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For the second installment this blog series, we’re excited to bring you an interview with Christie Buchovecky. Christie used her 2011 ASF grant to fund her study, Identifying Genetic Modifiers of Rett Syndrome in the MouseRead on to learn more about Christie, her passion for science, and where her work has led her.

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What originally inspired you to begin research in your field?

My cousin was diagnosed with autism when I was in high school. That was really the first time my family or I had heard of the disorder. Always a scientist at heart, I wanted to know more – I wanted to understand how his mind worked and what the future might look like for him and for our family. It didn’t take me long to realize that the Internet was full of misinformation about ASDs (and still is, though I applaud ASF for helping to combat that!). I knew pretty early on that I wanted to improve public understanding of ASDs and help understand what causes them.

In college at the University of Miami, a number of experiences shaped my current path and my outlook on autism and science in general. The single most influential person I met at UM was my first psychology professor, whose class should have been called “How to Think Critically”. One lesson I’d like to share with everyone: The correct answer is frequently “It depends”, meaning that we live in a world of complexity, gray areas, and incomplete and imperfect information – this is something every scientist should keep in mind. Also, for about a year in college, I spent my evenings and weekends working with a non-verbal boy with autism using ABA (applied behavioral analysis) techniques. It was some of the most rewarding and emotionally draining work I’ve ever done and gave me a great deal of respect for therapists and teachers. Lastly, I had many incredible biology professors and research mentors who inspired my love of genetics and encouraged me to pursue a Ph.D.

Baylor College of Medicine, where I am currently working toward my PhD in Molecular and Human Genetics, has a very large community of researchers working on Rett Syndrome, Autism, and other ASDs. Surprisingly, it turned out to be easy for me to decide on a project and mentor; when Dr. Monica Justice described her new research project to the incoming class, I was immediately intrigued.

Can you briefly describe the work that you did with the ASF grant?

The foundation of my work started before I ever joined the lab. That intriguing research project that Dr. Justice told us about in my first weeks of graduate school: She had received funding from the Rett Syndrome Research Trust to perform a mutagenesis screen in a mouse model of Rett Syndrome (Mecp2-null mice). The goal was to find out what biological pathways can be manipulated to improve Rett Syndrome symptoms. After creating random second-site mutations in Mecp2-null mice, she was able to identify mice in which Rett Syndrome symptoms were suppressed. Only then would we identify the mutations that caused symptom suppression and the biological pathways involved. Basically, she was throwing any expectations out the window and letting the health of the mice tell her what avenues to pursue.

All of this meant that I started my thesis project with a family of mice with greatly suppressed symptoms, but no idea what biological pathway I would end up working on. I’m extremely grateful to ASF for understanding the power of this technique and taking a leap of faith with us to identify the mutated gene and understand the involvement of the related pathway. With the help of our collaborators, we identified a mutation in the cholesterol biosynthesis pathway that improved longevity and motor symptoms. Since cholesterol metabolism had never before been implicated in Rett Syndrome, we then spent a lot of time examining that pathway in the Mecp2-null mice. Ultimately, we saw changes both in the brain and the rest of the body.

The nice thing about this finding is that we already have safe and effective ways to alter cholesterol metabolism. In the time since my ASF predoctoral fellowship, we’ve gone on to treat Mecp2-null mice with statins (FDA approved drugs like Lipitor that inhibit cholesterol synthesis), hoping to mimic the effect of our genetic mutation and improve symptoms. This turned out to work quite well and we recently published the whole story in Nature Genetics. There is still a lot to learn about cholesterol metabolism in Rett Syndrome patients. We hope our work will encourage more research into the topic and eventually lead to a treatment that will help improve quality of life for these patients and their families.

Can you describe what you’re doing now?

I’m starting to see the light at the end of the PhD tunnel, so I’m trying to tie things up and begin writing my thesis. I’ve started looking at how altering cholesterol metabolism affects Rett Syndrome symptoms at a neuronal level; this is a logical progression for the project and I’ve always been intrigued by neuroscience. We’re also pursing treatment with additional compounds that alter metabolism in the Mecp2-null mice and are trying to learn more about lipid and glucose metabolism, pathways which are closely related to cholesterol.

What would you like to see studied more in the field of autism research? Do you think there are any areas that are going to be the key to answers in the field for the future?

My graduate experience has instilled in me a sharp awareness that the brain does not exist as a separate entity from the rest of the body. Therefore, I’d like to see more good science being done looking into possible systemic changes observed in ASDs. These could turn out to be metabolic differences, immune system abnormalities, GI symptoms, or something else entirely. To make matters more complicated, it will probably be different in different people – there’s a reason we talk about “autisms”, after all. For example, we know that altered cholesterol biosynthesis plays a huge role in Smith-Lemli-Optiz Syndrome, and that Prader-Willi Syndrome has an endocrine component. Furthermore, we know that treating these aspects of the disease in affected individuals can improve behavior, and it certainly improves quality of life. I anticipate there will be similar (if less pronounced) findings in what we consider non-syndromic autisms.

Part of what makes the autism research community so powerful is the diverse background of the researchers in it and the collaborative efforts they undertake. By and large, however, we are heavy on psychologists, neuroscientists and geneticists and light on physiologists and biochemists. We need to bring more of these people into the field; when we notice a trend in the data and make some incidental finding far afield of our own expertise (because we all have those pages in lab notebooks of interesting things we didn’t have the knowledge base to follow up on), we need to reach out to our colleagues in other disciplines and get them excited about autism research.

Of our 2013 grantees, is there a study that you are most excited about?

Do I have to pick just one?

