Restless leg syndrome in parents of children with autism

The findings reported by Maureen Russell and colleagues [1] provide some blogging fodder today and the observation that: "Biological caregivers of children with ASD [autism spectrum disorder] demonstrated a high prevalence of RLS [Restless Legs Syndrome] symptoms and poorer mental health."

OK, I know some people might be asking 'just what is Restless Legs Syndrome'? It is a recognised condition complete with 'disease' title (Willis-Ekbom disease). Symptoms, as the name suggests, centre on 'an overwhelming, irresistible urge to move the legs'. But things might not just stop at 'jittery legs' when it comes to this condition, as various other parts of the body can also be involved and indeed, affect important functions such as sleep.

Russell et al surveyed 50 biological caregivers (parents) of children diagnosed with an autism spectrum disorder (ASD) with regards to sleep habits "that included RLS as determined by four questions." They also "compared the sleep quality and daytime behaviors of children with ASD in caregivers with and without symptoms of RLS."

They observed that just over a fifth of their caregiver cohort "fit the criteria for RLS symptomatology." They also reported that those 'biological caregivers' who reported RLS symptoms also reported "poorer mental health" based on responses to the "Medical Outcomes Survey (MOS) 12-Item Short Form (SF-12)." When it came to offspring parameters, authors reported that: "Caregivers with RLS described more night waking and greater internalized behavior problems in their children with ASD than the caregivers without RLS." They interpret this 'association' in the context that there is a degree of heritability attached to RLS and some of those sleeping issues noted in offspring could mean that the symptoms of RLS are also present in children diagnosed with ASD too.

Noting the relatively small scale of the Russell study in participant number terms, the very preliminary method of reporting on mental health and the fact that there isn't a single test for RLS, these are interesting findings. I note the lead author has her PhD online (see here) showing how this research fits into a larger scheme of work on sleep and quality of life in caregivers of children with autism.

Looking at the Russell findings in the context of 'hows and whys' there are some potentially important correlations that might be noteworthy. RLS has been linked with the presentation of attention-deficit hyperactivity disorder (ADHD), a not insignificant comorbidity noted in quite a bit of autism (see here). I don't want to make any connections where none might exist but it is reasonable to assume that an over-represented occurrence of ADHD in autism could be important. Insofar as the heritability of ADHD specifically across families, there is more to do in this area but it's not unheard of for ADHD symptoms to be present in other family members including parents. This could impact on the results reported by Russell et al.

Although certain medicines have been associated with the symptoms of RLS, there is also a body of peer-reviewed science suggesting that a deficiency in iron might also be important [2]. There is still a degree of debate specifically as to how iron deficiency might 'cause' RLS but one of the primary lines of thinking revolves around how iron is an important co-factor for the biological reactions that turn the amino acid tyrosine [eventually] into the neurotransmitter dopamine. Again, minus any 'I know all the answers' sentiments, iron levels in relation to autism have been a source of some investigation down the years (see here). Some researchers have also talked about maternal iron intake potentially affecting the 'risk' of offspring autism too (see here) (with appropriate caveats).

Whatever the reason(s) to account for the Russell findings, there is a requirement for further research in this area, for a start to assess just how prevalent RLS might be in both people diagnosed on the autism spectrum and their significant others. Knowing how much comorbidity seems to follow a diagnosis of autism (see here) I wouldn't be surprised to see yet another connection; this one however, might provide some rather important clues as to overlapping genetics and biology...

Music, and Gotye still has an amazing song...

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[1] Russell M. et al. Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders. J Clin Sleep Med. 2016 Oct 28. pii: jc-00043-16.

[2] Li X. et al. Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla. Sleep Med. 2016 Jun;22:75-82.

