The gut and 15q Duplication Syndrome

"The results indicate that GI [gastrointestinal] symptoms are common in Dup15q syndrome and may have an atypical presentation."

Let's just say I'm Frankenstein's monster.
And I'm looking for my creator.

That was the conclusion reached in the paper by Elias Shaaya and colleagues [1] following a review of medical records for a small-ish group of participants diagnosed with chromosome 15q duplication syndrome (dup15q syndrome), a genetic condition "involving copy number gains of the maternal chromosome 15q11.2-q13 region." Dup15q syndrome can manifest in a variety of ways including the presence of seizure disorders, poor muscle tone (hypotonia), issues with growth and neurodevelopmental issues.

Authors reported functional GI symptoms to be present in over three-quarters of their cohort, slightly varying in frequency depending on the nature of duplication (isodicentric vs. interstitial duplication) recorded. "The most commonly reported symptoms were gastroesophageal reflux (56.7%) and constipation (60%), with 30% of subjects reporting both" and: "Behaviors such as irritability and aggressiveness improved with treatment of GI symptoms in several subjects."

Why am I talking about dup15q syndrome on a blog that is supposed to be concentrating on autism research?

Well, three reasons: first, dup15q syndrome shares some overlap with the presentation of autism/autistic traits in the more general sense as per other commentaries on the topic (see here and see here). Second, the Shaaya study represents a second research foray into GI issues associated with genetic conditions with autism mentioned as part of some presentation, as per the discussions last year (2014) on GI issues appearing alongside 22q11.2 deletion syndrome (see here). Finally, dup15q has been mentioned on this blog before with the curious findings reported by Mitchell and colleagues [2] who implied that: "specific POPs [persistent organic pollutants] may predispose to genetic copy number variation of 15q11-q13." That last reason ties into my interest in how genes and environment [variably] intersect when it comes to health and wellbeing particularly associated with behaviourally-defined diagnoses.

The comment about how treatment of GI symptoms seemed to tie into a reduction in certain 'challenging behaviours' in cases of dup15q syndrome is also worthy of further promotion. As per my review of autism research in 2014, functional GI issues associated with quite a few cases of autism was an ascendancy topic of investigation, further compounded by papers such as the one from Zainab Ridha and colleagues [3] (see here) on autism being one of a number of "useful predictors of STC and FFR [slow transit constipation and functional fecal retention] in children." Alongside other research suggesting that issues such as anxiety and sensory 'over-responsivity' might also tie into the presentation of GI problems in autism (see here), one might see how management/treatment of bowel issues may very well impact on some behaviours. No-one likes to walk around with chronic constipation.

I know the Shaaya paper was based on a relatively small number of participants, so it is perhaps implied that further studies are needed to see how generalised GI issues might be in relation to dup15q syndrome. As per that Giardino study [4] on GI involvement in 22q11.2 deletion syndrome (del22), one wonders whether looking at things like "antigliadin (AGA) IgA and IgG, and antitissue transglutaminase (anti-TGase) titers" might also be a useful next step, alongside horror of horrors, the presence of any "abnormal intestinal permeability"?

Prefab Sprout - The King of Rock 'N' Roll to close.

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[1] Shaaya EA. et al. Gastrointestinal Problems in 15q Duplication Syndrome. European Journal of Medical Genetics. 2015. January 5.

[2] Mitchell MM. et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environ Mol Mutagen. 2012 Oct;53(8):589-98.

[3] Ridha Z. et al. Predictors of slow colonic transit in children. Pediatr Surg Int. 2014 Dec 31.

[4] Giardino G. et al. Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. Scand J Gastroenterol. 2014 Mar;49(3):274-9.

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Shaaya, E., Pollack, S., Boronat, S., Davis-Cooper, S., Zella, G., & Thibert, R. (2015). Gastrointestinal Problems in 15q Duplication Syndrome European Journal of Medical Genetics DOI: 10.1016/j.ejmg.2014.12.012

Gastrointestinal comorbidity for World Autism Awareness Day

Today (Tuesday 2 April 2013) is World Autism Awareness Day (WAAD).