The work by Dr. Aimee Badeaux and Dr. Yang Shi at Boston Children’s Hospital on the autism brain epigenome is really interesting. I can’t wait to learn more about what they’re planning and what they find out about epigenetic changes in the autistic brain. Epigenetics is a relatively new field and techniques for studying it are constantly evolving. I think this study and others like it will create one of those situations where the more you know, the more there is to learn. As a scientist, I love it when that happens – it’s like finding a whole new set of puzzles to solve!

I’m also really looking forward to seeing how the IGF-1 trial in patients with Phelan McDermid Syndrome (lead by Dr. Alexander Kolevzon at Mount Sinai) turns out. There is a parallel IGF-1 story going on in the Rett Syndrome field that I’ve been following for a while, especially given the role of insulin in metabolism (IGF-1 stands for insulin-like growth factor 1) and its relationship to our research. It’s an interesting and complicated story. Obviously, my fingers are crossed for its safety efficacy, but no matter the outcome, this study has the potential to teach us more about Phelan McDermid Syndrome in the process.

Lastly, is there anything you’d like to share about yourself that our readers may not know or expect?

I love to cook, but am completely incapable of making just a simple meal. Instead, everything is complicated traditional recipes – mostly Italian, as an homage to my heritage, but I also picked up a love of Cuban and Cajun foods in college. On Saturdays I like to hit the farmer’s market, then come home and cook for hours – usually dirtying every pot and pan in my kitchen in the process. Since I also tend to cook for an army, even though it’s just my fiancée and I, I’ve been known to bring containers full of jambalaya, minestrone, or bolognese to my other grad student friends on a whim… Of course we all know a graduate student never says no to free food. I’ve been incredibly lucky in my time here – both to have developed such wonderful friendships and to have had the opportunity to work on such a fascinating project.

Links to Christie Buchovecky’s work can be found below:

A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome

View an interview with Buchovecky on the ASF YouTube channel here

In order for great science to be done, there need to be great scientists. Dr. Matthew Maenner is one of those scientists and a former ASF grantee, as well as the first spotlight in our new series Getting to Know ASF Grantees. In 2010, ASF funded his study, Phenotypic Heterogeneity and Early Identification of ASD in the United States. More information about that study can be found here. Read on to see our Q&A with Dr. Maenner and the work he does in the autism science field.

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What originally inspired you to begin research in your field?

I first learned about autism when I was an undergraduate in college; I worked with children with ASD that had very challenging behaviors.  I really enjoyed spending time with the kids, but I also realized that parents frequently had to make difficult decisions regarding treatments or interventions and they usually had very little information to guide their decisions.  And I remember feeling frustrated when a family would be talked into buying into an unproven—but very expensive—therapy or treatment.  At the time, I didn’t know what epidemiology was, but I thought we should be studying large groups of people to know whether something was effective or not.

Can you describe the work that you did in 2010 with the ASF grant?

Clinical studies have shown certain behavioral “warning signs” to be useful for early ASD diagnosis, and public health campaigns focus on these behaviors to promote earlier ASD identification.  However, there was very little evidence whether these behaviors actually lead to earlier diagnosis in everyday clinical practice. Our study examined whether the behavioral symptoms indicated by research studies were associated with earlier ASD identification in community settings.

We found that children tended to be identified earlier if they were observed to have repetitive motor behaviors, inflexibility in routines, or impairments in nonverbal communication.  In contrast, children that were observed to have problems getting along with peers, holding a conversation, or had idiosyncratic speech were more likely to be identified later, compared to children without these symptoms.   The results also suggest that increasing the intensity of ASD screening practices will likely lead to increased ASD identification at both earlier and later ages if some symptoms are difficult to detect before a child reaches a certain developmental level.

Some scientists focus on clinical studies, while you are an epidemiologist. In what ways are both types of studies important?

Epidemiological studies and clinical studies can offer complementary insights into a particular question. An epidemiological study may observe an association between an exposure and ASD in the population; then, a focused clinical study could examine the hypothesized mechanism in much greater detail. The exchange of ideas can also go in the other direction—epidemiological studies can examine whether a finding from a clinical study “holds up” outside of a laboratory setting. Epidemiological studies can estimate what proportion of all ASD may be attributable to a mechanism identified in a clinical study, or it may indicate that a biological pathway is more complex than initially recognized. Evidence from both clinical and epidemiological studies help us better understand potential ASD causes and treatments, and both kinds of studies can help inform public health policy decisions.

Can you describe what you’re doing now at the CDC?

This summer, I became an Epidemic Intelligence Service (EIS) Officer, so I will be at the CDC for at least the next two years.  It’s an incredible opportunity to learn about how the broader public health system works, how decisions are made, and how to better communicate scientific or public health messages to the public.

What would you like to see studied more in the field of autism research?

I would love to see the development of more high-quality and freely-available screening/diagnostic tools for ASD.  One of the barriers to research and early ASD diagnoses—especially in low-resource settings—is the availability of free instruments and screening tools. This year I created www.disabilitymeasures.org, which we hope becomes a collaborative platform for disseminating diagnostic, screening, and research tools. Based on the reactions we’ve heard from others (like this recent article: http://www.scientificamerican.com/article.cfm?id=a-call-for-open-access-to-autism-diagnostic-tools), we think researchers want their work to be more accessible, and we want to make it easier to accomplish this.

Of our 2013 grantees, is there a study that you are most excited about?

All of the funded studies have the potential to make important contributions.  If I had to choose, I would say I am especially interested in Russell Port’s project with Dr. Roberts. When I was a postdoc at the Waisman Center last year, Dr. Roberts gave a compelling talk on electrophysiological signatures of language impairment in ASD, and I am eager to see where this work leads them.

