Advances in Autism Research
compiled by Teresa Binstock for
Autism Research Institute
April 2008
Autism and Gastrointestinal Pathology
1a. Intestinal pathophysiology in autism
White JF.
Exp Biol Med (Maywood). 2003 Jun;228(6):639-49.
http://www.ebmonline.org/cgi/content/full/228/6/639
[An excellent overview, with a section on intestinal permeability, another on vaccines including the MMR. White's essay gives perspective to contrary findings such as those in cites 2 and 3 hereinbelow.]
Autism is a life-long developmental disorder affecting as many as 1 in 500 children. The causes for this profound disorder are largely unknown. Recent research has uncovered pathology in the gastrointestinal tract of autistic children. The pathology, reported to extend from the esophagus to the colon, is described here along with other studies pointing to a connection between diet and the severity of symptoms expressed in autism. The evidence that there is impaired intestinal permeability in autism is reviewed, and various theories are discussed by which a leaky gut could develop. Lastly, some possible ways in which impaired gastrointestinal function might influence brain function are discussed.
PMID: 12773694
1b. Autism Spectrum Disorders: Concurrent Clinical
Disorders
Ming X et al.
Journal of Child Neurology, Vol. 23, No. 1, 6-13 (2008)
http://jcn.sagepub.com/cgi/content/abstract/23/1/6
Individuals with autism spectrum disorder are heterogeneous in clinical
presentation, concurrent disorders, and developmental outcomes. This study
characterized the clinical co-occurrences and potential subgroups in 160
children with autism spectrum disorders who presented to The Autism Center
between 1999 and 2003. Medical and psychiatric co-occurrences included sleep
disorders, epilepsy, food intolerance, gastrointestinal dysfunction, mood
disorder, and aggressive and self-injurious behaviors. Sleep disorders were
associated with gastrointestinal dysfunction (P < .05) and mood disorders (P
< .01). Food intolerance was associated with gastrointestinal dysfunction (P
= .001). Subjects with mood disorder tended to develop aggressive or
self-injurious behaviors (P < .05). Developmental regression was not
associated with increased co-occurrence of medical or psychiatric disorders.
Medical co-occurrence did not present as a risk factor for psychiatric
co-occurrence, and vice versa. These results showed a high prevalence of
multiple medical and psychiatric co-occurrences. There may be common
pathophysiologic mechanisms resulting in clinical subgroups of autism spectrum
disorders. Recognition of the co-occurrence of concurrent disorders may provide
insight into the therapeutic strategy.
2. Abnormal intestinal permeability in children with autism
D'Eufemia P et al.
Acta Paediatr. 1996 Sep;85(9):1076-9.
We determined the occurrence of gut mucosal damage using the intestinal permeability test in 21 autistic children who had no clinical and laboratory findings consistent with known intestinal disorders. An altered intestinal permeability was found in 9 of the 21 (43%) autistic patients, but in none of the 40 controls. Compared to the controls, these nine patients showed a similar mean mannitol recovery, but a significantly higher mean lactulose recovery (1.64% +/- 1.43 vs 0.38% +/- 0.14; P < 0.001). We speculate that an altered intestinal permeability could represent a possible mechanism for the increased passage through the gut mucosa of peptides derived from foods with subsequent behavioural abnormalities.
PMID: 8888921
3. Intestinal Permeability and Glucagon-like peptide-2 in Children with Autism: A Controlled Pilot Study
Robertson MA et al.
J Autism Dev Disord. 2008 Feb 29 [Epub ahead of print]
We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to feeding. Results were compared with sibling controls and children without developmental disabilities. We enrolled 14 children with autism, 7 developmentally normal siblings of these children and 8 healthy, developmentally normal, unrelated children. Our study did not detect differences in these measures of gastrointestinal function in a group of children with autism.