I don't exactly know how one is supposed to communicate this message ('Happy world autism awareness day' just doesn't roll off the tongue). So I guess all I will say is to reiterate the subtext of this blog on what the spectrum - the very wide spectrum - means: "To some it means a need for life-long support. To others it is part of the varied tapestry of humanity. To all it means a need to foster a welcoming society with appropriate support and opportunities."

Onwards. Having discussed the latest paper from Drs Stephen Walker and Arthur Krigsman on bowel pathology in cases of autism potentially denoting a distinct condition from other inflammatory bowel diseases and stumbling upon the paper by Peeters and colleagues* on functional defecation disorder and autistic traits, I thought it appropriate to pop into the DeLorean and revisit a paper which never really received the recognition it deserved.

The subject matter for today is the paper by Karoly Horvath and colleagues** published in 1999 as we begin another trip down the autism research memory lane, same as I did when covering the the Mary Goodwin paper from 1971 on the gut-brain axis and autism (see here) and the John Money autism and autoimmunity paper also from 1971 (see here).

Hadrian's Wall @ Wikipedia  

Remember my name
The name Karoly Horvath will probably be familiar to quite a few people who've been on the autism research scene for a while. Another of Dr Horvath's papers*** created a bit of stir a while back based on some very preliminary findings on the use of the digestive hormone, secretin for cases of autism.

Following some initial reports of "transient, marginally significant improvements in autistic behaviors" in some cases as per studies like the one from Coniglio and colleagues****, a whole slew of subsequent trials have painted a rather less positive picture on the use of secretin for autism as per the review by Krishnaswami and colleagues***** (open-access) which quite emphatically stated that "secretin as a treatment approach for ASDs warrants no further study".

I'm not one to normally challenge paper conclusions - particularly systematic reviews - but will perhaps contrast that quote with the closing remarks made by the Cochrane Library review of Williams and colleagues******. They left the secretin research door slightly ajar for those who were potentially able to  identify "important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing". I'm a great believer in subgroups when it comes to autism, or rather the autisms, and how a diagnosis of autism is seemingly protective of nothing when it comes to other conditions/states, so you can perhaps assume which quote was my preference.

Factoids
Anyhow, back to the Horvath 1999 paper. A few interesting factoids from their report:

• Thirty-six children all diagnosed with an autism spectrum disorder (ASD), mean age 5.7 years, formed the participant group. Children were all referred to the gastroenterology (GI) clinic where the authors worked following the presence of various GI symptoms ranging from abdominal pain to chronic diarrhoea and various other presentations.
• As well as quite a bit of review of participants' medical history, various clinical investigations were undertaken which included a "full upper gastrointestinal workup", analysis of digestive enzyme function in the small intestine and some histological examination.
• Results: quite a few important findings. Reflux esophagitis was present in nearly 70% of participants (25/36). Chronic inflammation of the gastric mucosa was determined in 15 children. Reduced disaccharidase activity was present in approximately 60% of children, and in particular low lactase levels. Following administration of secretin, participants with autism and diarrhoea comorbid showed signs of increased pancreatico-biliary fluid output potentially indicative of "upregulation of the secretin receptors" itself potentially related to "either a defect in secretin production or a problem of release from the intestinal S cells".
• "There was no evidence of either fungal or bacterial overgrowth in the duodenum" was another finding.

I know there is a lot to take in from those results so I'm going to try and put them into some kind of perspective with some of the other related literature in the peer-reviewed domain.