Lastly, what do you like to do when you’re not working?

As a scientist in the early stages of my career, the line between my hobbies and professional work is quite blurred.  However, my wife grows orchids and I’ve learned a lot from helping her grow and breed them over the past few years.  The amount of diversity is incredible—it is easy to see why Charles Darwin was so interested in them!

Links to Dr. Maenner’s work can be found below:

Phenotypic Heterogeneity of ASD and Its Association with Early Identification

Dr. Maenner Speaking about “Phenotypic Heterogeneity of ASD and Its Association with Early Identification”

Association Between Behavioral Features and Gastrointestinal Problems Among Children with Autism Spectrum Disorder

Potential Effect of DSM-5 Diagnostic Criteria on ASD Prevalence Estimates

By Alison Singer
President, Autism Science Foundation

 

This morning Stuart Spielman of Autism Speaks and I met with key leaders at the American Academy of Pediatrics and representatives from over 20 children’s health advocacy groups to talk about strategies for preventing wandering. A study sponsored by the Autism Science Foundation and a consortium of autism advocacy groups, and published in the journal Pediatrics, showed that 49% of children with autism attempted to wander at least once after age 4, which is four times the rate of unaffected siblings. 53 percent of those who eloped were missing long enough to cause concern. From age 8-11, 27 percent of children with ASD wandered, compared to only 1 percent of unaffected siblings.

In 2012, 25 children with autism died as a result of wandering. By way of comparison, 35 children in the U.S. died of flu and 19 died of whooping cough in 2012.  The AAP supports massive campaigns to prevent those deadly diseases, as it should. Our goal today was to encourage the AAP to increase the resources devoted to implementing and supporting wandering prevention measures as well.

Our efforts around wandering involve both prevention and recovery. Of course we want to prevent as many wandering incidents as possible from happening, so today we talked with AAP members about including information about wandering in what the AAP calls “anticipatory guidance,” which refers to the conversations doctors routinely have with parents at well-child visits to let them know what’s ahead for their children. Only 14 percent of parents of children with autism reported that they were warned about the potential for wandering by their pediatrician (Pediatrics).  We have to do better.  Parents who are aware of the potential for wandering can take precautions to ensure the environment is as safe as possible.  We also talked about providing more training and awareness materials to pediatricians so that they can share the information with their families.

On the recovery side, the group talked about working together to develop a “wandering alert” mechanism,  similar to an AMBER alert, for children with developmental disabilities, addressing the unique needs of this population, including the propensity to head toward water and the fact that our kids might not respond when called by  first responders or other searchers.  When children with autism wander, families can’t access the AMBER alert system because technically the children are not abducted.

Wandering is an issue of life and death. The data, and the newspapers, show that children with autism continue to die from wandering related incidents.  We are committed to doing all we can to reduce wandering and to protect as many children with ASD from wandering-related tragedies as possible.

 

Source:
Occurrence and Family Impact of Elopement in Children With Autism Spectrum Disorder
Connie Anderson,  J. Kiely Law, Amy Daniels, Catherine Rice, David S. Mandell, Louis Hagopian, and Paul A. Law
Pediatrics peds.2012-0762; published ahead of print October 8, 2012,doi:10.1542/peds.2012-0762

By Marcela De Vivo, mother of a child with a severe disability and freelance writer who works with Oltarsh law firms.  She writes on immigration law, health and special education law and inclusion. 

Individuals of all ages and all abilities can benefit from music therapy. Previously, music therapy has been used to support emotional, cognitive and social development in many populations. Music therapy may help to promote wellness by managing stress, enhancing memory, and improving communication.

A 2004 study from the Journal of Music Therapy found that music in interventions used with children and teens with ASD can improve social behaviors, increase focus and attention, increase communication attempts (vocalizations, verbalizations, gestures, and vocabulary), reduce anxiety, and improve body awareness and coordination.

Many additional studies have found that children and adults with autism spectrum disorders (ASD) respond well to music. Often, individuals with autism respond positively to music when little else is able to get their attention, which makes music a potential therapeutic tool.

Music encourages social interactions.

A 2009 study by Kim, Wigram, & Gold found that children with autism showed more emotional expression and social engagement during music therapy sessions than in play sessions without music. These children also responded to the therapist’s requests more frequently during music therapy than in play sessions without music.

Additionally, a skilled therapist can use music with children to increase their social interaction and improve social skills. Passing and sharing instruments, music and movement games, gathering around a central instrument, learning to listen and singing of greetings are just a few of the ways music therapy sessions can increase interaction.

kids music

Music can improve behavior.

In a 2012 study of 41 children with autism over a ten-month period, See found that weekly music therapy sessions seemed to improve overall behavior, with the most improvement seen in inattentive behaviors. Children in this study experienced hour-long sessions of music therapy once a week, and their conduct was monitored against a checklist of target behavior like restlessness, aggression and noisiness. More than half the group improved by one or two points on the scale after the music therapy sessions.

Music can improve communication.

Up to thirty-percent of children with autism are nonverbal, and many low-functioning children have difficulty following verbal commands, and have difficult time with social awareness like understanding body language.

Wan et. al. (2004) found music to improve the mapping of sounds to actions, by connecting the auditory and motor sections of the brain, which may help improve understanding of verbal commands. By pairing music with actions, and with repetitive training, the brain pathways needed to speak can be reinforced and improved.

Music can reduce anxiety.

Children with autism are more sensitive to anxiety than the average child, as they are unable to filter out provoking stimuli. A small four-week study, conducted at the University of Wisconsin La Crosse in 2006, found preliminary success in reducing anxiety in patients with autism through music therapy. After 16 short, 20-minute sessions, during which the treatment patients listened to rhythmic music, the participants who received the therapy appeared to have decreased anxiety-related behaviors.  

