanisms involved seem to be complex and heterogeneous, and the genotype-phenotype associations elusive. One possible strategy for decomposing the clinical and genetic complexity is to focus on endophenotypes, or intermediate phenotypes, to define more homogeneous pathophysiological categories. Among many biological endophenotypes reported in ASD, the increase of blood serotonin is well documented but still unexplained. Deficits in melatonin (which chemically derives from serotonin) have also been described. The aim of this work was to characterize the impairments of the serotonin-melatonin pathway in ASD, and to address their mechanisms and clinical correlates. Based on a comprehensive assessment of the serotonin-melatonin pathway from blood samples in a large cohort of 200 patients with ASD and their relatives, the prevalence of hyperserotonemia in ASD was estimated to be 45%, and that of melatonin deficit about 60%. Impairments of serotonin catabolism were shown, as well as impairments of melatonin synthesis, thus providing biochemical mechanisms for both endophenotypes. Abnormal melatonin synthesis, which may involve an increase in N-acetylserotonin, was confirmed on pineal gland and gastro-intestinal tract samples (i.e. the major sources of melatonin and serotonin) from patients with ASD. The genes involved in melatonin synthesis (coding for AANAT and ASMT enzymes) were studied in ASD and in related neurodevelopmental disorders. Abnormal melatonin synthesis may be associated with sleep disorders, frequently observed in patients with ASD
... The content of metallothioneines, GSH, selenium and fish high in omega-3 fatty acids appear to be strongly related with degree of inorganic and organic mercury toxicity, and with the protective detoxifying mechanisms in humans. In conclusion, depletion of GSH, breakage of mitochondria, increased lipid peroxidation, and oxidation of proteins and DNA in the brain, induced by mercury and his salts, appear to be important factors in conditions such as ALS and AD (Bains and Shaw 1997;Nicole et al. 1998;Spencer et al. 1998;Alberti et al. 1999). ...
... As one might expect, as bacterial composition has an effect on health and disease, the molecular metabolites that these microbes produce are the "tools" that carry out these biological changes. For example, individuals with autism have been cited as having sulfur metabolic deficiencies, to suffer from elevated oxidative stress and to have trouble detoxifying xenobiotic compounds and heavy metals [13][14][15]. It is therefore important to analyze the metabolome of these individuals and that of healthy individuals (for control) in order to identify useful biomarkers and perhaps even gain a greater understanding of the disorder. ...
Autism spectrum disorders are a group of mental illnesses highly correlated with gastrointestinal dysfunction. Recent studies have shown that there may be one or more microbial "fingerprints" in terms of the composition characterizing individuals with autism, which could be used for diagnostic purposes. This paper proposes a computational approach whereby metagenomes characteristic of "healthy" and autistic individuals are artificially constructed via genomic information, analyzed for the enzymes coded within, and then these enzymes are compared in detail. This is a text mining application. A custom-designed online application was built and used for the comparative metabolomics study and made publically available. Several of the enzyme-catalyzing reactions involved with the amino acid glutamate were curiously missing from the "autism" microbiome and were coded within almost every organism included in the "control" microbiome. Interestingly, there exists a leading hypothesis regarding autism and glutamate involving a neurological excitation/inhibition imbalance; but the association with this study is unclear. The results included data on the transsulfuration and transmethylation pathways, involved with oxidative stress, also of importance to autism. The results from this study are in alignment with leading hypotheses in the field, which is impressive, considering the purely in silico nature of this study. The present study provides new insight into the complex metabolic interactions underlying autism, and this novel methodology has potential to be useful for developing new hypotheses. However, limitations include sparse genome data availability and conflicting literature experimental data. We believe our software tool and methodology has potential for having great utility as data become more available, comprehensive and reliable.
... Several published metabolomics analyses of urine and fecal metabolites have revealed differential abundance of bacteria-produced metabolites that have the potential to directly affect neural processes (51Á54). Published urinary metabolites that positively correlate with ASD symptoms include 1) 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), a probable metabolite of a tyrosine analog that depletes catecholamines and causes symptoms of autism, such as stereotypical behavior, hyperactivity, and hyper-reactivity in experimental animals (51), 2) p-cresol, which can compete with neurotransmitters for enzymes and co-factors essential for sulfonation reactions in the liver (52,53), and 3) urocanate, which is regulated by the enzyme urocanase (55). Deficiency of urocanase raises levels of urocanate in the urine and leads to urocanic aciduria that is associated with neurological disorders (54). ...
