There is increasing interest in the use of gluten- and casein-free diets for children with autism spectrum disorders (ASDs). We report results from a two-stage, 24-month, randomised, controlled trial incorporating an adaptive 'catch-up' design and interim analysis. Stage 1 of the trial saw 72 Danish children (aged 4 years to 10 years 11 months) assigned to diet (A) or non-diet (B) groups by stratified randomisation. Autism Diagnostic Observation Schedule (ADOS) and the Gilliam Autism Rating Scale (GARS) were used to assess core autism behaviours, Vineland Adaptive Behaviour Scales (VABS) to ascertain developmental level, and Attention-Deficit Hyperactivity Disorder - IV scale (ADHD-IV) to determine inattention and hyperactivity. Participants were tested at baseline, 8, and 12 months. Based on per protocol repeated measures analysis, data for 26 diet children and 29 controls were available at 12 months. At this point, there was a significant improvement to mean diet group scores (time*treatment interaction) on sub-domains of ADOS, GARS and ADHD-IV measures. Surpassing of predefined statistical thresholds as evidence of improvement in group A at 12 months sanctioned the re-assignment of group B participants to active dietary treatment. Stage 2 data for 18 group A and 17 group B participants were available at 24 months. Multiple scenario analysis based on inter- and intra-group comparisons showed some evidence of sustained clinical group improvements although possibly indicative of a plateau effect for intervention. Our results suggest that dietary intervention may positively affect developmental outcome for some children diagnosed with ASD. In the absence of a placebo condition to the current investigation, we are, however, unable to disqualify potential effects derived from intervention outside of dietary changes. Further studies are required to ascertain potential best- and non-responders to intervention. The study was registered with ClincialTrials.gov, number NCT00614198.

Dietary intervention as a tool for maintaining and improving physical health and wellbeing is a widely researched and discussed topic. Speculation that diet may similarly affect mental health and wellbeing particularly in cases of psychiatric and behavioural symptomatology opens up various avenues for potentially improving quality of life. We examine evidence suggestive that a gluten-free, casein-free or combined gluten- and casein-free diet can ameliorate core and peripheral symptoms and improve developmental outcome in some cases of autism spectrum conditions. Although not wholly affirmative, the majority of published studies indicate statistically significant positive changes to symptom presentation following dietary intervention. In particular, changes to areas of communication, attention and hyperactivity are detailed, despite the presence of various methodological shortcomings. Specific characteristics of best- and non-responders to intervention have not been fully elucidated; neither has the precise mode of action for any universal effect outside of known individual cases of food-related co-morbidity. With the publication of controlled medium- and long-term group studies of a gluten- and casein-free diet alongside more consolidated biological findings potentially linked to intervention, the appearance of a possible diet-related autism phenotype seems to be emerging supportive of a positive dietary effect in some cases. Further debate on whether such dietary intervention should form part of best practice guidelines for autism spectrum conditions and onward representative of an autism dietary-sensitive enteropathy is warranted.

Para-cresol (p-cresol), and its primary human metabolite p-cresol sulfate (pCS), are among the most studied gut-derived metabolites relevant to autism spectrum disorder (ASD). P-cresol is produced by bacterial modification of phenylalanine or tyrosine and is one of many potentially deleterious metabolites produced by the gut microbiota. Seventeen studies have observed p-cresol and/or p-cresol sulfate as being higher in the urine of children with autism spectrum disorder (ASD) vs. controls. P-cresol has harmful effects on the body, including within the gut, brain, kidneys, liver, immune system, and mitochondria. Some of these effects may contribute to autism and comorbid symptoms. In the gut, p-cresol acts as an antibiotic, altering the gut microbiome to favor the bacteria that produce it. In the mitochondria, p-cresol disrupts ATP production and increases oxidative stress, which is also common in autism. In the brain, p-cresol impairs neuronal development. P-cresol inactivates dopamine beta-hydroxylase, which converts dopamine to noradrenaline. P-cresol sulfate impairs kidney function and is linked to chronic kidney disease (CKD), which is more common in ASD adults. P-cresol also interferes with immune function. Three animal studies have demonstrated that p-cresol causes autism-related symptoms in mice, and that mice can be recovered by the administration of fecal microbiota transplant from healthy mice. Similarly, it was found that microbiota transplant therapy treatment in children with ASD significantly reduced p-cresol sulfate levels to normal and led to significant improvements in gastrointestinal (GI) and ASD symptoms. In summary, p-cresol and pCS likely contribute to ASD core symptoms in a substantial subset of children with ASD.

Autism or autism spectrum disorder (ASD) is described as a lifelong condition with core behavioural symptoms appearing during infancy or early childhood. Genetic and other effects occurring during the earliest times of life are thought to play a significant contributory role to the presentation of autism, denoting that autism is typically seen as an innate or inborn condition. Such descriptions have, and continue to, define autism research and clinical practice. Inspection of the existing research literature, however, suggests that within the vast heterogeneity of autism, not everyone experiences autism in such a prescribed way. Various reports have observed the presentation of “acquired autism” following a period of typical development. Other findings have documented an abatement of clinically relevant autistic features and related comorbid pathology for some. Such reports offer important insights into the heterogeneity and complexity of autism.

The concept of “acquired autism” refers to the hypothesis that amongst the massive heterogeneity that encompasses autism spectrum disorder (ASD) there may be several phenotypes that are neither syndromic nor innate. Strong and consistent evidence has linked exposure to various pharmacological and infective agents with an elevated risk of a diagnosis of ASD including maternal valproate use, rubella and herpes encephalitis. Autoimmune encephalitis (AE) describes a group of conditions characterised by the body's immune system mounting an attack on healthy brain cells causing brain inflammation. The resultant cognitive, psychiatric and neurological symptoms that follow AE have also included ASD or autism-like traits and states. We review the current literature on AE and ASD. Drawing also on associated literature on autoimmune psychosis (AP) and preliminary evidence of a psychosis-linked subtype of ASD, we conclude that AE may either act as a potentially causative agent for ASD, and/or produce symptoms that could easily be mistaken for or misdiagnosed as autism. Further studies are required to discern the connection between AE and autism. Where autism is accompanied by regression and atypical onset patterns, it may be prudent to investigate whether a differential diagnosis of AE would be more appropriate.

The concept of autism continues to evolve. Not only have the central diagnostic criteria that define autism evolved but understanding of the label and how autism is viewed in research, clinical and sociological terms has also changed. Several key issues have emerged in relation to research, clinical and sociological aspects of autism. Shifts in research focus to encompass the massive heterogeneity covered under the label and appreciation that autism rarely exists in a diagnostic vacuum have brought about new questions and challenges. Diagnostic changes, increasing moves towards early diagnosis and intervention, and a greater appreciation of autism in girls and women and into adulthood and old age have similarly impacted on autism in the clinic. Discussions about autism in socio-political terms have also increased, as exemplified by the rise of ideas such as neurodiversity and an increasingly vocal dialogue with those diagnosed on the autism spectrum. Such changes are to be welcomed, but at the same time bring with them new challenges. Those changes also offer an insight into what might be further to come for the label of autism.