Classical music or music with a steady rhythm is thought to be the best for alleviating anxiety in children with autism due to the predictability of the beat.

  

Music is fun.

Perhaps most importantly of all, music therapy is engaging and enjoyable for children with autism. Music therapy is able to bring about changes in social behavior and cognitive ability only through repeated and prolonged sessions—and the best way to keep children working at something is to ensure that they enjoy it. Almost like another form of play, music therapy is something ASD children can engage in without having it feel like work.

Music is an effective way to communicate with and reach children with autism. Music therapy seems to be able to improve social skills, behavior, anxiety and more—and might be the one thing that can reach a child with autism when nothing else will.  

Marcela De Vivo is a writer, music enthusiast and mother of son with special needs. Through music therapy her son, who has severe cerebral palsy, is able to have fun and communicate more effectively with his family. Follow his journey by visiting www.PrayForNathan.org.

 

References:

Kim, J., Wigram, T., & Gold, C. (2009). Emotional, motivational and interpersonal responsiveness of children with autism in improvisational music therapy. Autism, 13(4), 389-409. PMID: 19535468

See, C. M. (2012) The Use of Music and Movement Therapy to Modify Behaviour of Children with Autism. Pertanika J. Soc. Sci. & Hum., 20 ( 4): 1103 – 1116

Wan CY, Bazen L, Baars R, Libenson A, Zipse L, et al. (2011) Auditory-Motor Mapping Training as an Intervention to Facilitate Speech Output in Non-Verbal Children with Autism: A Proof of Concept Study. PLoS ONE 6(9): e25505. doi:10.1371/journal.pone.0025505

Whipple J. (2004). Music in intervention for children and adolescents with autism: a meta-analysis. Journal of Music Therapy. 41(2):90-106. PubMed PMID: 15307805.

Jennifer H. Elder, PhD, RN, FAAN

Professor and Associate Dean of Research

University of Florida

 

Parents of children with autism spectrum disorder (ASD) are faced with difficult treatment decisions that are complicated by the vast information on the web. One of the most popular interventions continues to be the gluten-free, casein-free (GFCF) diet despite the fact that limited scientific evidence supports its use. This article will apprise  families about current research regarding the GFCF diet, and help them determine whether it is best suited to their child and family lifestyle.

The Gluten-Free, Casein-Free (GFCF) Diet

 The most popular rationale for this diet is the “opioid-excess theory”, which states that excess opioid-peptides, caused by the incomplete breakdown of foods with gluten and casein, trigger autistic symptoms (Panksepp, 1979; Reichelt, Ekrem, & Scott, 1990; Shattock, Kennedy, Rowell, & Berney, 1980). Another popular theory is that children with autism have “leaky gut syndrome”, which involves opioid-peptides crossing the intestinal and blood-brain barriers, and ultimately affecting the endogenous opiate and central nervous systems. Some assert this “leaky gut” may help explain why many children with ASD have gastrointestinal (GI) symptoms such as diarrhea and constipation in addition to social and communication deficits (Horvath & Perman, 2002a).

While these theories are interesting, they have not been well-studied.  The largest trial was conducted by Whiteley et al. (2010) with 72 subjects, and results were positive; indeed, children demonstrated improvements in the following: language, attention, concentration, interaction, communication, hyperactivity, motor coordination, repetitive behavior patterns, social integration, and self-injurious behavior/altered pain perception. There have been four other published randomized, controlled clinical trials of the GFCF diet, but they have been limited by small sample sizes, high dropout rates, and diet noncompliance (Elder et al., 2006; Hyman et al., 2010; Johnson, Handen, Zimmer, Sacco, & Turner, 2011; Knivsberg, Reichelt, Hoien, & Nodland, 2002). In addition, studies may be affected by the parent placebo effect, which occurs when parents are aware that their child is on the diet and report positive results that may not actually exist (Elder et al., 2006; Knivsberg et al., 2002). Finally, because ASD affects children differently, it is difficult to determine which children are likely to respond to the GFCF diet as well as its effects on symptoms.

Pros and Cons of the GFCF Diet

In evaluating treatment options, families should avoid hasty decisions that may result in falling prey to unsubstantiated or even bogus claims. Until the GFCF diet is further researched, parents should consider the following before implementation:

  1. While GFCF foods are more readily available, the diet can be costly, time-consuming, and more difficult in geographic areas that lack the appropriate ingredients.
  2. At least one family member should accurately record food intake and review the effects of the GFCF diet on symptoms regularly with health care providers.
  3. Families need plans about how to ensure dietary compliance at home and in different settings (i.e. school, home of friends or family). It is often helpful to identify another parent or professional who has implemented the diet and can offer practical advice for food preparation and compliance.
  4. The child’s health should be evaluated by a professional prior to diet implementation.  If the child is eligible, then health and weight should be monitored to avoid compromising nutritional status.

References

Elder, J., Shankar, M., Shuster, J., Theriaque, D., Burns, S., & Sherrill, L. (2006). The Gluten-Free, Casein-Free Diet In Autism: Results of A Preliminary Double Blind Clinical Trial. J. Autism Dev. Disord., 36(3), 413-420. doi: 10.1007/s10803-006-0079-0

Horvath, K., & Perman, J. A. (2002a). Autism and gastrointestinal symptoms. Current Gastroenterology Reports, 4(3), 251-258.