Recent studies suggest a role for the microbiota in autism spectrum disorders (ASD), potentially arising from their role in modulating the immune system and gastrointestinal (GI) function or from gut-brain interactions dependent or independent from the immune system. GI problems such as chronic constipation and/or diarrhea are common in children with ASD, and significantly worsen their behavior and their quality of life. Here we first summarize previously published data supporting that GI dysfunction is common in individuals with ASD and the role of the microbiota in ASD. Second, by comparing with other publically available microbiome datasets, we provide some evidence that the shifted microbiota can be a result of westernization and that this shift could also be framing an altered immune system. Third, we explore the possibility that gut-brain interactions could also be a direct result of microbially produced metabolites.
... 12,13 If the sulfation pathway is defective, as has been shown in autism, and/or there is impaired glucuronidation, acetaminophen will be increasingly converted to the alternative metabolic routes, increasing production of its more toxic compounds NAPQI and AM404. 56,57 In addition to liver toxicity caused by acetaminophen, individuals without liver toxicity may have severe metabolic acidosis if they are poorly nourished due to illness or dietary insufficiency. 39,40 In each of these cases, extremely high levels of pyroglutamic acid (also termed 5-oxoproline) are found in both the urine and blood serum. ...
It appears that the marked increase in the rate of autism, asthma, and attention deficit with hyperactivity throughout much of the world may be largely caused by the marked increase in the use of acetaminophen in genetically and/or metabolically susceptible children,
and the use of acetaminophen by pregnant women. Toxicity of acetaminophen may cause autism by overloading the defective sulfation pathway catalyzed by phenolsulfotransferase, which is deficient in autism, leading to overproduction of the toxic metabolite N-acetyl-p-benzoquinone
imine (NAPQI). Increased levels of NAPQI reduce the ability to detoxify a host of toxic chemicals in the environment, increasing oxidative stress, which leads to protein, lipid, and nucleic acid damage from free radicals. Epidemiological evidence also supports the association of increased
acetaminophen usage with autism, asthma, and attention deficit with hyperactivity. The marked increases in the incidences of autism, asthma, and attention deficit disorder in the United States coincide with the replacement of aspirin by acetaminophen in the 1980s. The characteristic loss of
Purkinje cells in the brains of people with autism is consistent with depletion of brain glutathione due to excess acetaminophen usage, which leads to premature brain Purkinje cell death. The anomalous hair mercury concentrations of children with autism are consistent with exposure of growing
hair proteins to NAPQI derived from acetaminophen, which competitively inhibits the reaction of mercury with hair sulfhydryl groups. Finally, large-scale faulty production of acetaminophen products, such that the labeled values were exceeded by the true concentrations, in addition to contamination
with bacteria and tribromoanisole, may have greatly increased the chances of children receiving overdosages of acetaminophen and potential toxins for perhaps as long as a decade.
Based on available data that include approximately 20 lines of evidence from studies in laboratory animal models, observations in humans, correlations in time, and pharmacological/toxicological considerations, it has been concluded without reasonable doubt and with no evidence to the contrary that exposure of susceptible babies and children to acetaminophen (paracetamol) induces many, if not most, cases of autism spectrum disorder (ASD). However, the relative number of cases of ASD that might be induced by acetaminophen has not yet been estimated. Here, we examine a variety of evidence, including the acetaminophen-induced reduction of social awareness in adults, the prevalence of ASD through time, and crude estimates of the relative number of ASD cases induced by acetaminophen during various periods of neurodevelopment. We conclude that the very early postpartum period poses the greatest risk for acetaminophen-induced ASD, and that nearly ubiquitous use of acetaminophen during early development could conceivably be responsible for the induction in the vast majority, perhaps 90% or more, of all cases of ASD. Despite over a decade of accumulating evidence that acetaminophen is harmful for neurodevelopment, numerous studies demonstrate that acetaminophen is frequently administered to children in excess of currently approved amounts and under conditions in which it provides no benefit. Further, studies have failed to demonstrate long-term benefits of acetaminophen for the pediatric population, leaving no valid rationale for continued use of the drug in that population given its risks to neurodevelopment.