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Russell M, Baldwin C, McClain D, Matthews N, Smith C, & Quan SF (2016). Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine PMID: 27855729

Neurotensin and autism

I've been trying to catch up with the various articles published this summer (2012) whilst I was on vacation which might be of interest to this blog. There is quite a list of papers which I will hopefully try and get through but for now I've settled on this paper by Angelidou and colleagues* (open-access) on the topic of autism, babies, brains and inflammation.

Corbita @ Wikipedia 

I'll state from the outset that the Angelidou paper is a talky-talky review paper and as per quite a few review papers, there is a healthy sprinkling of speculation also included. In this case it is the suggestion that a premature birth combined with a specific pattern of 'susceptibility' genes might predispose an infant via various triggers to mast cell activation (see my previous post on this topic) onwards to brain inflammation and autism.

I've already covered autism and SEN and prematurity in previous posts (see here for example), so won't dwell too much on that for now aside from directing you to another relevant paper in this area by Leavey and colleagues** recently published, quote confirming "the role of shortened gestation in ASD risk". As to the susceptibility genes side of things, well once again the ENCODE project really suggests that we should be looking a little further and a little wider when it comes to all things genetics but I'm going to leave that for now.

One specific part of the paper by Angelidou was however of particular interest to me: neurotensin (NT) and the evidence base with relation to autism. A quick description first: neurotensin is a peptide found in various tissues including brain and gastrointestinal (GI) tract. Originally categorised as a hypotensive (lowering blood pressure) by Carraway & Leeman*** it appears that this peptide has quite a few potential functions and relations as per the work on its neuromodulatory action on dopamine release (see this paper by Fawaz and colleagues**** open-access) and the lessons which could be learned for various pharmacotherapies such as the neuroleptics which may be of relevance to quite a few conditions. Other, seemingly quite diverse areas, also seem to have been linked to neurotensin chemistry including alcohol metabolism and some cancers. Indeed some pretty strong evidence of involvement for neurotensin and diseases associated with premature death was recently published.

With autism in mind, the current science base for neurotensin is a little bit limited. There are however some key papers to point out:

• The mast cell activation theme runs through a lot of the research starting with this paper by Angelidou (again!) and colleagues***** (open-access). Out of several peptides that are potentially able to stimulate mast cells (including beta-endorphin), the authors reported that only levels of neurotensin were found to be significantly elevated in their cohort of children with autism compared with controls. Having said that, with participant group numbers of n=19 (autism) and n=16 (controls), there was a very preliminary air to this data.
• Next on the list is this paper by Zhang and colleagues****** (open-access) again with some familiar names on the authorship list. This paper extends the previous findings of elevated neurotensin levels in cases of autism to suggest that such elevations might also have the propensity to influence the "release of extracellular mitochondrial DNA (mtDNA) that could act as "autoimmune" trigger". In case you want to read more about mitochondrial DNA and 'anti-mitochondrial antibody Type 2' take a look at these pages (here and here). I'll probably do a super-post on autism and mitochondria at some point given this and the growing literature in this area.
• And continuing the story, this paper by Asadi and Theoharides******* (open-access). Not too much more to say here aside from some indication "that stress and infection-mimicking extracellular mitochondrial components augment allergic inflammation that may be involved in the early pathogenesis of ASDs".
• Finally, Ghanizadeh******* (open-access), who seems to have a whole stream of ideas relating to autism and related conditions (see here), offers a brief but interesting opinion piece about how targeting neurotensin levels in cases of autism might have some interesting therapeutic advantages, bringing into play everyone's favourite excitatory amino acid and neurotransmitter, glutamate (and its receptors and signalling), alongside the calming effects of GABA. 

And rest.

There's not too much more to add at the moment to this body of work on neurotensin and autism. I've not for example talked about the neurotensin receptors (see here) nor the genetics of neurotensin (see here) despite there probably being some important connections to be made. Complementary to the mast cell activation investigations in cases of autism, there does appear to be some good reasoning to continue research in this area.

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* Angelidou A. et al. Perinatal stress, brain inflammation and risk of autism-review and proposal. BMC Pediatrics. 2012; 12: 89.

