Fatigue in adults with a 22q11.2 deletion syndrome

The genetic condition called 22q11.2 deletion syndrome (22q11.2DS) has, on occasion, provided some research fodder for this blog (see here and see here). The reason for its inclusion here has tended to be around the 'overlap' in the presentation of 22q11.2 and autism/autistic features and the importance of appropriate screening as and when an autism diagnosis is received (see here). Remember: receipt of an autism diagnosis is a starting point not the finishing line.

Today I'm once again talking about 22q11.2 and specifically the results reported by Vergaelen and colleagues [1] on the need for more research/investigation on fatigue as a potentially important symptom when it comes to 22q11.2. This work links into another area of interest to this blog: chronic fatigue (syndrome) (CFS).

OK, just for the record I'd like to point out that fatigue is not the same as chronic fatigue syndrome (indeed, as mentioned in a recent post, 'chronic disabling fatigue' is also not the same as chronic fatigue syndrome). Vergaelen et al relied on data from 29 people (adults) diagnosed with 22q11.2 who completed "the multidimensional fatigue inventory (MFI) measuring severity of fatigue." Results from the self-report schedule were "compared with published population norms" and suggested that: "Subscales and total MFI scores were significantly higher in adults with 22q11.2DS." Authors also noted that the presence of fatigue seemed to also affect scores on quality of life and depression in their cohort and recommend "a systematic clinical examination to exclude underlying somatic or psychiatric causes of fatigue."

There's little more to say on this topic aside from reiterating the point that further clinical examinations should be undertaken to assess the possible hows and whys of fatigue presenting alongside 22q11.2 deletion syndrome. Given for example, previous work suggesting that mitochondrial disease might manifest as fatigue (as part of CFS that is) (see here) and some work linking "some 22q11DS genes implicated in mitochondrial function" [2] that is one option to consider among [likely] many.

Music: and if like me, you watched the trailer to the new 'Logan' film and asked who 'sings that song?', well it was Johnny Cash and Hurt.

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[1] Vergaelen E. et al. High prevalence of fatigue in adults with a 22q11.2 deletion syndrome. Am J Med Genet A. 2017 Feb 12.

[2] Devaraju P. & Zakharenko SS. Mitochondria in complex psychiatric disorders: Lessons from mouse models of 22q11.2 deletion syndrome: Hemizygous deletion of several mitochondrial genes in the 22q11.2 genomic region can lead to symptoms associated with neuropsychiatric disease. Bioessays. 2017 Feb;39(2).

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Vergaelen E, Claes S, Kempke S, & Swillen A (2017). High prevalence of fatigue in adults with a 22q11.2 deletion syndrome. American journal of medical genetics. Part A PMID: 28190295

22q11.2 Deletion Syndrome and 'a highly increased risk of schizophrenia spectrum disorders'

22q11.2 deletion syndrome has turned out to be something of real interest to this blog. Not only because of the reported connection to the presentation of autism (see here) including some suggestion of a role for the immune system (see here) but also because of the idea that certain somatic comorbidity linked to the gastrointestinal (GI) tract might also figure as part of the presentation of at least some cases of Del22 (see here). Said GI issues have also cropped up across quite a few other labels including cases of autism.

One of the other important psychiatric comorbidities suggested to be over-represented where Del22 is present is that of schizophrenia and related conditions. Indeed, a recent paper by Anders Vangkilde and colleagues [1] confirms that: "Carriers of a 22q11.2 deletion who had been clinically identified had a highly increased risk of schizophrenia spectrum disorders."

Based on the analysis of data from one of those oh-so-grand Scandinavian nationwide registers (in this case based in Denmark), researchers identified just over 150 people diagnosed with 22q11.2 deletion syndrome. Further inspection of those carrying the 22q11.2 deletion revealed that "6 individuals were diagnosed with schizophrenia spectrum disorders." Although seemingly only a small number, the calculated risk of schizophrenia spectrum disorder (SSD) occurring alongside Del22 was judged to be quite a bit higher than when Del22 is not present: "an 8.13(95% CI: 3.65-18.09) fold increased risk."

Schizophrenia and related conditions appearing alongside Del22 is not new news. Quite a bit of peer-reviewed literature has been generated on this topic including the idea that there may be changes to cognitive skills preceding the development of a psychotic illness [2]. Such evidence has obvious repercussions for issues such as preferential screening and the like, but perhaps just as importantly is the idea that such an association might carry important information on the mechanism pertinent to at least some types of SSD. Take for example the findings reported by Monks et al [3] who, alongside reporting that psychotic illness was present in approaching a third of their cohort with Del22 also suggested that: "Psychosis proneness seems to be of genetic origin in 22q11.2DS" on the basis of their comparing features with "non-deleted individuals with schizophrenia." I say all this bearing in mind that plurality might be as much of a feature of schizophrenia (see here) as it is with autism (see here).

Although perhaps stretching the association a little, I am minded to bring in a few blog entries I've previously made about how the reported genetics and biology of schizophrenia might yield some more information about this Del22-SSD tie-up. Y'know, things like the much-discussed schizophrenia and microglia connection (see here) or the idea that markers of gluten sensitivity might show more than a passing connection to schizophrenia (see here). Continuing the theme of immune function being potentially linked to Del22, how about looking at various inflammatory markers in cases of Del22-SSD (see here) on the basis also that inflammation might have social cognition effects too (see here)? And finally, what about the suggestion that the use of fish oil supplementation might help prevent psychosis in 'at-risk' groups (see here)? The research list is potentially endless.