Disruptions to either sulfate supply or sulfation enzymes can affect brain development and have long-lasting effects on brain function, yet our understanding of the molecular mechanisms governing this are incomplete. Perineuronal nets (PNNs) are highly sulfated, specialized extracellular matrix structures that regulate the maturation of synaptic connections and neuronal plasticity. We have previously shown that mice heterozygous for the brain sulfate transporter Slc13a4 have abnormal social interactions, memory, exploratory behaviors, stress and anxiety of postnatal origin, pointing to potential deficits in PNN biology, and implicate SLC13A4 as a critical factor required for regulating normal synaptic connectivity and function. Here, we sought to investigate aberrant PNN formation as a potential mechanism contributing to the functional deficits displayed by Slc13a4+/- mice. Following social interactions, we reveal reduced neuronal activation in the somatosensory cortex of Slc13a4+/- mice, and altered inhibitory and excitatory postsynaptic currents. In line with this, we found a reduction in parvalbumin-expressing neurons decorated with PNNs, as well as reduced expression of markers for PNN maturation. Finally, we reveal that postnatal administration of N-acetylcysteine prevented PNN abnormalities from manifesting in Slc13a4+/- adult animals. Collectively, these data highlight a central role for postnatal SLC13A4 in normal PNN formation, circuit function and subsequent animal behavior.
Sulfotransferase enzymes (SULT) catalyse sulfoconjugation of drugs, as well as endogenous mediators, gut microbiota metabolites and environmental xenobiotics. To address the limited evidence on sulfonation activity from clinical research, we developed a clinical metabolic phenotyping method using paracetamol as a probe substrate. Our aim was to estimate sulfonation capability of phenolic compounds and study its intraindividual variability in man. A total of 36 healthy adult volunteers (12 men, 12 women and 12 women on oral contraceptives) received paracetamol in a 1 g-tablet formulation on three separate occasions. Paracetamol and its metabolites were measured in plasma and spot urine samples using liquid chromatography-high resolution mass spectrometry. A metabolic ratio (Paracetamol Sulfonation Index—PSI) was used to estimate phenol SULT activity. PSI showed low intraindividual variability, with a good correlation between values in plasma and spot urine samples. Urinary PSI was independent of factors not related to SULT activity, such as urine pH or eGFR. Gender and oral contraceptive intake had no impact on PSI. Our SULT phenotyping method is a simple non-invasive procedure requiring urine spot samples, using the safe and convenient drug paracetamol as a probe substrate, and with low intraindividual coefficient of variation. Although it will not give us mechanistic information, it will provide us an empirical measure of an individual’s sulfonator status. To the best of our knowledge, our method provides the first standardised in vivo empirical measure of an individual’s phenol sulfonation capability and of its intraindividual variability. EUDRA-CT 2016-001395-29, NCT03182595 June 9, 2017.
There are multiple lines of evidence for an impaired sulfur amino acid (SAA) metabolism in autism spectrum disorder (ASD). For instance, the concentrations of methionine, cysteine and S-adenosylmethionine (SAM) in body fluids of individuals with ASD is significantly lower while the concentration of S-adenosylhomocysteine (SAH) is significantly higher as compared to healthy individuals. Reduced methionine and SAM may reflect impaired remethylation pathway whereas increased SAH may reflect reduced S-adenosylhomocysteine hydrolase activity in the catabolic direction. Reduced SAM/SAH ratio reflects an impaired methylation capacity.
We hypothesize multiple mechanisms to explain how the interplay of oxidative stress, neuroinflammation, mercury exposure, maternal use of valproate, altered gut microbiome and certain genetic variants may lead to these SAA metabotypes. Furthermore, we also propose a number of mechanisms to explain the metabolic consequences of abnormal SAA metabotypes. For instance in the brain, reduced SAM/SAH ratio will result in melatonin deficiency and hypomethylation of a number of biomolecules such as DNA, RNA and histones. In addition to previously proposed mechanisms, we propose that impaired activity of “radical SAM” enzymes will result in reduced endogenous lipoic acid synthesis, reduced molybdenum cofactor synthesis and impaired porphyrin metabolism leading to mitochondrial dysfunction, porphyrinuria and impaired sulfation capacity. Furthermore depletion of SAM may also lead to the disturbed mTOR signaling pathway in a subgroup of ASD.
The proposed “SAM-depletion hypothesis” is an inclusive model to explain the relationship between heterogeneous risk factors and metabotypes observed in a subset of children with ASD.
Main risk factors of autism spectrum disorder (ASD) include both genetic and non-genetic factors, especially prenatal and perinatal events. Newborn screening dried blood spot (DBS) samples have great potential for the study of early biochemical markers of disease. To study DBS strengths and limitations in the context of ASD research, we analyzed the metabolomic profiles of newborns later diagnosed with ASD. We performed LC-MS/MS-based untargeted metabolomics on DBS from 37 case-control pairs randomly selected from the iPsych sample. After preprocessing using MZmine 2.41.2, metabolites were putatively annotated using mzCloud, GNPS feature-based molecular networking and MolNetEnhancer. 4360 mass spectral features were detected, of which 150 could be putatively annotated at a high confidence level. Chemical structure information at a broad level could be retrieved for 1009 metabolites, covering 31 chemical classes. Although no clear distinction between cases and controls was revealed, our method covered many metabolites previously associated with ASD, suggesting that biochemical markers of ASD are present at birth and may be monitored during newborn screening. Additionally, we observed that gestational age, age at sampling and month of birth influence the metabolomic profiles of newborn DBS, which informs us on the important confounders to address in future studies.
