George J. Fuchs

Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report

Autism spectrum disorders (ASDs) are common and clinically heterogeneous neurodevelopmental disorders. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are incompletely understood. A central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASDs is the communication difficulties experienced by many affected individuals. A multidisciplinary panel reviewed the medical literature with the aim of generating evidence-based recommendations for diagnostic evaluation and management of gastrointestinal problems in this patient population. The panel concluded that evidence-based recommendations are not yet available. The consensus expert opinion of the panel was that individuals with ASDs deserve the same thoroughness and standard of care in the diagnostic workup and treatment of gastrointestinal concerns as should occur for patients without ASDs. Care providers should be aware that problem behavior in patients with ASDs may be the primary or sole symptom of the underlying medical condition, including some gastrointestinal disorders. For these patients, integration of behavioral and medical care may be most beneficial. Priorities for future research are identified to advance our understanding and management of gastrointestinal disorders in persons with ASDs.

Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism

BACKGROUND Metabolic abnormalities and targeted treatment trials have been reported for several neurobehavioral disorders but are relatively understudied in autism. OBJECTIVE The objective of this study was to determine whether or not treatment with the metabolic precursors, methylcobalamin and folinic acid, would improve plasma concentrations of transmethylation/transsulfuration metabolites and glutathione redox status in autistic children. DESIGN In an open-label trial, 40 autistic children were treated with 75 microg/kg methylcobalamin (2 times/wk) and 400 microg folinic acid (2 times/d) for 3 mo. Metabolites in the transmethylation/transsulfuration pathway were measured before and after treatment and compared with values measured in age-matched control children. RESULTS The results indicated that pretreatment metabolite concentrations in autistic children were significantly different from values in the control children. The 3-mo intervention resulted in significant increases in cysteine, cysteinylglycine, and glutathione concentrations (P < 0.001). The oxidized disulfide form of glutathione was decreased and the glutathione redox ratio increased after treatment (P < 0.008). Although mean metabolite concentrations were improved significantly after intervention, they remained below those in unaffected control children. CONCLUSION The significant improvements observed in transmethylation metabolites and glutathione redox status after treatment suggest that targeted nutritional intervention with methylcobalamin and folinic acid may be of clinical benefit in some children who have autism. This trial was registered at (clinicaltrials.gov) as NCT00692315.

Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism.

Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of autism. We investigated the dynamics of an integrated metabolic pathway essential for cellular antioxidant and methylation capacity in 68 children with autism, 54 age-matched control children and 40 unaffected siblings. The metabolic profile of unaffected siblings differed significantly from case siblings but not from controls. Oxidative protein/DNA damage and DNA hypomethylation (epigenetic alteration) were found in autistic children but not paired siblings or controls. These data indicate that the deficit in antioxidant and methylation capacity is specific for autism and may promote cellular damage and altered epigenetic gene expression. Further, these results suggest a plausible mechanism by which pro-oxidant environmental stressors may modulate genetic predisposition to autism.

Recommendations for Evaluation and Treatment of Common Gastrointestinal Problems in Children With ASDs

Children with autism spectrum disorders (ASDs) can benefit from adaptation of general pediatric guidelines for the diagnostic evaluation of abdominal pain, chronic constipation, and gastroesophageal reflux disease. These guidelines help health care providers determine when gastrointestinal symptoms are self-limited and when evaluation beyond a thorough medical history and physical examination should be considered. Children with ASDs who have gastrointestinal disorders may present with behavioral manifestations. Diagnostic and treatment recommendations for the general pediatric population are useful to consider until the development of evidence-based guidelines specifically for patients with ASDs. Pediatrics 2010;125:S19-S29

Gastrointestinal Conditions in Children With Autism Spectrum Disorder: Developing a Research Agenda