PMID: 18311517
4. Polymorphism of bovine beta-casein and its potential effect on human health
Stanislaw Kaminski, Anna Cieslinska, Elzbieta Kostyra
Journal of Applied Genetics 48(3),2007, pp. 189 - 198
http://jag.igr.poznan.pl/2007-Volume-48/3/pdf/2007_Volume_48_3-189-198.pdf
Proteins in bovine milk are a common source of bioactive peptides. The peptides are released by the digestion of caseins and whey proteins. In vitro the bioactive peptide beta-casomorphin 7 (BCM-7) is yielded by the successive gastrointestinal proteolytic digestion of bovine beta-casein variants A1 and B, but this was not seen in variant A2. In hydrolysed milk with variant A1 of beta-casein, BCM-7 level is 4-fold higher than in A2 milk. Variants A1 and A2 of beta-casein are common among many dairy cattle breeds. A1 is the most frequent in Holstein-Friesian (0.310-0.660), Ayrshire (0.432-0.720) and Red (0.710) cattle. In contrast, a high frequency of A2 is observed in Guernsey (0.880-0.970) and Jersey (0.490-0.721) cattle. BCM-7 may play a role in the aetiology of human diseases. Epidemiological evidence from New Zealand claims that consumption of beta-casein A1 is associated with higher national mortality rates from ischaemic heart disease. It seems that the populations that consume milk containing high levels of beta-casein A2 have a lower incidence of cardiovascular disease and type 1 diabetes. BCM-7 has also been suggested as a possible cause of sudden infant death syndrome. In addition, neurological disorders, such as autism and schizophrenia, seem to be associated with milk consumption and a higher level of BCM-7. Therefore, careful attention should be paid to that protein polymorphism, and deeper research is needed to verify the range and nature of its interactions with the human gastrointestinal tract and whole organism.
PMID: 17666771
5. Relationship of dietary intake to gastrointestinal symptoms in children with autistic spectrum disorders
Levy SE et al.
Biol Psychiatry. 2007 Feb 15;61(4):492-7.
BACKGROUND: Gastrointestinal (GI) symptoms and abnormalities in stool consistency are frequently reported by parents of children with autism spectrum disorders (ASD). The purpose of this study was to 1) describe dietary intake of a cohort of children with ASD compared with normative data and 2) determine whether GI symptoms and stool consistency are related to dietary intake. METHODS: Data from diet diaries of children (3-8 years) with ASD (n = 62) were analyzed by a registered pediatric dietician to compare to RDA standards for total calories, protein, carbohydrate, and fat. Dietary intake was correlated with descriptors of stool consistency using cumulative logistic regression methods. RESULTS: Intake of calories, carbohydrates, and fat were in the average range; protein intake was increased (211% of RDA). Reported frequency of GI abnormalities, including abnormal stool consistency (e.g., bulky or loose), was increased (54%). No statistically significant relationships between stool consistency and dietary intake were observed. CONCLUSIONS: In this sample, there was a high rate of reported gastrointestinal symptoms, despite lack of medical causes. Intake was adequate for calories and carbohydrates and increased for protein. The children did not exhibit excessive carbohydrate intake. There was no association of nutrient intake to changes in stool consistency.
PMID: 17207470
6. Health implications of milk containing beta-casein with the A2 genetic variant
Bell SJ, Grochoski GT, Clarke AJ.
Crit Rev Food Sci Nutr. 2006;46(1):93-100.
Milk from dairy cows has long provided a high quality source of protein and selected micronutrients such as calcium to most populations. Recently, a relationship between disease risk and consumption of a specific bovine ss-casein fraction either A1 or A2 genetic variants has been identified. Populations, which consume milk containing high levels of ss-casein A2 variant, have a lower incidence of cardiovascular disease and type 1 diabetes. Furthermore, consumption of milk with the A2 variant may be associated with less severe symptoms of autism and schizophrenia. The mechanism of action focuses on ss-casein A1 and related forms preferentially that are able to produce a bioactive opioid peptide, ss-casomorphin-7 (ss-CM-7) during digestion. Infants may absorb ss-CM-7 due to an immature gastrointestinal tract. Adults, on the other hand, appear to reap the biological activity locally on the intestinal brush boarder. ss-CM-7 can potentially affect numerous opioid receptors in the nervous, endocrine, and immune systems. Whether there is a definite health benefit to milk containing the A2 genetic variant is unknown and requires further investigation.
PMID: 16403684
7. Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders
Jyonouchi H et al.
J Pediatr. 2005 May;146(5):605-10.
