Autistic Spectrum Disorder – Nature or Nurture? Aware or beware?


Since April was ‘Autism awareness month’ internationally, this blog is a little different, aiming to raise awareness of autism and how adults with autism and its associated disorders might differ from the neurotypical.

In March 2014, the US government released figures estimating the prevalence of autism as being 1 in 68 boys and 1 in 189 girls (thus creating a ratio of male:female prevalence of almost 3:1)1. This means that in most communities and workplaces, there will be at least one member who has been diagnosed as being ‘on the spectrum’, due to the expression of a ‘complex behavioural phenotype’, which now includes atypical disorders such as Asperger’s Syndrome or High Functioning Autism (those with an IQ higher than 80 and with good verbal skills).

The Nature-nurture debate

It is now commonly accepted that autistic traits run in families. It has even been argued that such traits are cumulative, resulting in children that are more autistic than their parents1. Recent studies have centred on mutations contained within nonsense DNA, that is to say, DNA which does not code for protein-coding genes, per se, but rather molecular modulators of gene expression. Such modulators include ‘enhancers’, of which more than 100 are now known to be present more in the brain than other tissues of the body, resulting in a significant influence over brain development in utero. Traditional gene studies, which focussed upon protein-coding genes, would actually miss more than 95 % of the human genome, therefore it’s of little wonder that our understanding of developmental pathways in neurological disorders lags behind that of more physically symptomatic diseases such as heart disease, or cancer. This is partly due to the phenomenon of ‘environmental fixation’, whereby families (particularly mothers) were blamed for their child’s autistic traits, to the extent of being branded ‘refrigerator mothers’, alluding to the alleged coldness with which they raised their children2. Furthermore, Harlow (1972) described behaviours in his rhesus monkeys, deprived of maternal contact, that were concordant with those of the autistic children carefully described by Kanner3, perpetuating the theory that families were to blame for the atypical behaviour of their child.  Thus, the pendulum of scientific opinion has swung between the two extremes of ‘nature’ versus ‘nurture’. Current models propose that multiple genetic, epigenetic and environmental factors may contribute to the etiology of autism, with the last decade of research revealing a significant genetic heterogeneity4. In summary, no two individuals diagnosed with ASD or Asperger Syndrome are the same!

The vast majority of studies into autism focus on children, as do the strategies designed to enable those diagnosed on the spectrum to cope with ‘day-to-day life’. However, children become adults, raising the challenge of both adaptation to an environment designed for neurotypical adults and also diagnosis for those adults who form the ‘lost generation’, people who were previously excluded from a diagnosis of classic autism either through ‘camouflage strategies’ (particularly prevalent in girls who are more likely to copy peers and thus appear ‘neurotypical’ to the untrained eye) or adaptation strategies, whereby an individual copies the actions of a neurotypical colleague, learning social rules as one might study a recipe, or protocol. A school friend of mine was such a case. She wore the same clothes as her best friend, did the same hobbies and was academically outstanding. Yet she failed to progress in her chosen career and was diagnosed with Asperger’s Syndrome aged 41. Her career choice of course was influenced by that of her peers, rather than her strengths.

So are HFAs and Aspies always doomed to failure in the workplace? Much is made of the drawbacks of HFA/Asperger’s Syndrome – appearing dissociated or uninterested, difficulties with social interaction, inappropriate conversation and lack of eye contact leading to perceptions of not telling the truth or being disinterested in a particular task or employment role to mention but a few – but shouldn’t we focus more on what autism has to offer?

For example, they may have the ability to focus intensely and for long periods on a difficult problem. There is often an enhanced learning ability, although this often is not applied to subjects they are uninterested in – and therefore it may be necessary to play to the strengths of employees or students, rather than attempting to counter-act weaknesses. HFAs and Aspies often present no problems in a supportive, well-resourced educational institution and often do well academically if they can be stimulated by good teachers. People with HFA and Asperger’s often have intense and deep knowledge of an obscure or difficult subject and a passion for pursuing it in an organized and scholarly manner. This makes them more likely to excel in ‘niche’ topics, particularly neglected areas of research. They are usually intelligent, gifted, honest, hard workers when interested in a task and excellent problem solvers. People with high-functioning autism are thought to become excellent scientists and engineers or enter other professions where painstaking, methodical analysis is required.

