Chronic Fatigue Syndrome and Autism: Speculation a Go-Go

Not knowing.

I don’t think anyone would argue with the fact that our present understanding of autism, with all its heterogeneity, elevated risk of comorbidity and slightly more fluidic expression than perhaps originally thought [1], still remains quite limited.

Allowing for islands of potentially linked factors to the onset of symptoms such as the presence of phenylketonuria (PKU) [2] (and perhaps other inborn errors of metabolism [3]), congenital rubella [4], tuberous sclerosis [5] and fragile X syndrome [6], little more is currently known about what might “cause” autism and the mechanisms of effect, despite several theories and speculations [7-9]. In this context, autism in the majority is perhaps best described as a disorder of unknown origin – idiopathic if you prefer.

Autism however is not alone in this categorization. Just about all of the cognitive and behaviourally defined conditions also share a similar “not knowing” state in the majority of cases, despite considerable efforts from various disciplines to determine common underlying features. Likewise, heterogeneity and issues of description, in some cases combined with episodic presentation (e.g. schizophrenia, depression) complicate efforts to determine cause/s in these other conditions too.

Whilst this lack of knowledge hinders efforts to predict, aid in early diagnosis, and intervene to positively affect quality of life in autism, there has been some (limited) progress in defining what autism isn’t. Autism for example, is not a condition caused by bad parenting. Neither, one could argue, is it a psychological or emotional disorder in the same vein as post-traumatic stress disorder (PTSD) for example, despite the appearance of cognitive and psychological symptoms.

Whilst genes probably have some involvement in autism, there is currently no universal, reliable genetic marker for the condition despite the various headlines [10]. As with the known “causes” of autism, such as PKU, environment may also play a role in some cases (see my previous post on epigenetics and autism). In short, autism is an organic condition primarily affecting the brain and possibly linked to other parts of the body also.

This may to many people with autism and their families, not seem like much progress in understanding autism. Spare a thought however for other conditions of unknown origin, which, at the current time, carry no universal opinion on whether they are organic or not. Indeed welcome to the world of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME).

CFS/ME: organic or psychological?

I tread carefully in this post so as not to offend anyone in the autism or CFS/ME worlds. Primarily defined by long-lasting, chronic mental and physical fatigue but also encapsulating a wide variety of other symptoms [11], there are lots of opinions as to the nature of CFS/ME.

The World Health Organisation (WHO) currently defines CFS as a neurological disorder (post-viral fatigue syndrome) with aetiology listed as being either “viral or immunologic”. That being said, there are at least three different diagnostic definitions of CFS/ME which have invariably led to some confusion particularly when translating research findings to a wider audience.

Given the neurological and viral focus of its description, it is intriguing that differences occur in the way that CFS/ME is managed worldwide. In the UK for example, the current advice [12] for intervention is primarily based on the use of cognitive-behavioural therapy (CBT), graded exercise therapy (GET) and pacing techniques in managing activity and energy levels. Analgesics and antidepressants are also indicated where and when required.

Such a package of interventions primarily focused on the psychology and overt physical presentation of the condition seems to some people with CFS/ME and some on the outside looking in, slightly at odds with the definition of the condition and predicted underlying pathology. Indeed, tensions have run high when it comes to defining CFS/ME and understanding and deciding on the best ways to tackle core pathology.

A link?

I want to stress that based on the evidence currently available, I am not in any way, shape or form suggesting that conditions like CFS/ME and autism are anything like each other in terms of presentation or indeed possible underlying pathology. As far as I am aware, PKU or fragile X syndrome are not for example indicated in cases of CFS/ME. That being said, I do want to explore the possibility of ‘overlap’ and shared physiology in some cases between the conditions.

There are various anecdotal accounts of familial overlap between autism and CFS/ME dotted around cyberspace and beyond. Given the tendency for CFS/ME to present more frequently in females, reports have predominantly originated from mums.

Perhaps even more anecdotally, cases of CFS/ME presenting comorbid to autism have also been described, reiterating the fact that a diagnosis of autism is seemingly protective of nothing when it comes to comorbidity. Accurate estimates on the rate of CFS/ME in autism are, however, missing.

The scientific literature on a possible link between CFS/ME and autism is sparse, very sparse. Aside from speculations on a possible link between stealth viruses as neuropathogens [13] mentioning both conditions, immune dysfunction and the controversial area of XMRV – xenotropic murine leukemia virus-related virus make up the cumulative research story so far.

The soap opera of XMRV

Having made mention of XMRV and CFS/ME and autism, I can’t possibly do justice to the whole who, where, what and why of XMRV particularly with CFS/ME in mind so I won’t—aside from suggesting you Google “XMRV and CFS” and go through the mountains of opinion.