OBJECTIVE: To evaluate an association between cytokine production with common dietary proteins as a marker of non-allergic food hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young children with autism spectrum disorders (ASD). STUDY DESIGN: Peripheral blood mononuclear cells (PBMCs) were obtained from 109 ASD children with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N = 34], from children with NFH (N = 15), and control subjects (N = 19). Diarrhea and constipation were the major GI symptoms. We measured production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2), and regulatory cytokines by PBMCs stimulated with whole cow's milk protein (CMP), its major components (casein, beta-lactoglobulin, and alpha-lactoalbumin), gliadin, and soy. RESULTS: PBMCs obtained from GI (+) ASD children produced more tumor necrosis factor-alpha (TNF-alpha)/interleukin-12 (IL-12) than those obtained from control subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin, irrespective of objective GI symptoms. They also produced more TNF-alpha with gliadin, which was more frequently observed in the group with loose stools. PBMCs obtained from GI (-) ASD children produced more TNF-alpha/IL-12 with CMP than those from control subjects, but not with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine production with casein and soy were unremarkable. CONCLUSION: A high prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs with CMP and its major components indicates a role of NFH in GI symptoms observed in children with ASD.
PMID: 15870662
8. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention
Jyonouchi H et al.
Neuropsychobiology. 2005;51(2):77-85.
OBJECTIVE: Our previous study indicated an association between cellular immune reactivity to common dietary proteins (DPs) and excessive proinflammatory cytokine production with endotoxin (lipopolysaccharide, LPS), a major stimulant of innate immunity in the gut mucosa, in a subset of autism spectrum disorder (ASD) children. However, it is unclear whether such abnormal LPS responses are intrinsic in these ASD children or the results of chronic gastrointestinal (GI) inflammation secondary to immune reactivity to DPs. This study further explored possible dysregulated production of proinflammatory and counter-regulatory cytokines with LPS in ASD children and its relationship to GI symptoms and the effects of dietary intervention measures. METHODS: This study includes ASD children (median age 4.8 years) on the unrestricted (n = 100) or elimination (n = 77) diet appropriate with their immune reactivity. Controls include children with non-allergic food hypersensitivity (NFH; median age 2.9 years) on the unrestricted (n = 14) or elimination (n = 16) diet, and typically developing children (median age 4.5 years, n = 13). The innate immune responses were assessed by measuring production of proinflammatory (TNF-alpha, IL-1beta, IL-6, and IL-12) and counter-regulatory (IL-1ra, IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells (PBMCs) with LPS. The results were also compared to T-cell responses with common DPs and control T-cell mitogens assessed by measuring T-cell cytokine production. RESULTS: ASD and NFH PBMCs produced higher levels of TNF-alpha with LPS than controls regardless of dietary interventions. However, only in PBMCs from ASD children with positive gastrointestinal (GI(+)) symptoms, did we find a positive association between TNF-alpha levels produced with LPS and those with cow's milk protein (CMP) and its major components regardless of dietary interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced higher IL-12 than controls and less IL-10 than GI(-) ASD PBMCs with LPS. GI(+) ASD but not GI(-) ASD or NFH PBMCs produced less counter-regulatory cytokines with LPS in the unrestricted diet group than in the elimination diet group. There was no significant difference among the study groups with regard to cytokine production in responses to T-cell mitogens and other recall antigens. Conclusion: Our results revealed that there are findings limited to GI(+) ASD PBMCs in both the unrestricted and elimination diet groups. Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(-) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities. Copyright 2005 S. Karger AG, Basel.
PMID: 15741748
9. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder
Jyonouchi H, Sun S, Itokazu N.
Neuropsychobiology. 2002;46(2):76-84.