The primary treatment for autism is educational, an intensive behavioral approach that has become widespread despite some lingering controversy. Biological treatments are strictly adjunctive at present. These consist of primarily psychotropic medications that address certain aspects of the core symptoms such as stimulants for hyperactivity and inattention, clonidine for insomnia, selective serotoninreuptake inhibitors (SSRIs) for repetitive obsessive-compulsive-like behaviors and antipsychotics for aggression. When these medications are effective they often also have a beneficial effect on language and social relatedness. In summary, they have a limited impact on some autistic symptoms in some patients.
This brief report examines the implementation of dietary intervention utilizing the specific carbohydrate diet (SCD) for the management of gastrointestinal issues in a 4 year old boy diagnosed with Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS). Data relating to anthropometrics, dietary intake, blood markers, gastrointestinal (GI) symptoms, sleep issues, and behavioral concerns were gathered at baseline and after 4 months of dietary intervention. The dietary intervention was well tolerated. Improvements in nutrient status, GI symptoms, and behavioral domains were reported. The use of the SCD protocol in children with ASD/FXS and GI symptoms warrants further investigation.
This study involved a randomized, controlled, single-blind 12-month treatment study of a comprehensive nutritional and dietary intervention. Participants were 67 children and adults with autism spectrum disorder (ASD) ages 3–58 years from Arizona and 50 non-sibling neurotypical controls of similar age and gender. Treatment began with a special vitamin/mineral supplement, and additional treatments were added sequentially, including essential fatty acids, Epsom salt baths, carnitine, digestive enzymes, and a healthy gluten-free, casein-free, soy-free (HGCSF) diet. There was a significant improvement in nonverbal intellectual ability in the treatment group compared to the non-treatment group (+6.7 ± 11 IQ points vs. −0.6 ± 11 IQ points, p = 0.009) based on a blinded clinical assessment. Based on semi-blinded assessment, the treatment group, compared to the non-treatment group, had significantly greater improvement in autism symptoms and developmental age. The treatment group had significantly greater increases in EPA, DHA, carnitine, and vitamins A, B2, B5, B6, B12, folic acid, and Coenzyme Q10. The positive results of this study suggest that a comprehensive nutritional and dietary intervention is effective at improving nutritional status, non-verbal IQ, autism symptoms, and other symptoms in most individuals with ASD. Parents reported that the vitamin/mineral supplements, essential fatty acids, and HGCSF diet were the most beneficial.
Are the symptoms of autism caused by a treatable metabolic syndrome that traces to the abnormal persistence of a normal, alternative functional state of mitochondria? A small clinical trial published in 2017 suggests this is possible. Based on a new unifying theory of pathogenesis for autism called the cell danger response (CDR) hypothesis, this study of 10 boys, ages 5-14years, showed that all 5 boys who received antipurinergic therapy (APT) with a single intravenous dose of suramin experienced improvements in all the core symptoms of autism that lasted for 6-8weeks. Language, social interaction, restricted interests, and repetitive movements all improved. None of these improvements were observed in the placebo group. Larger and longer studies are needed to confirm this promising discovery. This review introduces the concept of M2 (anti-inflammatory) and M1 (pro-inflammatory) mitochondria that are polarized along a functional continuum according to cell stress. The pathophysiology of the CDR, the complementary functions of M1 and M2 mitochondria, relevant gene-environment interactions, and the metabolic underpinnings of behavior are discussed as foundation stones for understanding the improvements in ASD behaviors produced by antipurinergic therapy in this small clinical trial.
The patient with autism can present quite a challenge in the dental office. With an increasing prevalence of the disorder, it is likely that dental health care workers will be required to care for an individual with autism. There are a variety of behavior guidance techniques and medical immobilization concepts to effectively treat patients with autism in the dental office. Treatment planning and preventive strategies need to be individualized for these patients. There is much more to know than just patient management issues. There are numerous issues specific to dentistry related to mercury, fluoride, nitrous oxide, antibiotics and acetaminophen. These patients frequently have allergies, immune system problems, gastrointestinal disturbances, and seizures. Dentists should be aware of the patient’s history, diagnosis, and communication abilities treatment strategies for adults and children. Despite the challenges, maintaining good oral health for the patient with autism can be an especially rewarding experience.