So should we beware of Autism? Or accept what it has to offer? Besides, what exactly is normal?

Blog written by Diane Lee, who has recently moved to the School of Veterinary Medicine at the Universityof Surrey.

1 Sylvie Goldman, MD, Albert Einstein College of Medicine, Opinion: Sex, Gender and the Diagnosis of Autism – A Biosocial View of the Male Preponderance (p.1-2) http://www.sciencedirect.com/science/article/pii/S1750946713000317

2Judith Miles: Autism spectrum disorders—A genetics review; Genetics in Medicine (2011) 13, 278–294; doi:10.1097/GIM.0b013e3181ff67ba

3Kanner L. (1949). Problems of nosology and psychodynamics of early infantile autism. Am. J. Orthopsychiatry 19, 416–426

4Geschwind D. H. (2008). Autism: many genes, common pathways? Cell 135, 391–39510.1016/j.cell.2008.10.016

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Chemical and Biological Therapeutic Approaches to Neurological Disorders Symposium


On Monday 18th April, the 3rd symposium on Chemical and Biological Therapeutic Approaches to Neurological Disorders took place at Burlington House in London. Dr Paul Beswick and I (Tristan Reuillon) represented the Sussex Drug Discovery Centre (SDDC) at this one day conference, organised by the Royal Society of Chemistry. Paul gave a talk on the use of structural biology for the design of ligands for glutamate ionotropic receptors, an approach which has been and is being used on different projects at the SDDC, while I presented a poster on recent developments in the field of AMPA receptor positive allosteric modulators.

Some of the leading researchers in the field of neuroscience were presenting, such as Dr Eric Karran, former head of research at Alzheimer Research UK now at AbbVie or Prof John Hardy from UCL, recent winner of the Breakthrough Prize in Life Sciences for his pioneering research into the genetic causes of Alzheimer’s disease (AD). Dementia was the major focus of the symposium, with Dr Eric Karran introducing the statistics on AD and giving a detailed overview of the different theories believed to underlie AD (amyloid-beta (Aβ) and tau pathologies). According to Dr Karran the readouts of some critical clinical trials on AD drugs within the next two years will be extremely important to understand if the drug discovery efforts have been heading in the right direction and to guide further the current research on dementia. Prof John Hardy presented the genetic causes behind AD and amyloid deposition, with an emphasis on some specific proteins, such as TREM2, which represent very attractive drug discovery targets. Prof Nigel Hooper from the University of Manchester presented research focussed on Aβ, trying to identify what forms of Aβ oligomers and fibrils are neurotoxic and trying to link the alpha-secretase ADAM10 with Aβ production. Finally Dr Suchira Bose from Eli Lilly gave an in-depth analysis of the tau pathophysiology and different modulations of this physiological pathway which could lead to novel therapeutic approaches to AD.

Other neurological disorders were also discussed during the symposium. Dr Hasane Ratni from Roche presented the discovery of RG7800, a drug currently tested in phase II clinical trials for the treatment of Spinal Muscular Atrophy, a rare neurodegenerative disease affecting mainly children. RG7800 acts as a SMN2 splicing modifier. Dr Richard Mead from the University of Sheffield talked about his current research on Motor Neuron Disease, also termed Amyotrophic Lateral Sclerosis, with a focus on the NRF2-ARE pathway, an indicator and modulator of oxidative stress in neurodegeneration. Different attempts to identify activators of this pathway, such as apomorphine, were discussed. The presentation of Dr Paul Beswick on glutamate potentiators was centred on the identification of novel drugs to treat the cognitive dysfunction associated with Schizophrenia, a major symptom, for which there is a clear unmet medical need. Finally, Prof Kristian Stromgaard from the University of Copenhagen, presented a few drug discovery approaches that his group has undertaken to disrupt protein-protein interactions in the CNS, such as the PSD-95-NMDA interaction. Owning to the lack of success in identifying small molecule hits, his research has focussed on peptidomimetics, which are surprisingly brain penetrant and are currently in preclinical development.

I found this symposium extremely interesting, with some fantastic and innovative research being disclosed, and would highly recommend it for anyone interested in neuroscience research. I hope to have given you through this blog article a flavour of the different topics which were discussed on that day and maybe tempted you to attend the 4th symposium in this series which will take place next year.

 

Blog written by Tristan Reuillon