Hyman, S., Stewart, P., Smith, T., Foley, J., Cain, U., & Peck, R. (2010). The gluten free and casein free (GFCF) diet: A double blind, placebo controlled challenge study. Paper presented at the International Meeting for Autism Research, Philadelphia, PA.

Johnson, C., Handen, B., Zimmer, M., Sacco, K., & Turner, K. (2011). Effects of Gluten Free / Casein Free Diet in Young Children with Autism: A Pilot Study. Journal of Developmental and Physical Disabilities, 23(3), 213-225. doi: 10.1007/s10882-010-9217-x

Knivsberg, A. M., Reichelt, K. L., Hoien, T., & Nodland, M. (2002). A randomized, controlled study of dietary intervention in autistic syndromes. Nutritional Neuroscience, 5, 251-261.

Panksepp, J. (1979). A neurochemical theory of autism. Trends Neurosci., 2, 174-177.

Reichelt, K. L., Ekrem, J., & Scott, H. (1990). Gluten milk proteins and autism: Dietary intervention effect on behavior and peptide secretion. J. Appl. Nutr., 42, 1-11.

Shattock, P., Kennedy, A., Rowell, F., & Berney, T. (1980). Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunction, 3, 315-327.

Whiteley, P., Haracopos, D., Knivsberg, A.-M., Reichelt, K. L., Parlar, S., Jacobsen, J., . . . Shattock, P. (2010). The ScanBrit randomised, controlled, single-blind study of a gluten-and casein-free dietary intervention for children with autism spectrum disorders. Nutritional neuroscience, 13(2), 87-100.

Susan L. Hyman, M.D.

Professor - Department of Pediatrics, Neurodevelopmental & Behavioral Pediatrics

University of Rochester Medical Center, School of Medicine and Dentistry

Some families come into my office and tell me that they observe that their child with an Autism Spectrum Disorder (ASD) experiences behavioral change with constipation.**  Many families report selective eating and express concern how a limited variety of foods their child is willing to eat might affect their health. Other families don’t associate variability in their child’s behavior with gastrointestinal (GI) symptoms until asked about other signs of discomfort. In this blog I will discuss some of the commonly asked questions I hear from families about these and other potential associations between GI symptoms and ASD.

How often do children with ASD have constipation or other gastrointestinal (GI) symptoms?

The rate of GI symptoms reported by families for their children with ASD is 20-70% depending on the definitions used and the groups studied (Mazurek et al., 2013; Mourisden et al 2013; Wang et al, 2011; Buie et al, 2010; Ibrahim et al. 2009).  The two GI problems that research data consistently report occurring with greater frequency among children and youth with autism are constipation and feeding problems. Medical chart review of children and teens with ASD compared to controls in Olmstead County Minnesota identified that constipation (34% vs 18%) and food refusal (25% vs 16%) were the only two GI problems reported more commonly in the group with ASD (Ibrahim et al., 2009).  Families participating in the Autism Treatment Network registry reported GI symptoms in 24% of the children; with the most common symptoms being constipation in 12% and abdominal discomfort in 11.7% (Mazurek et al., 2013). No difference in stool patterns or consistency was reported for children less than 42 months of age later diagnosed with ASD compared to controls (Sandhu et al., 2012). In this same large prospective study in the UK, children later diagnosed with ASD were reported to be more selective in their eating patterns by 15 months of age, however (Emond et al., 2012).  Even less is known about the GI symptoms of adults with ASD. A longitudinal study of a registry of people with ASD in Denmark found no increase in hospital care for GI disorders compared to the general population, except for disorders of the oral cavity (including dental disease).  While not statistically significant, there was the observation that GI problems may be more common among people with  lower IQ (Mouridsen et al, 2013; Mouridsen et al 2010).

Why is constipation more commonly reported?

The studies of GI symptoms in children with ASD use different definitions so it is difficult to compare them. Some do not define what they consider as constipation. Some report on lifetime prevalence to date of a reported symptom, some report on symptoms within a shorter time frame, some ask about chronic symptoms. Constipation is typically defined as less than 3 stools per week and/or stools that are difficult or painful  to pass. Constipation might be increased in people with ASD because of behavioral stool withholding due to stress or discomfort around having a bowel movement, decreased fluid intake, decreased consumption of fiber, decreased activity, medications used for other purposes that affect intestinal motility, or perhaps primary intestinal problems. To date the research literature has not confirmed that people with autism have abnormal motility or movement of their intestines to cause constipation (Buie et al, 2010). One study did not find an association of constipation with diet or with medication use (Gorrindo et al, 2012).  The typical interventions used for constipation in children can be effective for children with ASD, (Buie 2010) so children with infrequent and difficult to pass stools should  be seen by their health care provider for evaluation and management. Toolkits for families and clinicians regarding constipation management have been developed by both the American Academy of Pediatrics (published in the AAP Autism Toolkit) and  the Autism Treatment Network (online publication).

Why might children with ASD have feeding problems?  

Food selectivity might be related to perseveration or repetitive behaviors, discomfort related to food allergies/intolerances, discomfort related to gastrointestinal reflux, sensory differences, or other behavioral influences. Future postings will discuss feeding behaviors further including behavioral and nutritional suggestions.  While there is not documentation that children with ASD have an increased rate of gastrointestinal reflux, this is a common medical problem and needs to be considered if a child has food refusal, vomiting after meals, belching after meals or signs of chest or abdomen discomfort.

Does the food itself cause GI symptoms?   