Using genomic applications to glean insights into human biology, we systematically searched for nonsense, single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two non-linked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical, sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. Both SLC13A1 R12X and W48X were independently associated with a 27.6% (P=2.7x10(-8)) and 27.3% (P=6.9x10(-14)) decrease in serum sulfate, respectively (P=8.8x10(-20) for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P=4.4x10(-12)). Consistent with sulfate's role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to non-carriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally-occurring, homozygous, loss-of-function mutations in Slc13a1 This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity.
Autistic spectrum disorder (ASD) is a spectrum of early-onset lifelong neurodevelopmental disorders that severely impact social and behavioral functioning. It is a debilitating disorder that affects 1 % of the global children population with increasing prevalence and presented huge economic burden to the family and the nation. Current diagnosis for ASD is very subjective mainly because of the multifactorial nature of the disorders. The etiology of ASD is highly complex and multifaceted involving the gene, environment, and diet and is associated with various abnormalities that include immunologic, metabolic, and, more recently, the host–gut microbiome stability (Fig. 14.1). The gut microbiota is a consortium of bacteria that coexisted and coevolved with the host from the time of birth. As such the gut microbiome–mammalian “superorganism” represents a level of biological evolutionary development where true symbiosis is characterized by extensive “transgenomic” modulation of metabolism and functions between the two entities. The gut microbiota is involved in various mammalian biological processes including defense against pathogens, immunity, intestinal microvilli development, and recovery of metabolic energy through fermentation of otherwise nondigestible dietary fiber. In addition, the gut microbiota has been shown to communicate with the brain via the gut–brain axis to modulate brain development, function, and behavior. Recent evidence indicated that the gut microbiota influenced central nervous system development and responses to stress. Current understanding on the potential and extend of gut microbe involvement in brain development and host metabolic signaling is still in its infancy. Coupled with ever-increasing awareness on the importance of the gut microbiome in health and disease particularly autism, understanding the fundamental mechanistic interaction between host brain development and gut microbiota is crucial for unraveling the mystery behind the etiopathology of autism.
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders that affect an individual’s ability to communicate and socialize, often associated with repetitive movements or behaviors. Frequently patients associate intellectual disability or digestive problems. Autism is more common in males and affects 1 in 88 children in USA. The mechanism that leads to ASD is very complex, involving genetic, epigenetic, immune and environmental factors that could act in different proportions, at different developmental stages (prenatal, perinatal or postnatal) and on different pathways. The general prototype consists in an initial systemic dysfunction, such as immune dysregulation, inflammation, impaired detoxification or oxidative stress in an individual with genetic predisposition. In this context, ASD may arise due to the harmful action of environmental factors that lead to neuroinflammation and abnormal brain development. Environmental factors involved in autism determinism could be very diverse and include classical extrinsic factors (toxicants, environmental pollutants, medications, food additives, electromagnetic fields and even social influences), maternal disorders or lifestyle factors, as well as intrinsic factors (hormones, inflammatory mediators, microbiota and other biological molecules that make up the microenvironment around the developing fetal or neonatal brain). The aim of the present review is to discuss actual theories concerning genetic, epigenetic, immunologic and environmental factors interplay in ASD determinism, to present a practical and global approach of this complex problem, as well as to point some of the new directions for ASD prevention and therapy.
The role of artificial food additives and food chemicals in abetting certain behavioural conditions has been the subject of behavioural nutrition research over several decades. However, a few studies have also raised questions regarding a similar role possibly played by naturally occurring phytochemicals in general and salicylates in particular. Such studies have, however, been rather few and far between. More importantly, till date, there has been no attempt to collate the findings from the few studies that have been carried out at different points in time by different researchers across different countries and cultures. This gap in the extant body of knowledge is made especially prominent by the fact that naturally occurring salicylates abound in many green vegetables and fruit, which are common constituents of a healthy diet. The aim of this review article is two-fold - firstly, to collate and present the related researches on the effects of salicylates in general and natural salicylates in particular on mental health; and secondly, to identify promising research directions for the future.