** Leavey A. et al. Gestational age at birth and risk of autism spectrum disorders in Alberta, Canada. The Journal of Pediatrics. September 2012.

*** Carraway R. & Leeman SE. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. Journal of Biological Chemistry. 1973; 248: 6854-6861.

**** Fawaz CS. et al. Presynaptic action of neurotensin on dopamine release through inhibition of D2 receptor function. BMC Neuroscience. 2009; 10: 96.

***** Angelidou A. et al. Neurotensin is increased in serum of young children with autistic disorder. Journal of Neuroinflammation. 2010; 7: 48.

****** Zhang B. et al. Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. Journal of Neuroinflammation. 2010; 7: 80.

******* Ghanizadeh A. Targeting neurotensin as a potential novel approach for the treatment of autism. Journal of Neuroinflammation. 2010; 7: 58.

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Angelidou A, Asadi S, Alysandratos KD, Karagkouni A, Kourembanas S, & Theoharides TC (2012). Perinatal stress, brain inflammation and risk of autism-Review and proposal. BMC pediatrics, 12 (1) PMID: 22747567

The kynurenic acid hypothesis of schizophrenia

I'm back to tryptophan again in this post. No matter how hard I try, I just can't seem to get away from this interesting aromatic amino acid and its seemingly far-reaching effects on many aspects of human health.

Kynurenic acid @ Wikipedia

Today I'm exploring an interesting hypothesis looking at how a metabolite of tryptophan, kynuernic acid, might hold some connection to cases of schizophrenia in the so-called kynurenic acid hypothesis of schizophrenia*.

OK, probably best to start with a few caveats. Me = not an expert on schizophrenia, is probably the biggest caveat and so apologies in advance for any errors or important omissions you might find in this post. Schizophrenia, from a conceptual point of view, probably shares some similarity with quite a few other behaviourally defined conditions like autism, insofar as being defined as a spectrum condition. This, together with the risk/effect of certain comorbidity, almost certainly implies that finding 'specifics' in terms of universal theories of causation or effect, are probably going to be difficult at best. Many roads might lead to Rome.

Schizophrenia unlike autism however, does not seem to be a developmental condition present from early infancy (despite the history linking the two conditions). This is not to say however that there may not be a strong genetic component to schizophrenia if you like 'waiting in the wings' to express itself as maturation and environment play their hands. Instead schizophrenia has been associated with different stages of symptom presentation: a prodromal period, an acute phase and a relapse phase (see here) with some marked inter-individual variation on the timing of these phases. One therefore has to be quite careful when ascribing markers or generic theories to schizophrenia based on all these factors.

Back to the kynurenic acid theory, and the finding of elevated kynurenic acid (kynurenate) in post-mortem brain samples from people with schizophrenia** represents one of the first discoveries of some possible connection. The connection between elevated levels of kynurenate in certain brain areas is matched by a suggestion of reduced glutamate receptor function. Reports of elevations of kynurenic acid in cerebrospinal fluid in cases of schizophrenia followed*** and not just once (here and here). 

Then things start to get a little more speculative as questions start being asked as to why elevated kynurenic acid is there in the first place. The enzymes (and their cofactors) along the pathway to the formation of kynurenic acid have come under scrutiny as for example, per this preliminary report from Holtze and colleagues**** (full-text) on SNPs in the kynurenine 3-monooxygenase (KMO) enzyme. That and reduced levels of mRNA and lower enzyme activity have been found*****. Another enzyme suggested to show some involvement in this tangled hypothesis is that of indoleamine 2,3-dioxygenase (IDO). The suggestion is that the immune system may be able to affect the functioning of IDO in cases of schizophrenia (here) and hence increase production of kynurenic acid with some interesting knock-on effects based on the antagonistic effects on things like N-methyl-D-aspartate (NMDA) and its receptor.