Lactose intolerance
I'll start with the disaccharidase activity side of things. The Horvath results were in some respects ahead of their time with their findings in this area. I've talked previously about the Rafail Kushak paper and their findings of the frequency "of lactase deficiency was 58% in autistic children ≤ 5 years old and 65% in older patients". Notice the similarity in the percentages between Horvath and Kushak. Indeed, this whole area of carbohydrate malabsorption present in cases of autism was very nicely continued by the Brent Williams paper looking at enzyme activity and autism. I know a few people have talked about how some of these findings might overlap with for example, the various reports on the use and effectiveness of a gluten- and casein-free (cereal grains and mammalian dairy free) diet in some cases of autism. Certainly, I wouldn't rule out a possible overlap to account for any results.

Reflux and GERD
Gastroesophageal reflux and reflux esophagitis - states pertaining to inflammation of the esophagus - were also commonly reported in the participant group and indeed also correlated with various behavioural manifestations noted in some cases (nighttime wakening, signs of irritability, abdominal discomfort) which are "typically reported by non-autistic children with esophagitis". A little reading around this topic suggests that many cases of such esophagitis are tied into things like GERD - gastroesophageal reflux disease - which is basically about stomach acid rising up instead of staying where it should be and causing damage. That being said, other explanations have also surfaced to potentially account for the damage done during GERD (see the paper by Souza and colleagues*******) highlighting a possible role for cytokines in this process. I'm also conscious of the findings of eosinophilic esophagitis being reported in individual cases of autism (see here). In terms of management options and without heading down any medical advice giving path, I was very interested to see a body of work appearing supporting the use of baclofen for cases of GERD********, a derivative of which - arbaclofen - has recently been touted as a potential intervention option for cases of autism. One has to wonder whether kum-ba-arbaclofen might be doing so much more than just affecting GABA receptors?

I'm going to stop there with the Horvath paper and its quite important observations. Once again it is a good example of how, just because we see a rising tide of new findings on autism or any other condition or state, we shouldn't neglect the older literature (published pre-social media) and the valuable insights that it has provided. Indeed, I am going to champion the paper by Horvath et al as an important one; particularly when it came to the assessment of carbohydrate digestive enzyme activity because it was truly ahead of its time and very possibly something that you might hear more about in the coming years of autism research.

Importantly for WAAD, the Horvath paper is a stark reminder that awareness of the autism spectrum should extend beyond just the triad (very soon to be dyad) of core symptoms and into the range of often very pronounced comorbidities which can also exist and affect quality of life. And just in case you need a more recent example of this, have a look at this paper from Francisca van Steensel and colleagues********* (open-access) and their findings on the over 50% rate of psychiatric comorbidity reported in their pediatric cohort. Their focus on 'anxiety disorders' does not need any more chatter from me.

To close, something musically, a little more contemporary. Bruno Mars and Locked Out Of Heaven.

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* Peeters B. et al. Autism spectrum disorders in children with functional defecation disorders. J Pediatr. March 2013.

** Horvath K. et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999; 135: 559-563.

*** Horvath K. et al. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys. 1998; 9: 9-15.

**** Coniglio SJ. et al. A randomized, double-blind, placebo-controlled trial of single-dose intravenous secretin as treatment for children with autism. J Pediatr. 2001; 138: 649-655.

***** Krishnaswami S. et al. A systematic review of secretin for children with autism spectrum disorders. Pediatrics. 2011; 127: e1322–e1325.

****** Williams K. et al. Intravenous secretin for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2012; 4: CD003495.

******* Souza RF. et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009; 137: 1776-1784.

******** Cossentino MJ. et al. Randomised clinical trial: the effect of baclofen in patients with gastro-oesophageal reflux - a randomised prospective study. Aliment Pharmacol Ther. March 2012.

********* van Steensel FJA. et al. Psychiatric comorbidity in children with autism spectrum disorders: a comparison with children with ADHD. J Child Fam Stud. 2013; 22: 368–376.

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Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, & Tildon JT (1999). Gastrointestinal abnormalities in children with autistic disorder. The Journal of pediatrics, 135 (5), 559-63 PMID: 10547242