Autism is a complex, multifactorial disorder of uncertain etiology. Initially described as a psychological disorder involving communication failure, relationship dysfunction, and ritualistic, repetitive behavior, autism is associated with measurable defects in many organ systems. Neurotransmitter, enzymatic, and structural abnormalities have been observed in the " nervous system. Autoimmunity is common, as are loss of gut integrity and coagulation abnormalities. At a metabolic level, not only is mitochondrial function seriously impaired, but also numerous enzymes and substrates are deficient in quantity or activity. Various therapies addressing isolated metabolic impairments have shown partial benefit in limited subgroups. The complex range of stigmata seen in autism is consistent with a pathological state of oxidative stress and inflammation. Various therapies addressing oxidative stress and inflammation have had some success and are reviewed here. We postulate that effective strategies dealing with the primary causative sources of oxidative stress can result in definitive resolution of many of the symptoms associated with the autism spectrum disorders. Suggestions are made for future therapeutic modalities addressing possible underlying causes of oxidative stress.
Sulphation capacity was measured in autistic children and age-matched child controls, using paracetamol (acetaminophen) as an in vivo probe drug. Excretion of the sulphate conjugate (but not the glucuronide metabolite) was significantly reduced in autistic children. Plasma levels of inorganic sulphate were also significantly lower in autism as was the activity of platelet phenolsulphotransferase, the enzyme catalyzing the sulphation of paracetamol. These results suggest that a factor in some cases of autism may be decreased capacity to detoxify endogenous and exogenous phenols and amines via sulphation.
Dietary intervention was tried in 15 autistic children (aged 6–22 yrs) according to the urinary peptide pattern used for classification. Improvement was noted in tests for autistic behavior and several educational measures (e.g., Illinois Test of Psycholinguistic Abilities and Progressive Matrices). A normalization of the urinary peptide secretion was also noted. An etiologic model is presented. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Conflicting reports make it difficult to determine if foods, food coloring, or allergies are related to hyperactivity. Twenty-four hyperactive children were tested with sublingual foods and dyes followed by a seven-day diet omitting milk, wheat, egg, cocoa, corn, sugar, and food coloring, and by subsequent individual ingestion challenges with these same food items. More than 70% of the children had evidence of allergy in their personal and family history, as well as positive allergy skin tests. The sublingual dye, but not the sublingual mixed-food test, correlated well with repeated ingestion challenges. Twelve children improved to a moderate or marked degree during the seven-day diet. A simple sublingual food-coloring test or a one-week experimental diet can be used to detect a subgroup of children hyperactive from specific food dyes or foods. Improvement persisted in children who avoided offending food dyes or foods for at least 12 weeks.
The effect of particular foods on levels of hyperactivity, uncontrolled laughter, and disruptive behaviors was studied in an 8-year-old autistic boy. The floor of the child's room was taped off into six equal-sized rectangles to measure general activity level. Frequency data were recorded on screaming, biting, scratching, and object throwing. A time-sample technique was used to record data on laughing. Data were gathered during four phases. During an initial 4-day period the child was fed a normal American diet. A 6-day fasting period followed, during which time only spring water was allowed. The third phase lasted 18 days and involved the presentation of individual foods. During the final phase of the study the child was given only foods that had not provoked a reaction in the third phase. Results showed that foods such as wheat, corn, tomatoes, sugar, mushrooms, and dairy products were instrumental in producing behavioral disorders with this child.
1. Low dose (500 mg) paracetamol (acetaminophen) was administered to patients with rheumatoid arthritis (RA) and to age-matched healthy controls and to hospital controls. 2. At this dose level, patients with RA excreted decreased amounts of paracetamol sulphate (controls means 11.3 +/- 5.1, 10.6 +/- 5.9; RA mean 3.02 +/- 3.7). This difference is statistically significant (P less than 0.001). 3. The mean ratio of excretion of paracetamol sulphate/paracetamol glucuronide was 5.6 +/- 12.1, 5.3 +/- 10.7 in controls but 2.1 +/- 2.7 in RA patients (P less than 0.001). 4. Patients with RA appear to have less capacity for excreting paracetamol as non-toxic conjugates and may be more susceptible to paracetamol toxicity, especially on chronic dosage.
1. Low dose (500 mg) paracetamol (acetaminophen) was administered to patients with Parkinson's disease, motor neurone disease and to age-matched controls. 2. At this low dose level the controls excreted proportionately more sulphate and less glucuronide conjugate than has been reported for administration of 1000 mg of paracetamol. 3. Both groups of patients with chronic neurological disease excreted decreased amounts of paracetamol sulphate (control mean 11.2 +/- 5.4% dose; Parkinson's disease 3.9 +/- 3.7%; motor neurone disease, 5.0 +/ 4.1%). 4. The mean ratio of excretion of paracetamol sulphate/paracetamol glucuronide was 5.6 +/- 11.7 in controls, but 1.1 +/- 1.7 and 1.2 +/- 1.7 in Parkinson's disease and motor neurone disease respectively. These differences are statistically significant (p less than 0.001).