OBJECTIVES: Children with autism spectrum disorder (ASD) frequently reveal various gastrointestinal (GI) symptoms that may resolve with an elimination diet along with apparent improvement of some of the behavioral symptoms. Evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses. This may predispose ASD children to sensitization to common dietary proteins (DP), leading to GI inflammation and aggravation of some behavioral symptoms. METHODS: We measured IFN-gamma, IL-5, and TNF-alpha production against representative DPs [gliadin, cow's milk protein (CMP), and soy] by peripheral blood mononuclear cells (PBMCs) from ASD and control children [those with DP intolerance (DPI), ASD siblings, and healthy unrelated children]. We evaluated the results in association with proinflammatory and counter-regulatory cytokine production with endotoxin (LPS), a microbial product of intestinal flora and a surrogate stimulant for innate immune responses. RESULTS: ASD PBMCs produced elevated IFN-gamma and TNF-alpha, but not IL-5 with common DPs at high frequency as observed in DPI PBMCs. ASD PBMCs revealed increased proinflammatory cytokine responses with LPS at high frequency with positive correlation between proinflammatory cytokine production with LPS and IFN-gamma and TNF-alpha production against DPs. Such correlation was less evident in DPI PBMCs. CONCLUSION: Immune reactivity to DPs may be associated with apparent DPI and GI inflammation in ASD children that may be partly associated with aberrant innate immune response against endotoxin, a product of the gut bacteria. Copyright 2002 S. Karger AG, Basel
PMID: 12378124
10. Real-time PCR quantitation of clostridia in feces of autistic children
Song Y, Liu C, Finegold SM.
Appl Environ Microbiol. 2004 Nov;70(11):6459-65.
http://aem.asm.org/cgi/content/full/70/11/6459?view=long&pmid=15528506
Based on the hypothesis that intestinal clostridia play a role in late-onset autism, we have been characterizing clostridia from stools of autistic and control children. We applied the TaqMan real-time PCR procedure to detect and quantitate three Clostridium clusters and one Clostridium species, C. bolteae, in stool specimens. Group- and species-specific primers targeting the 16S rRNA genes were designed, and specificity of the primers was confirmed with DNA from related bacterial strains. In this procedure, a linear relationship exists between the threshold cycle (CT) fluorescence value and the number of bacterial cells (CFU). The assay showed high sensitivity: as few as 2 cells of members of cluster I, 6 cells of cluster XI, 4 cells of cluster XIVab, and 0.6 cell of C. bolteae could be detected per PCR. Analysis of the real-time PCR data indicated that the cell count differences between autistic and control children for C. bolteae and the following Clostridium groups were statistically significant: mean counts of C. bolteae and clusters I and XI in autistic children were 46-fold (P = 0.01), 9.0-fold (P = 0.014), and 3.5-fold (P = 0.004) greater than those in control children, respectively, but not for cluster XIVab (2.6 x 10(8) CFU/g in autistic children and 4.8 x 10(8) CFU/g in controls; respectively). More subjects need to be studied. The assay is a rapid and reliable method, and it should have great potential for quantitation of other bacteria in the intestinal tract.
PMID: 15528506
11. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children
Parracho HM, Bingham MO, Gibson GR, McCartney AL.
J Med Microbiol. 2005 Oct;54(Pt 10):987-91.
http://jmm.sgmjournals.org/cgi/content/full/54/10/987
Children with autistic spectrum disorders (ASDs) tend to suffer from severe gastrointestinal problems. Such symptoms may be due to a disruption of the indigenous gut flora promoting the overgrowth of potentially pathogenic micro-organisms. The faecal flora of patients with ASDs was studied and compared with those of two control groups (healthy siblings and unrelated healthy children). Faecal bacterial populations were assessed through the use of a culture-independent technique, fluorescence in situ hybridization, using oligonucleotide probes targeting predominant components of the gut flora. The faecal flora of ASD patients contained a higher incidence of the Clostridium histolyticum group (Clostridium clusters I and II) of bacteria than that of healthy children. However, the non-autistic sibling group had an intermediate level of the C. histolyticum group, which was not significantly different from either of the other subject groups. Members of the C. histolyticum group are recognized toxin-producers and may contribute towards gut dysfunction, with their metabolic products also exerting systemic effects. Strategies to reduce clostridial population levels harboured by ASD patients or to improve their gut microflora profile through dietary modulation may help to alleviate gut disorders common in such patients.
PMID: 16157555
12. Therapy and epidemiology of autism--clostridial spores as key elements
Finegold SM.
Med Hypotheses. 2008;70(3):508-11. Epub 2007 Sep 29.