The basic story circles round the reported discovery of a gammaretrovirus (XMRV) in quite a few cases of CFS (originally also reported in prostate cancer), issues with replication of the original results, a suggestion of contamination of the cell lines used to confirm the virus, and lots of subsequent scientific retractions.

It is indeed timely that this post goes out shortly after the big “final say” study on XMRV being published by microbe/virus hunter Prof. Ian Lipkin and colleagues [14] (Lipkin also being an author on the recent discovery of Sutterella bacteria in cases of autism and gastrointestinal dysfunction). At the time of writing I don’t yet know what they have or haven’t found but by the time you read this, the world will know.

Quite surprisingly, XMRV has also been looked at with autism in mind; not once [15] but twice [16]. Part of the reason for these studies goes back to speculation expanding the now retracted findings from CFS/ME to autism. In both studies on autism, the answer was quite a resounding “no virus detected”.

Mitochondrial dysfunction?

There is perhaps one area of potential commonality between CFS/ME and autism: mitochondrial disorder. Looking at autism first, Rossignol and Frye [17] conducted quite a detailed review of the current literature on mitochondrial dysfunction being related to some cases. To quote: “Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD.” More recent evidence similarly implies the need for further analysis on the possible mitochondrial link in cases of autism [18].

With CFS/ME in mind and given the very overt symptoms associated with fatigue and energy levels, the notion of mitochondrial dysfunction in cases is also gaining ground. Booth and colleagues [19] recently reported on a quite a detailed analysis of mitochondrial dysfunction in their cohort of patients with CFS/ME. In short, there was some good evidence of mitochondrial involvement with a continuing need for much more study.

Again, I am not suggesting that such overlap in the area of mitochondrial dysfunction implies any connection between autism and CFS/ME; merely that a common area of potential research interest may overlap the two diagnoses.

As per the title of this post, science has perhaps partially given way to speculation on any possible link between autism and CFS/ME. I am doubtful of any particularly strong relationship between the conditions; certainly not to the same degree that the various features of the immune system and autoimmunity for example, seem to be quite consistently cropping up in cases of autism [20]. That being said, with only little investigation being carried out on a possible relationship, one has to be careful not to assume “no link” where “no research” is perhaps the more realistic viewpoint.

 

References.

[1] Fountain C. et al. Six developmental trajectories characterize children with autism. Pediatrics. 2012; 129: e1112-1120.

[2] Baieli S. et al. Autism and phenylketonuria. JADD. 2003; 33: 201-204.

[3] Novarino G. et al. Mutations in BCKD-kinaselLead to a potentially treatable form of autism with epilepsy. Science. September 2012.

[4] Chess S. Follow-up report on autism in congenital rubella. Journal of Autism & Childhood Schizophrenia. 1977; 7: 69-81.

[5] Smalley S. Autism and tuberous sclerosis. JADD. 1998; 28: 407-414.

[6] Levitas A. et al. Autism and the fragile X syndrome. JDBP. 1983; 4: 151-158

[7] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002; 6: 175-183.

[8] Hornig M. et al. An infection-based model of neurodevelopmental damage. PNAS. 1999; 96: 12102-12107.

[9] Kong A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012; 488: 471-475.

[10] Skafidas S. et al. Predicting the diagnosis of autism spectrum disorder using gene pathway analysis. Mol Psychiatry. September 2012.

[11] Whiteley P. et al. Correlates of Overlapping Fatigue Syndromes. J Nutr Enviro Med. 2004; 14: 247-259.

[12] http://www.nice.org.uk/nicemedia/live/11824/36193/36193.pdf

[13] Martin WJ. Stealth viruses as neuropathogens. CAP Today. 1994; 8: 67-70.

[14] http://cii.yewda.com/Blog.aspx?LOfRcb

[15] Satterfield BC. et al. PCR and serology find no association between xenotropic murine leukemia virus-related virus (XMRV) and autism. Mol Autism. 2010; 1: 14

[16] Lintas C. et al. Lack of infection with XMRV or other MLV-related viruses in blood, post-mortem brains and paternal gametes of autistic individuals. PLoS ONE. 2011; 6: 16609.

[17] Rossignol DA. & Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012; 17: 290-314.

[18] Ginsberg MR. et al. Brain transcriptional and epigenetic associations with autism. PLoS ONE. 2012; 7: 44736.

[19] Booth NE. et al. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012 ;5: 208-220.

[20] Kohanne IS. et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS ONE.  2012; 7: 33224.

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