Wednesday 19 November 2014

Down Syndrome Disintegrative Disorder

"Down syndrome disintegrative disorder seems an appropriate name for this newly recognized clinical association, which may be due to autoimmunity."
"Hi, everyone. I'm Olaf and I like warm hugs!"

That was the bottom line of the study published by Gordon Worley and colleagues [1] reviewing a small number of cases (N=11) of children diagnosed with Down's syndrome presenting at clinic "with a history of new-onset... or worsening... autistic characteristics" among other things. Based on some potentially important hunches (see here for a summary of the grant proposal for the project), researchers at Duke University and the Duke Down Syndrome Comprehensive Clinic reported results based on various behavioural and biochemical findings including that: "Ten of 11 cases (91%) had elevated ("positive") thyroperoxidase antibody titers compared to only 5 of 21 (23%) age-matched control subjects with Down syndrome".

As preliminary as these findings were, I was really rather interested to read about this study. Not only because of the link established between Down's syndrome (DS) and the presentation of autistic features harking back to some other important work (see here), but also the idea that autoimmunity might potentially be a driving force to such regressive features. Of course we already have something of a template for such a 'disintegrative disorder' in the description of Heller's syndrome, also known as childhood disintegrative disorder (CDD) (see here for some background). Until recently, CDD was included under the category 'Pervasive Developmental Disorder' roughly translating as part of the autism spectrum; although in the DSM update (DSM-5), the diagnosis no longer appears as such (see here). CDD and autism have a somewhat convoluted history intersecting with one and another during various research times and under different circumstances (see here).

Insofar as those anti-thyroid peroxidase (anti-TPO) antibodies being [positively] reported in quite a few cases of Down syndrome disintegrative disorder (DSDD), my interest is maintained. Issues potentially affecting thyroid function in relation to DS are not uncommonly reported in the research literature [2] and so one might not necessarily be surprised to hear that the presence of anti-TPO antibodies have been recorded previously [3]. Whether this finding overlaps with the Worley results in terms of early evidence for DSDD is a question we can't answer at the moment.

Indeed, autoimmunity in general, has something of a relationship with DS as per reviews such as the one by Chistiakov [4] (open-access). The fact that mention is made of coeliac disease (CD) as part of that autoimmune burden is something of particular interest to me; as the paper by Mårild and colleagues [5] noted: "a sixfold increased risk of CD in individuals with DS". These findings are all the more pertinent given that they also include one Jonas Ludvigsson on the authorship list, he of 'gluten issues not quite coeliac disease linked to some autism' (see here).

Going back specifically to the anti-TPO antibodies, I note that with the 'autistic characteristics' in mind, very little peer-reviewed research has been published in this area. It could be that anti-TPO antibodies are not something commonly seen in relation to autism or perhaps because very few people have actually looked at this issue. I will draw your attention to some of the work by Gustavo Román and colleagues [6] (see this post) which reported: "No [autism] risk was found for children of TPO-antibody–positive mothers".

That would have been all I would have said on the matter had the paper from Alan Brown and colleagues [7] not recently emerged indicating that within their cohort: "The odds of autism were increased by nearly 80% among offspring of mothers who were TPO-Ab + [positive for anti-TPO antibodies] during pregnancy (OR = 1.78, 95% CI = 1.16–2.75, p = 0.009), compared to mothers negative for this autoantibody". As interesting as this finding is, it still tells us very little about anti-TPO antibody status for those diagnosed with autism or an autism spectrum disorder (ASD) and how this might overlay with the DSDD description. I might also add that I have talked previously about research suggesting that such autoantibodies might have some link to certain kinds of depression (see here) which also draw in the possibility of comorbidity playing some role [8].

The Worley results, as preliminary as they are, are certainly worthy of further research consideration. It is a revelation to me even having an extended family member with DS, that beyond the classical presentation, there may be quite a bit more medical comorbidity which may require clinical attention. If Worley et al are indeed correct that for those with DSDD autoimmunity plays such an important role, it strikes me that directing efforts to tackle specific symptoms [9] or even autoimmune processes (as per other autoimmune conditions) might yield quite a few benefits for at least some.

Music: The Clash - Rock the Casbah.


[1] Worley G. et al. Down Syndrome Disintegrative Disorder: New-Onset Autistic Regression, Dementia, and Insomnia in Older Children and Adolescents With Down Syndrome. J Child Neurol. 2014 Nov 3. pii: 0883073814554654.

[2] Prasher VP. Down syndrome and thyroid disorders: a review. Downs Syndr Res Pract. 1999 Aug;6(1):25-42.

[3] Chen MH. et al. Thyroid dysfunction in patients with Down syndrome. Acta Paediatr Taiwan. 2007 Jul-Aug;48(4):191-5.

[4] Chistiakov D. Down syndrome and coexistent autoimmune diseases. J Applied Biomed. 2007; 5: 71-76.

[5] Mårild K. et al. Down syndrome is associated with elevated risk of celiac disease: a nationwide case-control study. J Pediatr. 2013 Jul;163(1):237-42.

[6] Román GC. et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol. 2013 Aug 13. doi: 10.1002/ana.23976.

[7] Brown AS. et al. Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2014. 29 October.

[8] Walker JC. et al. Depression in Down syndrome: a review of the literature. Res Dev Disabil. 2011 Sep-Oct;32(5):1432-40.

[9] Hegedüs L. et al. Influence of thyroxine treatment on thyroid size and anti-thyroid peroxidase antibodies in Hashimoto's thyroiditis. Clin Endocrinol (Oxf). 1991 Sep;35(3):235-8.

---------- Worley G, Crissman BG, Cadogan E, Milleson C, Adkins DW, & Kishnani PS (2014). Down Syndrome Disintegrative Disorder: New-Onset Autistic Regression, Dementia, and Insomnia in Older Children and Adolescents With Down Syndrome. Journal of child neurology PMID: 25367918

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