This manuscript reviews evidence indicating that intestinal bacteria, specifically clostridia, may play a role in certain cases of autism and hypothesizes that the clostridial spores (which are notably resistant to antimicrobial agents and commonly used germicides) are involved in: (1) relapse in the autistic subject after a response to an agent such as oral vancomycin, after the drug is discontinued, (2) the unexplained increased incidence of autism in recent years, and (3) the unexplained increase in numbers of multiple cases in the same family. Hypothesis (1), if established as valid, would spur research to find well-tolerated and safe agents that could be given together with vancomycin (or other appropriate antimicrobial agent) to eliminate spores; this would revolutionize the therapeutic approach. Hypotheses (2) and (3) relate to widespread use of antimicrobial agents, poor hygiene in young autistic children, and difficulty in removing spores from the home environment. These latter two hypotheses have major implications with regard to the epidemiology of this important and distressing disease and would encourage research into methods to eliminate clostridial spores from the home and other environments.
PMID: 17904761
13. Tight junctions, leaky intestines, and pediatric diseases
Liu Z, Li N, Neu J.
Acta Paediatr. 2005 Apr;94(4):386-93.
BACKGROUND: Tight junctions (TJs) represent the major barrier within the paracellular pathway between intestinal epithelial cells. Disruption of TJs leads to intestinal hyperpermeability (the so-called "leaky gut") and is implicated in the pathogenesis of several acute and chronic pediatric disease entities that are likely to have their origin during infancy. AIM: This review provides an overview of evidence for the role of TJ breakdown in diseases such as systemic inflammatory response syndrome (SIRS), inflammatory bowel disease, type 1 diabetes, allergies, asthma, and autism. CONCLUSION: A better basic understanding of this structure might lead to prevention or treatment of these diseases using nutritional or other means.
PMID: 16092447
14. Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder
Adams JB, Holloway C.
J Altern Complement Med. 2004 Dec;10(6):1033-9.
OBJECTIVE: Determine the effect of a moderate dose multivitamin/mineral supplement on children with autistic spectrum disorder. DESIGN: Randomized, double-blind, placebo-controlled 3-month study. SUBJECTS: Twenty (20) children with autistic spectrum disorder, ages 3-8 years. RESULTS: A Global Impressions parental questionnaire found that the supplement group reported statistically significant improvements in sleep and gastrointestinal problems compared to the placebo group. An evaluation of vitamin B(6) levels prior to the study found that the autistic children had substantially elevated levels of B6 compared to a control group of typical children (75% higher, p < 0.0000001). Vitamin C levels were measured at the end of the study, and the placebo group had levels that were significantly below average for typical children, whereas the supplement group had near-average levels. DISCUSSION: The finding of high vitamin B(6) levels is consistent with recent reports of low levels of pyridoxal-5-phosphate and low activity of pyridoxal kinase (i.e., pyridoxal is only poorly converted to pyridoxal-5-phosphate, the enzymatically active form). This may explain the functional need for high-dose vitamin B(6) supplementation in many children and adults with autism.
PMID: 15673999
15. The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder
Wakefield AJ et al.
Eur J Gastroenterol Hepatol. 2005 Aug;17(8):827-36.
BACKGROUND: Intestinal mucosal pathology, characterized by ileo-colonic lymphoid nodular hyperplasia (LNH) and mild acute and chronic inflammation of the colorectum, small bowel and stomach, has been reported in children with autistic spectrum disorder (ASD). AIM: To assess ileo-colonic LNH in ASD and control children and to test the hypothesis that there is an association between ileo-colonic LNH and ASD in children. PATIENTS AND METHODS: One hundred and forty-eight consecutive children with ASD (median age 6 years; range 2-16; 127 male) with gastrointestinal symptoms were investigated by ileo-colonoscopy. Macroscopic and histological features were scored and compared with 30 developmentally normal (non-inflammatory bowel disease, non-coeliac disease) controls (median age 7 years; range 1-11; 25 male) showing mild non-specific colitis in 16 cases (13 male) and normal colonic histology in 14 cases (12 male). Seventy-four ASD children and 23 controls also underwent upper gastrointestinal endoscopy. The influence on ileal LNH of dietary restriction, age at colonoscopy, and co-existent LNH elsewhere in the intestine, was examined. RESULTS: The prevalence of LNH was significantly greater in ASD children compared with controls in the ileum (129/144 (90%) vs. 8/27 (30%), P < 0.0001) and colon (88/148 (59%) vs. 7/30 (23%), P = 0.0003), whether or not controls had co-existent colonic inflammation. The severity of ileal LNH was significantly greater in ASD children compared with controls, with moderate to severe ileal LNH present in 98 of 144 (68%) ASD children versus 4 of 27 (15%) controls (P < 0.0001). Severe ileal LNH was associated with co-existent colonic LNH in ASD children (P = 0.01). The presence and severity of ileal LNH was not influenced by either diet or age at colonoscopy (P = 0.2). Isolated ileal LNH without evidence of pathology elsewhere in the intestine was a rare event, occurring in less than 3% of children overall. On histopathological examination, hyperplastic lymphoid follicles are significantly more prevalent in the ileum of ASD children (84/138; 61%) compared with controls (2/23; 9%, P = 0.0001). CONCLUSION: Ileo-colonic LNH is a characteristic pathological finding in children with ASD and gastrointestinal symptoms, and is associated with mucosal inflammation. Differences in age at colonoscopy and diet do not account for these changes. The data support the hypothesis that LNH is a significant pathological finding in ASD children.