* Abbreviations: ASD — : autism spectrum disorder GI — : gastrointestinal 5-HT — : serotonin Autism spectrum disorders (ASDs) are a set of complex neurodevelopmental disorders defined behaviorally by impaired social interaction, delayed and disordered language, repetitive or stereotypic behavior, and a restricted range of interests. ASDs represent a significant public health issue with recent estimates indicating that as many as 1% of children in the United States are diagnosed with an ASD.1,2 Many individuals with ASDs have symptoms of associated medical conditions, including seizures, sleep problems, metabolic conditions, and gastrointestinal (GI) disorders, which have significant health, developmental, social, and educational impacts. Gastrointestinal complaints are a commonly reported concern for parents and may be related to problem behaviors and other medical issues such as dysregulated sleep (ATN Annual Registry Report, unpublished data, November 2009).3 Despite the magnitude of these issues, potential GI problems are not routinely considered in ASD evaluations. This likely reflects several factors, including variability in reported rates of GI disorders, controversies regarding the relationship between GI symptoms and the putative causes of autism, the limited verbal capacity of many ASD patients, and the lack of recognition by clinicians that certain behavioral manifestations in children with ASDs are indicators of GI problems (eg, pain, discomfort, or nausea).4–10 Whether GI issues in this population are directly related to the pathophysiology of autism, or are strictly a comorbid condition of ASD remains to be determined, but clinical practice and research to date indicate the important role of GI conditions in ASDs and their impact on children as well as their parents and clinicians.9 On November 15, 2009, a symposium addressing these issues was organized as an adjunct to the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. A … Address correspondence to Daniel L. Coury, MD, Professor of Pediatrics and Psychiatry, The Ohio State University, Chief, Developmental & Behavioral Pediatrics, Nationwide Childrens Hospital, 700 Childrens Dr, Timken G-350, Columbus OH 43205-2696

Obesity promotes 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in female zucker rats

IntroductionHigh body mass index has been associated with increased risk for various cancers, including breast cancer. Here we describe studies using 7,12-dimethylbenz(a)anthracene (DMBA) to investigate the role of obesity in DMBA-induced mammary tumor susceptibility in the female Zucker rat (fa/fa), which is the most widely used rat model of genetic obesity.MethodFifty-day-old female obese (n = 25) and lean (n = 28) Zucker rats were orally gavaged with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly for detection of mammary tumors. Rats were killed 139 days after DMBA treatment.ResultsThe first mammary tumor was detected in the obese group at 49 days after DMBA treatment, as compared with 86 days in the lean group (P < 0.001). The median tumor-free time was significantly lower in the obese group (P < 0.001). Using the days after DMBA treatment at which 25% of the rats had developed mammary tumors as the marker of tumor latency, the obese group had a significantly shorter latency period (66 days) than did the lean group (118 days). At the end of the study, obese rats had developed a significantly (P < 0.001) greater mammary tumor incidence (68% versus 32%) compared with the lean group. The tumor histology of the mammary tumors revealed that obesity was associated with a significant (P < 0.05) increase in the number of rats with at least one invasive ductal and lobular carcinoma compared with lean rats.ConclusionOur results indicate that obesity increases the susceptibility of female Zucker rats to DMBA-induced mammary tumors, further supporting the hypothesis that obesity and some of its mediators play a significant role in carcinogenesis.

Efficacy of zinc in young infants with acute watery diarrhea

BACKGROUND Recent studies reported that zinc significantly reduced the duration and volume of acute watery diarrhea in children aged > or = 4 mo, but there were no data specifically on infants aged < 6 mo. OBJECTIVE This study investigated the effect of zinc on the duration of illness and the stool quantity in acute watery diarrhea of infants aged 1-6 mo by comparing a 20 mg Zn/d dose with a 5 mg Zn/d dose. DESIGN Infants hospitalized with at least some dehydration (by World Health Organization classification) were enrolled in a double-blind, randomized, placebo-controlled trial. Infants were randomly assigned to receive 20 mg Zn (acetate)/d, 5 mg Zn/d, or placebo for the duration of illness. RESULTS Two hundred seventy-five infants were enrolled between 20 September 1998 and 18 December 2000. Neither diarrhea duration nor mean stool volume differed between groups. There were no significant differences in fluid intake, the need for unscheduled intravenous fluid, weight gain, or vomiting rates between the groups. CONCLUSIONS Zinc supplementation did not affect diarrhea duration or stool volume in young infants. Young infants tolerated both zinc doses. A beneficial effect on subsequent illness cannot be ruled out.