The sulfates of norepinephrine, dopamine (DA), and serotonin (5-hydroxytryptamine [5HT]) are present in the cerebrospinal fluid (CSF) of laboratory animals and humans. The amounts of sulfated amines in human CSF always greatly exceed the amounts of the free amines. The enzyme responsible for sulfation, phenol sulfotransferase (PST) (EC 2.8.2.1), has been detected in the brain tissue of several species, including humans. PST in the human brain has a high affinity for the amines but it is a low-capacity enzyme. Accordingly, sulfation appears to be of greater significance in the economy of the amines under quiescent conditions than during conditions of increased release of transmitter. Recent evidence suggests that a fraction of the conjugated amines in CSF enters from plasma because in the African green monkey, DA sulfate and 5HT sulfate cross the blood-CSF barrier after i.v. injection. In addition, in humans there are no increases in the concentration of amine sulfates from lumbar to ventricular CSF that would also be compatible with a partly peripheral origin for the amine sulfates. However, it appears that at least a portion of the amine sulfates in CSF originate in the central nervous system because the ratios of [CSF amine sulfates]/[plasma sulfates] are never as high after i.v. injection as under basal conditions.
The ratio between urinary 6-beta-OH-cortisol and 17-OH-corticosteroids was taken as an indirect estimate of monoxygenase activity in a population of controls and epileptic patients undergoing therapy with diphenylhydantoin and phenobarbital. Cortisol hydroxylation was increased in the group of epileptics with large inter-individual variations notwithstanding a similar dosage of inducers. The levels of some phase II conjugating enzymes were followed by administering paracetamol and measuring the urinary excretion of its main metabolites. Paracetamol glucuronate was increased by levels of cysteine and mercapturic derivatives of paracetamol did not vary, whereas sulfate derivatives were decreased in epileptic patients. Plasma N-acetyl-transferase activity did not vary in either group. Hydroxylated cortisol and paracetamol glucuronide excretion were not correlated in the same individuals, and no correlation was found between the ratio of 6-beta-OH-cortisol/17-OH-corticosteroids and the plasma levels of diphenylhydantoin or phenobarbital. Oxidation of cortisol and conjugation of paracetamol were controlled with different mechanisms, varied considerably between individuals and were not predictive of the pharmacokinetics of the inducers in treated patients.
Twenty-four-hour urine samples from psychotic and autistic children were precipitated with benzoic acid at pH 4.3. Fractionation of the aromatic complexes thus formed with benzoic acid-protein and peptides and uric acid, proteins and peptides on G-25 columns-yielded filtration patterns that may be of diagnostic value. Peptide material could be extracted from the formed complexes and refractionated on P2 gels. Increased levels of peptide material, especially of N-substituted peptides, could be demonstrated. Several bioactive factors (Reichelt et al. 1981) are under study. Possible etiological factors are discussed, and a working hypothesis is presented.
Human platelet phenolsulphotransferase exists in two functional forms. M and P. In this study the substrate specificity of the two forms has been further delineated by correlating activities in different individuals with various substrates. m-Tyramine, noradrenaline, adrenaline, 5-hydroxytryptamine, p-hydroxyamphetamine, isoprenaline, salbutamol and l-naphthol were all specific substrates for the M form of the enzyme. Paracetamol, a mixed substrate, was predominantly metabolized by the M form. Salicylamide at 5 microM was a substrate for the P form but became and M substrate at higher concentration. Phenol itself, a specific substrate for phenolsulphotransferase P at 10 microM, also became an M substrate at 1 mM concentration. These substrate specificities were confirmed with the selective inhibitor, dichloronitrophenol. In this study, we measured phenolsulphotransferase activity in platelets from 13 individuals selected on the basis of their wide variation in ability to sulphoconjugate paracetamol and salicylamide in vivo. There was no significant relationship between the in vivo pattern with either drug and the activity of platelet phenolsulphotransferase assayed with paracetamol or salicylamide respectively.
The authors studied the distribution of the paracetamol conjugation in a Hungarian population (53 adult Caucasian persons). The data indicated that the excretion of paracetamol glucuronide and sulphate were not normally distributed. Bimodality were apparent in both conjugation pathways: 15.1% of subjects was relatively extensive glucuronidators, and the 24.5% of subjects was extensive sulphatators. Monitoring the ratios of various urinary paracetamol conjugates/paracetamol may be useful as a tool for determining the glucuronide and sulphate conjugation capacity in humans.