PMID: 16003132
16. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10
Ashwood P et al.
J Clin Immunol. 2004 Nov;24(6):664-73.
A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal paediatric controls, of which 38 had signs of histological inflammation. Detection of CD3+ lymphocyte staining for spontaneous intracellular TNFalpha, IL-2, IL-4, IFNgamma, and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls (p<0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3(+)TNFalpha+ cells in ASD children was significantly greater compared with noninflamed controls (p<0.002) but not coeliac disease controls. In addition, LP and epithelial CD3(+)IL-2+ and CD3(+)IFNgamma+, and epithelial CD3(+)IL-4+ cells were more numerous in ASD children than in noninflamed controls (p<0.04). In contrast, CD3(+)IL-10+ cells were fewer in ASD children than in noninflamed controls (p<0.05). In the colon, LP CD3(+)TNFalpha+ and CD3(+)IFNgamma+ were more frequent in ASD children than in noninflamed controls (p<0.01). In contrast with Crohn's disease and non-Crohn's colitis, LP and epithelial CD3(+)IL-10+ cells were fewer in ASD children than in nondisease controls (p<0.01). There was a significantly greater proportion of CD3(+)TNFalpha+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet (p<0.05). There is a consistent profile of CD3+ lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities. The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.
PMID: 15622451
17. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms
Ashwood P, Wakefield AJ.
J Neuroimmunol. 2006 Apr;173(1-2):126-34. Epub 2006 Feb 21.
Gastrointestinal pathology, characterized by lymphoid nodular hyperplasia and entero-colitis, has been demonstrated in a cohort of children with autistic spectrum disorder (ASD). Systemic and intestinal mucosal immune dysregulation was assessed in ASD children with gastrointestinal (GI) symptoms (n = 18), and typically developing controls (n = 27), including non-inflamed controls (NIC) and inflamed GI control children with Crohn's disease (CD), by analysis of intracellular cytokines in CD3+ lymphocytes. In both peripheral blood and mucosa, CD3+ TNFalpha+ and CD3+ IFNgamma+ were increased in ASD children compared with NIC (p < 0.004) and reached levels similar to CD. In contrast, peripheral and mucosal CD3+ IL-10+ were markedly lower in ASD children with GI symptoms compared with both NIC and CD controls (p < 0.02). In addition, mucosal CD3+ IL-4+ cells were increased (p < 0.007) in ASD compared with NIC. There is a unique pattern of peripheral blood and mucosal CD3+ lymphocytes intracellular cytokines, which is consistent with significant immune dysregulation, in this ASD cohort.
PMID: 16494951
18. Autism spectrum disorders: concurrent clinical disorders
Xue Ming , Brimacombe M, Chaaban J, Zimmerman-Bier B, Wagner GC.