Specific foods can cause GI symptoms based on allergy, food intolerance, or medical conditions that are not specific to ASD. An example is the excess consumption of juice that results in “toddlers diarrhea” in children with and without autism.  Other common medical problems like lactose intolerance, the inability to digest milk sugars, might result in abdominal pain or diarrhea with exposure to milk products. Lactose intolerance runs in families.  It can occur temporarily after a viral diarrheal illness or antibiotic use. If a family or patient identifies discomfort or GI symptoms related to a specific food, further evaluation by an allergist or gastroenterologist may be necessary. If a food group like dairy products are eliminated on a trial basis, other products need to be substituted that can provide the nutrients that would otherwise be found in that food.

What about gluten? 

GI disorders that occur in other people also occur in people with ASD. We do not have evidence at this time that celiac disease is more common among children with ASD then among other children. Although some immune response to gluten that is different from that seen in celiac disease might be found more frequently in children with ASD (Lau et al, 2013). Celiac disease is an immunologic intolerance to the peptide gluten found in food products containing barley, rye and wheat.  The population prevalence of celiac disease is about  1:100, which is fairly common, so celiac disease should be considered in the work up of GI symptoms or poor growth in children with and without ASD.  There is now a blood test that serves as first level test for celiac disease. Many families elect a trial of removal of gluten and/or casein from their child’s diet. The reason they do this is not because of food allergy or celiac disease and is based on individual observations relating diet and behavior. Diet and ASD will also be discussed in future blogs in this series.

Can GI discomfort lead to behavioral symptoms?

Since many individuals with ASD do not report pain in a typical fashion or do not have the language to report discomfort, a change in behavior may be the only clue the family or clinician has that a painful condition is present. GI problems like gastrointestinal reflux or constipation benefit from conventional medical treatment. The family and clinician must be alert for symptoms like belching after meals and air swallowing in addition to the more classic symptoms of gastrointestinal reflux of vomiting after meals or report of heartburn.  Painful conditions in general may lead to behavioral change in people with ASD, so dental pain, headaches, minor injuries, and other general medical conditions need to be considered with an acute change in behavior. GI symptoms have been associated with challenging behaviors like opposition, sleep problems, and  food selectivity (Maennur et al, 2012 ).

Isn’t anxiety associated with GI symptoms?   

Anxiety is associated with abdominal pain in children and youth with and without ASD.  An association between GI symptoms, anxiety and reported sensory symptoms was identified in children participating in the Autism Treatment Network (Mazurek et al, 2013). Anxiety may be more common among people with ASD for biological reasons, because of problems with state dysregulation, or perhaps because they cannot predict what will happen in the environment.  Research needs to be done to determine if treatment of the anxiety improves GI symptoms or if treatment of the GI symptoms improves anxiety.

Are the bacteria and other microbes in the intestines associated with GI symptoms?

There is a lot of interest in the role of the bacteria and yeasts that live in the intestine that aide in both absorption of nutrients and in normal GI functioning.  Current research studies are investigating if there are differences in the patterns of intestinal bacteria in children with ASD (Gondalia et al., 2012; Williams et al, 2011).  Whether probiotic supplements provide benefit to people taking a balanced diet requires further research. They are typically without side effects.

Has research demonstrated other differences in the GI tract in people with ASD?

There are several hypotheses about GI function in people with ASD that have conflicting evidence. Some studies are not of the quality to allow scientific conclusions to be drawn. Theories that are as yet unproven include the hypothesis that people with autism have an alteration in the production of digestive enzymes (Williams et al, 2011, Munasingh et al, 2010), the hypothesis that there is altered microscopic appearance to the intestinal lining (Chen et al, 2011; McDonald, 2007) and the hypothesis that there is a “leaky gut” that allows abnormal absorption of nutrients that produce behavioral change in people with ASD (Buie, 2010). Because the development of intestine and brain are both directed by genes early in fetal life, it is plausible that future research might find genetic or environmental influences that impact the development of both brain and gut.

In summary, when people with ASD have GI symptoms they need to be evaluated for the common –and if indicated, uncommon – conditions that produce GI symptoms in other people including anxiety.  With acute behavioral change, all sources of potential discomfort need to be considered.  Children with ASD have increased rates of constipation and feeding problems compared to other children.  Clinical and basic research is required to answer the many questions related to the specific causes and treatments for the GI symptoms of individuals with ASD.

References:

Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, Vandewater J, Whitaker AH, Atkins D, Bauman ML, Beaudet AL, Carr EG, Gershon MD, Hyman SL, Jirapinyo P, Jyonouchi H, Kooros K, Kushak R, Levitt P, Levy SE, Lewis JD, Murray KF, Natowicz MR, Sabra A, Wershil BK, Weston SC, Zeltzer L, Winter H. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010 Jan;125 Suppl 1:S1-18. doi: 10.1542/peds.2009-1878C

Buie T, Fuchs GJ 3rd, Furuta GT, Kooros K, Levy J, Lewis JD, Wershil BK, Winter H. Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs. Pediatrics. 2010 Jan;125 Suppl 1:S19-29.

Chen B, Girgis S, Elmasry M, El-Matary W Abnormal Gastrointestinal Histopathology in Children With Autism Spectrum Disorders.J Pediatr Gastroenterol Nutr. 2011 Feb 2.

Emond A, Emmett P, Steer C, Golding J. Feeding symptoms, dietary patterns, and growth in young children with autism spectrum disorders. Pediatrics. 2010 Aug;126(2):e337-42.

Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D, Austin DW. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res. 2012 Dec;5(6):419-27

Gorrindo P, Williams KC, Lee EB, Walker LS, McGrew SG, Levitt P. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

Ibrahim SH, Voigt RG, Katusic SK, Weaver AL, Barbaresi WJ. Incidence of gastrointestinal symptoms in children with autism: a population-based study. Pediatrics. 2009 Aug;124(2):680-6

Lau NM, Green PH, Taylor AK, Hellberg D, Ajamian M, Tan CZ, Kosofsky BE, Higgins JJ, Rajadhyaksha AM, Alaedini A.Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS One. 2013 Jun 18;8(6):e66155

Macdonald TT, Domizio P.Autistic enterocolitis: is it a histopathological entity?Histopathology. 2007 Feb;50(3):371-9; discussion 380-4.