Causal Relationship of Helicobacter pylori With Iron-Deficiency Anemia or Failure of Iron Supplementation in Children

BACKGROUND & AIMS We investigated Helicobacter pylori (H pylori)-infection as a cause of iron deficiency (ID) and iron-deficiency anemia (IDA) or treatment failure of iron supplementation. METHODS We randomized 200 Hp-infected children (positive urea breath test) 2-5 years of age with IDA (hemoglobin level <110 g/L; serum ferritin level <12 microg/L; and soluble transferrin receptor >8.3 mg/L) or ID (serum ferritin level <12 microg/L or soluble transferrin receptor level >8.3 mg/L) to 1 of 4 regimens: 2-week anti-Hp therapy (amoxicillin, clarithromycin, and omeprazole) plus 90-day oral ferrous sulfate (anti-Hp plus iron), 2-week anti-Hp therapy alone, 90-day oral iron alone, or placebo. Sixty noninfected children with IDA received iron treatment as negative control. RESULTS Hp-infected children receiving iron had significantly less frequent treatment failure compared with those with no iron in correcting IDA (11% [95% confidence interval (CI), 2%-20%] for anti-Hp plus iron, 0% for iron alone vs 33% [95% CI, 26%-46%] for anti-Hp and 45% [95% CI, 31%-59%] for placebo; chi(2) = 127; P < .0001), ID (19% [95% CI, 8%-30%] for anti-Hp plus iron, 7% [95% CI, 0%-14%] for iron alone vs 65% [95% CI, 52%-78%] for anti-Hp alone, and 78% [95% CI, 66%-90%] for placebo; chi(2) = 124; P < .0001), or anemia (34% [95% CI, 20%-40%] for anti-Hp plus iron, 27% [95% CI, 14%-40%] for iron alone vs 65% [95% CI, 52%-78%] for anti-Hp alone and 78% [95% CI, 66%-90%] for placebo; chi(2) = 46; P < .0001). Cure rates of IDA, ID, or anemia with iron were comparable with that of the negative control group. Improvements in iron status also were significantly greater in groups with iron. CONCLUSIONS H pylori is neither a cause of IDA/ID nor a reason for treatment failure of iron supplementation in young Bangladeshi children.

Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status

Treatments targeting metabolic abnormalities in children with autism are limited. Previously we reported that a nutritional treatment significantly improved glutathione metabolism in children with autistic disorder. In this study we evaluated changes in adaptive behaviors in this cohort and determined whether such changes are related to changes in glutathione metabolism. Thirty-seven children diagnosed with autistic disorder and abnormal glutathione and methylation metabolism were treated with twice weekly 75 µg/Kg methylcobalamin and twice daily 400 µg folinic acid for 3 months in an open-label fashion. The Vineland Adaptive Behavior Scale (VABS) and glutathione redox metabolites were measured at baseline and at the end of the treatment period. Over the treatment period, all VABS subscales significantly improved with an average effect size of 0.59, and an average improvement in skills of 7.7 months. A greater improvement in glutathione redox status was associated with a greater improvement in expressive communication, personal and domestic daily living skills, and interpersonal, play-leisure, and coping social skills. Age, gender, and history of regression did not influence treatment response. The significant behavioral improvements observed and the relationship between these improvements to glutathione redox status suggest that nutritional interventions targeting redox metabolism may benefit some children with autism.

Compositional Requirements of Follow-Up Formula for Use in Infancy: Recommendations of an International Expert Group Coordinated by the Early Nutrition Academy

The follow-up formula (FUF) standard of Codex Alimentarius adopted in 1987 does not correspond to the recently updated Codex infant formula (IF) standard and current scientific knowledge. New Zealand proposed a revision of the FUF Codex standard and asked the non-profit Early Nutrition Academy, in collaboration with the Federation of International Societies for Paediatric Gastroenterology, Hepatology, and Nutrition (FISPGHAN), for a consultation with paediatric nutrition experts to provide scientific guidance. This global expert group strongly supports breastfeeding. FUF are considered dispensable because IF can substitute for breastfeeding throughout infancy, but FUF are widely used and thus the outdated current FUF standard should be revised. Like IF, FUF serve as breast milk substitutes; hence their marketing should respect appropriate standards. The compositional requirements for FUF for infants from 6 months onwards presented here were unanimously agreed upon. For some nutrients, the compositional requirements for FUF differ from those of IF due to differing needs with infant maturation as well as a rising contribution of an increasingly diversified diet with advancing age. FUF should be fed with adequate complementary feeding that is also appropriate for partially breastfed infants. FUF could be fed also after the age of 1 year without safety concerns, but different compositional requirements should be applied for optimal, age-adapted milk-based formulations for young children used only after the age of 1 year. This has not been considered as part of this review and should be the subject of further consideration.