J Child Neurol. 2008 Jan;23(1):6-13. Epub 2007 Dec 3
Individuals with autism spectrum disorder are heterogeneous in clinical presentation, concurrent disorders, and developmental outcomes. This study characterized the clinical co-occurrences and potential subgroups in 160 children with autism spectrum disorders who presented to The Autism Center between 1999 and 2003. Medical and psychiatric co-occurrences included sleep disorders, epilepsy, food intolerance, gastrointestinal dysfunction, mood disorder, and aggressive and self-injurious behaviors. Sleep disorders were associated with gastrointestinal dysfunction (P < .05) and mood disorders (P < .01). Food intolerance was associated with gastrointestinal dysfunction (P = .001). Subjects with mood disorder tended to develop aggressive or self-injurious behaviors (P < .05). Developmental regression was not associated with increased co-occurrence of medical or psychiatric disorders. Medical co-occurrence did not present as a risk factor for psychiatric co-occurrence, and vice versa. These results showed a high prevalence of multiple medical and psychiatric co-occurrences. There may be common pathophysiologic mechanisms resulting in clinical subgroups of autism spectrum disorders. Recognition of the co-occurrence of concurrent disorders may provide insight into the therapeutic strategy.
PMID: 18056691
19. Regression in autism: prevalence and associated factors in the CHARGE Study
Hansen RL et al.
Ambul Pediatr. 2008 Jan-Feb;8(1):25-31.
OBJECTIVE: The aim of this study was to examine the prevalence of regressive autism and associated demographic, medical, and developmental factors by using 2 different definitions of regression based on the Autism Diagnostic Interview, Revised. METHODS: Subjects were aged 2 to 5 years, with autism (AU) or autism spectrum disorder (ASD) confirmed by standardized measures. Children with regression, defined as a) loss of both language and social skills or b) loss of either language or social skills, were compared with each other and to children with AU or ASD with no reported loss of skills on developmental and adaptive functioning. Parents reported on seizure, gastrointestinal, and sleep concerns. RESULTS: Fifteen percent (50/333) of the combined AU-ASD group lost both language and social skills; 41% (138/333) lost either language or social skills. No differences were found between the 2 samples of children with regression. Few developmental, demographic, or medical differences were found between the combined regression group and children without loss of skills, in both the larger AU-ASD sample and the more homogeneous AU-only sample. Children with regression had significantly lower communication scores than children without regression. CONCLUSIONS: The prevalence of regression in a large sample of young children with AU and ASD varies depending on the definition used; requiring loss of language significantly underestimates the frequency of developmental regression. Children with regression performed significantly less well than those without regression on 2 measures of communication, but the clinical meaningfulness of these differences is uncertain because of the small effect sizes.
PMID: 18191778
20. Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease
Valicenti-McDermott M et al.
J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S128-36.
This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD.
PMID: 16685179
21. Early medical history of children with autism spectrum disorders
Niehus R, Lord C.
J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S120-7.
Previous studies have suggested that children with autism spectrum disorders (ASD) may have different medical histories than nonspectrum children in several areas: their reactions to vaccinations, number of ear infections, chronic gastrointestinal problems, and use of antibiotics. Furthermore, some studies have found associations between regressive autism and gastrointestinal (GI) symptoms. The present study analyzes the medical records from birth to the age of 2 years of 99 children (24 typically developing; 75 with ASD, of whom 29 had parent-reported regression). Data were coded in the following areas: frequency and purpose of pediatrician visits, frequency and type of illnesses and medications, type and chronicity of GI complaints, date of vaccinations, growth data, and whether the pediatrician noted behaviors indicative of an ASD before the age of 2 years. Children with ASD were found to have significantly more ear infections than the typically developing children as well as to use significantly more antibiotics. Typically developing children had significantly more illness-related fevers. There was a nonsignificant trend toward the ASD group having more chronic gastrointestinal problems. There were no significant differences between the groups for the age of vaccination or for number of pediatrician visits. Finally, pediatricians noted symptoms of onset of possible autism, including language delay, for 44 of the 75 children with ASD and 2 of the 24 typical children. Results are discussed in terms of needs for future research.
PMID: 16685178
22. Disruption of cerebral cortex MET signaling in autism spectrum disorder
Campbell DB et al.
Ann Neurol. 2007 Sep;62(3):243-50.