Maenner MJ, Arneson CL, Levy SE, Kirby RS, Nicholas JS, Durkin MS. Brief report: Association between behavioral features and gastrointestinal problems among children with autism spectrum disorder. J Autism Dev Disord. 2012 Jul;42(7):

Mazurek MO, Vasa RA, Kalb LG, Kanne SM, Rosenberg D, Keefer A, Murray DS, Freedman B, Lowery LA. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. 2013 Jan;41(1):165-76

Mouridsen SE, Isager T, Rich B. Diseases of the gastrointestinal tract in individuals diagnosed as children with atypical autism: a Danish register study based on hospital diagnoses. Autism. 2013 Jan;17(1):55-63.

Mouridsen SE, Rich B, Isager T. A longitudinal study of gastrointestinal diseases in individuals diagnosed with infantile autism as children. Child Care Health Dev. 2010 May;36(3):437-43.

Munasinghe SA, Oliff C, Finn J, Wray JA Digestive enzyme supplementation for autism spectrum disorders: a double-blind randomized controlled trial. J Autism Dev Disord. 2010 Sep;40(9):1131-8

Sandhu B, Steer C, Golding J, Emond A. The early stool patterns of young children with autistic spectrum disorder.Arch Dis Child. 2009 Jul;94(7):497-500.

Wang LW, Tancredi DJ, Thomas DW. The prevalence of gastrointestinal problems in children across the United States with autism spectrum disorders from families with multiple affected members. J Dev Behav Pediatr. 2011 Jun;32(5):351-60.

Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, Wick I, Bennett A, Jabado O, Hirschberg DL, Lipkin WI. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One. 2011;6(9):e24585

Barbara McElhanon, MD (1) & William G. Sharp, PhD (1, 2)

1 Department of Pediatrics, Emory University School of Medicine (Atlanta, GA), 2Marcus Autism Center (Atlanta, GA)

Background 

Gastrointestinal dysfunction is frequently cited among children with autism spectrum disorders (ASD) and many causal and therapeutic hypotheses of ASD involve the gastrointestinal system (Buie et al., 2010). The importance of the gut in ASD, however, is not thoroughly understood. Multiple aspects of gastrointestinal physiology are being investigated, including possible deviations in the intestinal microbiome (Mulle, Sharp, & Cubells, 2013), gene variants (Campbell, Li, Sutcliffe, Persico, & Levitt, 2008), and intestinal permeability (D’Eufemia et al., 1996). Moreover, interventions such as restricted diets, nutritional supplements, enzymes, and antimicrobial agents are being promoted and implemented, but not founded on a large body of scientific evidence.Many diets target gluten and casein, dietary components first proposed in the 1950′s by Asperger and others to be involved in the emergence and/or maintenance of autistic behaviors (Mahikoa, 1996).This molecular hypothesis proposes that opioid-like peptides, gliadomorphin and casomorphin, escape the intestinal barrier, are absorbed into the blood stream, and subsequently disrupt brain functioning as the body’s immune system attacks these molecules and substances (Reichelt, Knivsberg, Lind, & Nodland, 1991). There is no strong evidence, however, indicating that gluten-free and/or casein-free diets improve autistic symptoms or that individuals with ASD have increased intestinal permeability to support the “opioid excess theory” or “leaky gut hypothesis” (Elder et al., 2006; Millward, Ferriter, Calver, & Connell-Jones, 2008). 

The development of causal and therapeutic hypotheses relating the gastrointestinal system to ASD is driven by many factors including: 1) an apparent increase in the prevalence of  ASD, with approximately 1 in every 88 children currently meeting diagnostic criteria in the United States (CDC, 2012); 2) a level of urgency by primary caregivers and practitioners to determine the etiology of ASD and identify interventions to remediate symptoms; 3) frequent reporting of gastrointestinal symptoms with associated cost burden(Croen et al., 2012); and 4) a fivefold increase in the odds of developing a feeding problem in ASD when compared with peers, often with unknown organic origin (Sharp et al., 2013). Unfortunately, research focusing on gastrointestinal disease in children with ASD has been clouded by Dr. Andrew Wakefield’s now retracted publications naming a new pathologic entity, “autistic enterocolitis” related to the MMR vaccine, as responsible for developmental regression in 12 children (Wakefield, Murch, Anthony, et al., 1998 [Retracted]). The medical community has blamed Wakefield directly and indirectly for causing a decrease in vaccination rates and a re-emergence of once eradicated pediatric diseases. Furthermore, while the nature of the impact on gastrointestinal research in ASD is speculative, this controversy likely averted investigators from dedicating resources to examine the relationship between gastrointestinal symptoms and ASD. 

The Evidence Base

In the last few years, the most cited paper on this topic involved a literature review and consensus report that found “an absence, in general, of high-quality clinical research data” supporting an increased risk of gastrointestinal disorders in ASD and, consequently, children with ASD should be treated to have as many gastrointestinal disorders as their non-ASD peers (Buie et al., 2010).  This conclusion was based on a pool of 11 studies involving a wide degree of methodological variability; only 5 studies involved a comparison groups and there was a extremely wide range of prevalence estimates of gastrointestinal disorders in patients with ASD (range: 9% to 91%).  This article has been cited 26 times in peer-reviewed publications (as of April 2013) and is likely a primary source of guidance for caregivers and healthcare providers faced with these issues, highlighting the need for further research in this area. 

