Monday, 20 January 2014

The gut and 22q11.2 deletion syndrome

A rather peculiar thing seems to be happening in autism research. For years, to make mention that at least some cases of autism might also show involvement of the gastrointestinal (GI) tract would in some quarters, automatically invoke eye-rolling, furrowed brows and in some cases, sanctions. Then, slowly but surely, research started to accumulate suggesting that yes, in at least some cases of autism, GI issues - whether functional or more pathological - do seem to be present and in some cases, over-represented.
Genes not jeans @ Wikipedia 

Last year (2013), details started to emerge about the form those GI issues might take, as per papers like the one from Ludvigsson and colleagues* on the possibility of a non-coeliac gluten sensitivity - type condition potentially being related. Then came the mouse models of autism suggestive of intestinal involvement; first in the maternal immune activated (MIA) model (see here) and then in the valproate model (see here and more recently here**). Talking about GI issues and autism became, well, not so taboo.

Today's post adds to the interest with the findings from Giardino and colleagues*** suggesting involvement of the GI tract in cases of 22q11.2 deletion syndrome, using words like "abnormal intestinal permeability" and "high prevalence of AGA [anti-gliadin] IgA and IgG positivity".

From the beginning: 22q11.2 deletion syndrome or Del22 as Giardino et al call it, is a genetic condition occurring when a small piece of genetic material is deleted from chromosome 22. The q11.2 bit refers to an area on the chromosome, thought to contain about 30 genes, which is affected. Name- and presentation-wise, Del22 is varied and includes both physiological and behavioural pathology (see here with thanks to Robert for the link). The precise nature of any concurrent psychopathology however is still a source of investigation.

Insofar as the autism connection, well autism or the presentation of autistic symptoms, certainly does seem to be a feature of some cases of Del22 as per the paper by Vorstman and colleagues**** for example. The research chatter a few months back about children being misdiagnosed with autism when in fact they presented with Del22 supports this strong link between the two conditions*****.

In their paper, Giardino and colleagues asked some further questions about whether there may be some GI involvement in cases of Del22 based on a suite of different variables: "Plasma levels of hemoglobin, iron, ferritin, albumin, total protein, calcium, phosphorus, transaminase levels, antigliadin (AGA) IgA and IgG, and antitissue transglutaminase (anti-TGase) titers were measured". They found that within their small participant group (N=26) "GI involvement was identified in the 58% of patients" comprising things like abdominal pain and constipation. Further when it came to the presentation of coeliac (celiac) disease, or at least some of the outwards signs and symptoms linked to coeliac disease, the talk was about quite a few of the participants presenting with things like short stature and/or failure to thrive. Oh and "Celiac disease (CD) was suspected in three patients, and in one of them confirmed by histology".

Then comes those words again: "an abnormal intestinal permeability" (yes, leaky gut) alongside the presence of those anti-gliadin antibodies. In short, there appears to be something going on with regards to the gut in quite a proportion of cases of Del22. Commonalities with other research are present particularly implicating an immune response to certain foods.

Now, far be it from to jump to too many conclusions, but it strikes me that we seem to have a pattern emerging in quite a few conditions with an autism link. I assume most people have heard about the gut-brain axis (see here) and how brain and 'second brain' seem to show quite an important connection in at least some presentations of autism. The potential importance of detecting both autism or autistic traits in cases of Del22 alongside other GI related comorbidity in that research has a sort of 'heads-up' in terms of where one might start looking if we're to assume that said GI comorbidity might have a genetic element to it. By saying that, I don't want to imply that all GI comorbidity in relation to autism is purely a result of genetic issues, despite evidence for example from the very important de Magistris paper****** on possible hereditary issues in relation to gut hyperpermeability. But still looking at what might be 'deleted' in cases of Del22 is an obvious starting point.

Assuming that the Giardino findings are replicated, the obvious question is how deep the rabbit hole really goes? Are there other conditions defined by the presence of known genetic findings which present as autism or autistic traits which might also be ripe for inquiry into the presence of GI findings? How about the discovery of that BCKDK phenotype for example, supposedly "treatable" by the branched-chain amino acids? Questions, questions, questions.

Some music to close. How about Björk Guðmundsdóttir and Venus as a Boy?


* Ludvigsson JF. et al. A nationwide study of the association between celiac disease and the risk of autistic spectrum disorders. JAMA Psychiatry. 2013 Nov;70(11):1224-30.

** Kim JW. et al. Gastrointestinal tract abnormalities induced by prenatal valproic Acid exposure in rat offspring. Toxicol Res. 2013 Sep;29(3):173-9.

*** Giardino G. et al. Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. Scand J Gastroenterol. 2013 Dec 18.

**** Vorstman JA. et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J Am Acad Child Adolesc Psychiatry. 2006 Sep;45(9):1104-13.

***** Angkustsiri K. et al. Social Impairments in Chromosome 22q11.2 Deletion Syndrome (22q11.2DS): Autism Spectrum Disorder or a Different Endophenotype? J Autism Dev Disord. 2013 Sep 18.

****** de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

---------- Giardino G, Cirillo E, Maio F, Gallo V, Esposito T, Naddei R, Grasso F, & Pignata C (2013). Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. Scandinavian journal of gastroenterology PMID: 24344832