OBJECTIVE: Multiple genes contribute to autism spectrum disorder (ASD) susceptibility. One particularly promising candidate is the MET gene, which encodes a receptor tyrosine kinase that mediates hepatocyte growth factor (HGF) signaling in brain circuit formation, immune function, and gastrointestinal repair. The MET promoter variant rs1858830 allele "C" is strongly associated with ASD and results in reduced gene transcription. Here we examined expression levels of MET and members of the MET signaling pathway in postmortem cerebral cortex from ASD cases and healthy control subjects. METHODS: Protein, total RNA, and DNA were extracted from postmortem temporal cortex gray matter samples (BA 41/42, 52, or 22) belonging to eight pairs of ASD cases and matched control subjects. MET protein expression was determined by Western blotting; messenger RNA expression of MET and other related transcripts was assayed by microarray and quantitative reverse transcriptase polymerase chain reaction. RESULTS: MET protein levels were significantly decreased in ASD cases compared with control subjects. This was accompanied in ASD brains by increased messenger RNA expression for proteins involved in regulating MET signaling activity. Analyses of coexpression of MET and HGF demonstrated a positive correlation in control subjects that was disrupted in ASD cases. INTERPRETATION: Altered expression of MET and related molecules suggests dysregulation of signaling that may contribute to altered circuit formation and function in ASD. The complement of genes that encode proteins involved in MET activation appears to undergo long-term compensatory changes in expression that may be a hallmark contribution to the pathophysiology of ASD.
PMID: 17696172
23. A genetic variant that disrupts MET transcription is associated with autism
Campbell DB et al.
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16834-9. Epub 2006 Oct 19.
http://www.pnas.org/cgi/content/full/103/45/16834
There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P = 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P = 0.001) and in the combined sample (P = 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P = 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P = 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P = 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.
PMID: 17053076
24. Short report: Autistic gastrointestinal and eating symptoms treated with secretin: a subtype of autism
Pallanti S et al.
Clin Pract Epidemol Ment Health. 2005 Nov 15;1:24.
http://www.cpementalhealth.com/content/1/1/24
Pervasive Developmental Disorders (PDD) are chronic, lifelong disorders for which there is as yet no effective cure, and medical management remains a challenge for clinicians. The current report describes two patients affected by autistic disorder with associated gastrointestinal symptoms. They received multiple doses of intravenous secretin for a six-month period and were assessed with several specific outcome measures to evaluate drug effect. The administration of secretin led to some significant and lasting improvement in only one case. Gastroesophageal reflux may contribute to some of the behavioural problems and explain the effect of secretin since its suppressive effect on gastric secretion is well known. It is also true that autistic children with gastroesophageal reflux and a higher IQ could constitute a subtype which responds to secretin administration and that could be labelled as a "gastrointestinal subtype".
PMID: 16287506
25. Constipation with acquired megarectum in children with autism
Afzal N et al.
Pediatrics. 2003 Oct;112(4):939-42.
http://pediatrics.aappublications.org/cgi/content/full/112/4/939
OBJECTIVE: Recent evidence suggests that autistic children may have significant gastrointestinal symptoms. Although constipation occurs in 2% to 5% of healthy children, its clinical diagnosis is often difficult in children with behavioral disorders. We thus aimed to assess the prevalence of fecal loading in autistic children with gastrointestinal symptoms and to identify possible predictors of constipation. METHODS: We studied abdominal radiographs of 103 autistic children (87 boys) who were referred for gastroenterological assessment, in comparison with 29 control radiographs from children who were referred to the emergency department, most with abdominal pain. Radiographs were scored independently, in blinded manner, by 4 pediatric gastroenterologists and a radiologist. The severity of constipation was determined using a validated index. Details of stool habit, abdominal pain, dietary history, and laxative use were obtained from case notes. RESULTS: The incidence of constipation in the control subjects with abdominal pain was higher than reported for normal children. Despite this, moderate or severe constipation was more frequent in the autistic group than in the control subjects (36% vs 10%). Analysis of rectosigmoid loading showed more striking differences (54.4% of autistic children had moderate/severe loading or acquired megarectum compared with 24.1% of control subjects). Multivariate regression analysis showed consumption of milk to be the strongest predictor of constipation in the autistic group, whereas stool frequency, gluten consumption, soiling, and abdominal pain were not predictive of constipation. CONCLUSIONS: Constipation is a frequent finding in children with gastrointestinal symptoms and autism, particularly in the rectosigmoid colon, often with acquired megarectum. The absence of any correlation between the clinical history and the degree of fecal impaction in autistic children confirms the importance of an abdominal radiograph in the assessment of their degree of constipation.
PMID: 14523189
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