More recently, our research group completed the first comprehensive review and meta-analysis surveying the medical literature in order to identify studies using empirical methods to investigate gastrointestinal symptoms among children with ASD using a comparison group (McElhanon, McCracken & Sharp, 2013 – manuscript in preparation).  We identified a total of 15 studies published between January 1980 and September 2012 involving a total sample of 2215 children with ASD. The results of the meta-analysis suggest children with ASD are at increased risk for gastrointestinal issues. Specifically, our analysis indicated greater levels of general concerns regarding gastrointestinal symptoms reported by parents compared with siblings (roughly an 8 fold increase in the risk) and peers (roughly a 3.5 fold increase in the risk), with areas of specific concern including abdominal pain, constipation, and diarrhea.  The summarized research was based largely on parent report and medical chart reviews and often did not account for variation in diet, behavior problems (e.g., toileting issues), and/or ASD diagnostic status. As a result, conclusions regarding the relationship between these factors and possible gastrointestinal dysfunction are unavailable at this time.       

In line with conclusions by Buie et al. (2010), our results suggests, at a minimum, parents and health care providers should be educated about possible underlying gastrointestinal problems in children with ASD. Children suspected of possible gastrointestinal issues should then be screened accordingly. With this in mind, one difficulty in identifying and studying gastrointestinal dysfunction in ASD is that individuals often present with limited verbal communication and their symptom presentation may be atypical compared with peers (Buie et al., 2010). For example, aggression and irritability without clear environmental influence (i.e., antecedents or consequences) may be the only indication of an underlying gastrointestinal problem. This highlights the need to promote greater awareness in the ASD community regarding possible gastrointestinal concerns in this population. Clinical and research activities would also benefit from an ASD-specific gastrointestinal screening instrument which, combined with increased awareness in the ASD community, would promote early detection and intervention.

In addition to better screening and early treatment, special considerations must be addressed when developing treatment plans for children with autism. For example, Furuta et al. (2012) published details on managing constipation in children with ASD. Of note, the guidelines are the same as the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition for all constipated children, with added details such as the expert opinion that children with ASD may not like the taste of magnesium citrate(Glenn et al., 2010). Moving forward, ongoing research is required to elucidate the role of the gut in autistic characteristics, including whether certain phenotypes of children with autism do have different gastrointestinal physiology which could, as an example, respond to dietary changes. In addition, standardized clinical screening of gastrointestinal symptoms in patients should be pursued to promote early intervention and, thus, the best standard of care.

References

Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, Vandewater J, et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010;125(suppl 1):S1-18

Mulle JG, Sharp WG, Cubells JF. The gut microbiome: a new frontier in autism research. Curr Psychiatry Rep. 2013;15(2):337. doi: 10.1007/s11920-012-0337-0. Epub 2013 Feb 15

Campbell DB, Li C, Sutcliffe JS, Persico AM,  Levitt P. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res. 2008; 1: 159–168. doi: 10.1002/aur.27

D’Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagiiini M, Cardi E, Giardini 0. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996;85:1076-9. Stockholm. ISSN 0803-5253

Kulani Mahikoa, Gastrointestinal Illness in Autism: An Interview with Tim Buie, M.D. Autism Advocate 5th edition 2006

Reichelt KL, Knivsberg A-M, Lind G, Nodland M. Probable etiology and possible treatment of childhood autism. Brain Dysfunct. 1991; 4: 308-19

Elder JH, Shankar M, Shuster J, Theriaque D, Burns S, Sherrill L. The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord. 2006;  36 (3): 413–20

Millward C, Ferriter M, Calver SJ, Connell-Jones GG. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD003498. DOI: 10.1002/14651858.CD003498.pub3

Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders — autism and developmental disabilities monitoring network, 14 sites, United States, 2008. Morbidity and Mortality Weekly Report. Vol. 61, March 30, 2012. Available online: http://www.cdc.gov/ncbddd/autism/documents/ADDM-2012-Community-Report.pdf

Croen LA, Najjar DV, Ray GT, Lotspeich L, Bernal P. A comparison of health care utilization and costs of children with and without autism spectrum disorders in a large group-model heath plan. Pediatrics. 2006; 118(4): e1203 – e1211

Sharp WG, Berry RC, McCracken C, Nuhu NN, Marvel E, Saulnier CA, Klin A, Jones W,  Jaquess DL. Feeding Problems and Nutrient Intake in Children with Autism Spectrum Disorders: A Meta-analysis and Comprehensive Review of the Literature. J Autism Dev Disord. 2013; DOI 10.1007/s10803-013-1771-5. Epub 2013 Feb 1

Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, nonspecific colitis, and pervasive developmental disorder in children. Lancet. 1998; 351(9103): 637-641

McElhanon, BO, McCracken C, Sharp WG.Gastrointestinal Disorder in Children with Autism Spectrum Disorders: A meta-analysis and comprehensive review of the literature. Oral presentation at Mead-Johnson North American Pediatric Gastroenterology, Hepatology and Nutrition 3rd Year Fellows’ Research Conference.  Scottsdale, Arizona, 2013, February.

Furuta, et al. Management of constipation in children and adolescents with autism spectrum disorders. Pediatrics. 2012; 130;S98

Glenn T. Furuta, Kent Williams, Koorosh Kooros, Ajay Kaul, Rebecca Panzer, Daniel L. Coury and George Fuchs. Management of Constipation in Children and Adolescents with Autism Spectrum Disorders. Pediatrics 2012;130;S98

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