Fair enough. But are the findings actually related to schizophrenia or purely epiphenomenal? There have been a few clues suggesting specific effects from elevated kynurenic acid as per this paper****** on various cognitive functions related to schizophrenia. Indeed extrapolating from rodent studies seems to have been quite a popular thing to do with kynurenic acid in mind as per other papers (here, here and here). There are some interesting themes to this work focused on things like the timing of kynurenic acid exposure; so, adolescence seems to be quite a sensitive period. I assume this makes such work all the more 'attractive' given the timing of symptom onset (see here) in many cases of schizophrenia.

On balance, the collected evidence does seem to be at least pointing the way to kynurenic acid elevations as being related to cases of schizophrenia. But it doesn't just stop there. I've already mentioned a possible role for immune function in accounting for kynurenic acid levels in schizophrenia. Various infectious agents have been suggested to show some 'connection' to activation of the kynurenine pathway including influenza A (here) and an old friend, Toxoplasma gondii (here). Of course one has to be quite careful not to put all your inflammatory eggs in one basket when it comes to immune function and inflammation.

Accepting all this collected data, the question then turns to what can be done about kynurenic acid and any excessive production and what implications that might have for the presentation of schizophrenia. I think I've probably said it before but I will repeat myself: when we talk about medication to treat/manage this condition or that condition or any condition, interventions don't just generally affect one system and one system alone, they most likely with affect lots of different systems and exert quite a few effects. Antipsychotics for example, have been suggested to be quite good antiparasitics also (see here) bearing in mind the T.gondii link suggested with cases of schizophrenia. So it is with kynurenic acid in mind, as Myint and colleagues******* demonstrated in their study looking at the effects of antipsychotics on the kynurenine pathway among other things.

Perhaps even more surprising is the suggestion that medications which target some of the processes involved with inflammation such as the COX-2 inhibitors might also show some potential with kynurenic acid and schizophrenia in mind (here) together with a growing evidence base on the use of non-steroidal anti-inflammtory drugs (NSAIDs) for cases of schizophrenia (here). At this point I will stress that I am not providing or intending to provide medical advice nor endorsement about these strategies.

I've focused on schizophrenia and kynurenic acid in this post but recognise that this might not be an exclusive relationship bearing in mind all the issues previously cited on diagnosis and symptom presentation. Indeed I was particularly drawn to this paper******** by McFarlane and colleagues looking at the Dangermouse that is the BTBR mouse (see this post), and how hidden away in all the findings of this mouse model, issues with KMO might just have some function in cases of autism. Perhaps an area ripe for further investigation and in particular, when overlap exists in the dual presentation of autism and schizophrenia?

This post has been quite a brief overview of the potential role of kynurenic acid in cases of schizophrenia and as such I've only scratched the surface of the potential meaning of this work and tie-ups with other areas and other theories. What I hope I've demonstrated is that once again, looking at amino acid chemistry might hold some valuable clues about behaviourally-defined conditions, and in particular how the aromatic amino acids seem to be potentially big players in such conditions.

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* Erhardt S. et al. The kynurenic acid hypothesis of schizophrenia. Physiology & Behaviour. 2007; 92: 203-209.

** Schwarz R. et al. Increased cortical kynurenate content in schizophrenia. Biological Psychiatry. 2001; 50: 521-530.

*** Erhardt S. et al. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neuroscience Letters. 2001; 313: 96-98.

**** Holtze M. et al. Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls. Journal of Psychiatry & Neuroscience. 2012: 37: 53-57.

***** Wonodi I. et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Archives of General Psychiatry. 2011; 68: 665-674.

****** Akagbosu CO. et al. Exposure to kynurenic acid during adolescence produces memory deficits in adulthood. Schizophrena Bulletin. December 2010.

******* Myint AM. et al. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients. Brain, Behavior & Immunity. 2011; 25: 1576-1581.

******** McFarlane HG. et al. Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes, Brain & Behavior. 2008; 7: 152-163.