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[1] Vangkilde A. et al. Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population-A Nationwide Register Study. Schizophr Bull. 2016 Jan 5. pii: sbv195.

[2] Vorstman JA. et al. Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome. JAMA Psychiatry. 2015 Apr;72(4):377-85.

[3] Monks S. et al. Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome. Schizophr Res. 2014 Mar;153(1-3):231-6.

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Vangkilde, A., Olsen, L., Hoeffding, L., Pedersen, C., Mortensen, P., Werge, T., & Trabjerg, B. (2016). Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population—A Nationwide Register Study Schizophrenia Bulletin DOI: 10.1093/schbul/sbv195

Autism manifests across a range of genetic and metabolic syndromes

"Autism spectrum disorder (ASD) phenomenology is reported to be more common in individuals with some genetic syndromes than in the general population."

That was the starting point for the systematic review and meta-analysis published by Caroline Richards and colleagues [1] who set about 'synthesising' the various peer-reviewed data "to provide accurate estimates about ASD phenomenology in genetic and metabolic syndromes." A scan of the cumulative literature in this area ("168 papers reporting the prevalence of ASD phenomenology") revealed that autism presentation is indeed a feature of quite a few conditions compared with "the general population taking the current estimate of one in 68 people."

To those with an eye on the autism research scene the list of conditions where autism manifests is not likely to be a surprise. Rett syndrome represented one of the conditions where relative risk and odds ratio "compared to the general population" was highest. Tuberous sclerosis (TS) is also mentioned as is neurofibromatosis type 1 (NF1). I was however a little surprised that Fragile X syndrome was a little further down the frequency line than it was - "male individuals only 30%; mixed sex 22%" - given the quite classical association that I remember being discussed with autism. Down syndrome is also mentioned and perhaps reflects an increasing interest in autism being comorbid that has graced this blog previously (see here) as has the growing connection with Del22 (see here).

The authors conclude by calling for more research "including how ASD in genetic and metabolic syndromes differs from idiopathic autism [autism spontaneously arising with unknown aetiology] and what that can tell us about the mechanisms underlying ASD." This is a discussion also included in a recent paper by Sacrey and colleagues [2]. I would agree with those sentiments within the context of the Richards paper providing more evidence for the plurality of autism - the autisms (see here). I might add that if one extends the findings to autism comorbid to metabolic disorders (as in conditions such as the various inborn errors of metabolism) (see here), further details may indeed be revealing about just how many types of autism there may be, and where desired, what intervention options may present (see here).

Music: The Lumineers - Ho Hey.

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[1] Richards C. et al. Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry. 2015. Sept 1.

[2] Sacrey LR. et al. Early Infant Development and Intervention for Autism Spectrum Disorder. J Child Neurol. 2015 Aug 31. pii: 0883073815601500.

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Caroline Richards, Christopher Jones, Laura Groves, Jo Moss, & Chris Oliver (2015). Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis The Lancet Psychiatry

Immune related genes and pathways feature in 22q11DS-ASD

A quick post for your consumption today based on the findings reported by Maria Jalbrzikowski and colleagues [1] (open-access available here) who undertook "genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes." 22q11DS - 22q11.2 Deletion Syndrome - is a genetic condition characterised by a deletion of a small piece of genetic material of chromosome 22. Autism is among several presentations that can co-occur in cases of 22q11DS (sometimes called Del22) alongside other psychiatric presentation such as psychosis [2].

Jalbrzikowski et al reported that in amongst the various gene expression differences noted in their small-ish cohort diagnosed with Del22, for those also assessed as having an autism spectrum disorder (ASD) (n=16) termed '22q11DS-ASD+' "Both DE [differential expression] analysis and WGCNA [weighted gene co-expression network analysis] showed converging evidence that alterations in immune-related pathways are associated with ASD." Additional comparisons led the authors to conclude that: "findings suggest that ASD pathology may be related to an innate immune system response to neuronal disturbances."

It's not necessarily new news that some of the suspected genetics of autism might not necessarily just implicate the brain as being related to symptom onset and diagnosis. I've covered other examples of immune-related genes linked to autism appearing the peer-reviewed literature (see here). This comes on top of other more recent reviews stressing how immune function, in various guises, might hold something of a central role for [some] autism aetiology and pathology [3].

Of course, one has to be aware that Del22 already has some pretty extensive links to immune function and in particular, the heightened risk of various autoimmune related conditions. There is always the possibility that the relationship being suggested by Jalbrzikowski and colleagues is just what would be expected in view of the small cohort included for study. Further study is implied; perhaps such investigations might also take into account another possible autism-link previously noted in the Del22 peer-reviewed literature: gastrointestinal issues and in particular, intestinal hyperpermeability and immune reactivity to gluten?

Music: Kodaline - Ready.

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[1] Jalbrzikowski M. et al. Transcriptome Profiling of Peripheral Blood in 22q11.2 Deletion Syndrome Reveals Functional Pathways Related to Psychosis and Autism Spectrum Disorder. PLoS One. 2015 Jul 22;10(7):e0132542.

[2] 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.

[3] Estes ML. & McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015 Jul 20;16(8):469-86.

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Jalbrzikowski M, Lazaro MT, Gao F, Huang A, Chow C, Geschwind DH, Coppola G, & Bearden CE (2015). Transcriptome Profiling of Peripheral Blood in 22q11.2 Deletion Syndrome Reveals Functional Pathways Related to Psychosis and Autism Spectrum Disorder. PloS one, 10 (7) PMID: 26201030

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?

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* 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.

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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