We have studied the distribution and nature of sulphated glycosaminoglycans (GAGs) within normal and inflamed intestine. There is increasing evidence that these negatively charged polysaccharides, which both regulate the ability of albumin to leave the vasculature and inhibit thrombosis, may be affected by inflammatory cells and their products. We obtained samples of freshly resected intestinal tissue from eight controls, eleven patients with Crohn's disease, and six with ulcerative colitis. Sulphated GAGs were detected by means of a gold-conjugated poly-L-lysine probe, and the tissue density of anionic sites was assessed semiquantitatively by means of a Lennox graticule. In normal intestine there was staining in the vascular endothelium and the subepithelial basal lamina and throughout the extracellular matrix of the lamina propria and submucosa. Tissue from the patients with inflammatory bowel disease showed inflammation macroscopically and on histology. There were profound abnormalities of extracellular matrix GAGs, limited to the mucosa in ulcerative colitis and greatest in the submucosa in Crohn's disease. There was also substantial loss of GAGs from the subepithelial basal lamina in both disorders and from the vascular endothelium in submucosa in Crohn's disease. The extent of local GAG disruption was associated with the distribution of macrophages immunoreactive for tumour necrosis factor alpha and the activation marker RM 3/1. We suggest that inflammatory disruption of vascular and connective tissue GAGs may be an important pathogenetic mechanism, contributing to the leakage of protein and fluid, thrombosis, and tissue remodelling seen in inflammatory bowel disease.
To study the metabolism of single doses of paracetamol in paediatric patients with chronic liver disease admitted to a hospital liver disease clinic.
Thirteen paediatric patients, aged 7 months to 12 years, with chronic liver disease of varying severity were studied. In these children, paracetamol elimination half-life was negatively correlated with serum albumin and positively with prothrombin time, as previously reported in adults with liver disease. The rate constant of glucuronide formation was higher in the children with liver disease compared to the value reported in healthy children of similar ages. The rate constant of the formation of paracetamol sulphate was no different from that in normal children. The 36 h urinary paracetamol glucuronide to sulphate ratio was 1.4 (95% CI 0.8 to 1.7). This mean ratio was higher than in healthy children (0.81 and 0.75) but not significantly so, probably because of a Type 1 error due to the inevitable small sample size arising from the nature of the population being studied.
The present study provides reassuring additional data to indicate that, at least for single doses, there is no cause for concern in the use of paracetamol in children with chronic liver disease.
1. The mammalian phenolsulphotransferase enzymes are known to play a major role in both the detoxification and possibly the activation of pre-carcinogenic phenols and aromatic amines. 2. Vegetable cytosol preparations were tested in vitro for their ability to affect the sulphation of two reference compounds (rho-nitrophenol and dopamine, which are selective substrates for the phenol and monoamine forms of phenolsulphotransferase respectively), and to act as substrates for the enzymes in comparison with the same reference compounds. 3. The majority of cytosols greatly decreased (> 80%) the sulphation of either or both the reference compounds. This effect may have been due to either enzyme inhibition or substrate binding. 4. Whereas some of the cytosols were sulphated under the assay conditions, most were not. Additionally, it was found that a cytosol that decreased the sulphation of the two reference compounds was not necessarily poorly sulphated itself. 5. It is concluded that dietary factors have the potential to play a major role in modulating the sulphation detoxification pathway, and have wide ranging implications with regard to adverse drug reactions.
Paracetamol was used as a "probe" drug to study the circadian rhythms of metabolite ratios in man. Paracetamol was orally administered to six volunteers at different times of day, 0-8 h and 8-24 h urine samples being measured for sulphate and glucuronide formation. Results showed a wide interindividual variation in paracetamol metabolite excretion among the six subjects. However, when a 500 mg dose was administered, free paracetamol excretion was minimal when the dose was given at 12.00 h and maximal when given at 20.00 h for the 0-8 h collection period. Sulphate excretion rose slightly at night and decreased gradually during the day. Glucuronide excretion was greatest with drug administration at 16.00 h and least if paracetamol was ingested at 08.00 h. The 8-24 h profiles were roughly similar. At a higher dose (1500 mg), free paracetamol excretion showed a minimum from dosing at 20.00 h and a maximum from dosing at 24.00 h in both 0-8 h and 8-24 h collections, while the sulphate conjugate peaked for doses at 20.00 h and 8.00 h with collections at 0-8 h and 8-24 h respectively. The glucuronide conjugate was maximal for paracetamol administration at 16.00 h for both 0-8 h and 8-24 h collections. There appears to be a 12 hour phase variation in excretion; this may result from circadian rhythms in absorption and enzyme activities. These parameters may also affect metabolism at higher dose levels, so that the hepatotoxicity of paracetamol could vary with the time of dose.
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