HMB200H1 Final: L10 What is Autism?

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Human Biology
Franco Taverna

Lecture 10 What is Autism? Is Autism Simply an Adaptation to an Intense World? Kolb & Whishaw 5E: § Clinical Focus 8.2 Autism Spectrum Disorder “What are ASDs”, “What is ASD” Crawley (2008), Bourgeron (2015), Garber (2007) Why did the chicken cross the road? Tuesday, March 28 Lecture Outline: • Development of nervous system and how it’s shaped by environment I. What is Autism Spectrum Disorder? • Signaling and plasticity at the synapse II. Possible Causes of ASD • Motivated and reproductive behaviours, addictive behaviours III. Genetics of ASD IV. Phenotypes of ASD • Fear conditioning, learning and memory (implicit and explicit) V. Case Study: R451C Mouse Model of ASD We can approach this question from many different aspects, but we need to understand how to study this. What is Autism? “Autism Spectrum Disorder (ASD), also called ‘Autism’, is a According to Geneva Centre for Autism… lifelong neurodevelopmental disorder that affects how • There are other potential disabilities involved in other subtypes, but people communicate and relate to others. The range and communication/interaction and repetition are the most common intensity of disability varies, but all people affected by ASD • Personal perceptions are at the heart of how we acquire knowledge – have difficulty with communication, social interaction, and Daniel Tammet restricted or repetitive interests and actions. Many have o Marvel observations difficulty responding appropriately to their environment. The Autism “Spectrum” • • “Rage for Order” “I was intrigued by both the narrowness and the complexity of these • Preoccupations vs. perception preoccupations.” – Oliver Sacks • Which is it? “Here are the numbers 1-12 as I see them… I pull them all together into a rolling, numerical landscape.” – Daniel Tammet Origins of the Term “Autism” – Busting Myths • Psychiatry was considered of the mind, but not necessarily Autism biological • The word “autism” was coined by Eugen Bleuler to describe one • Along with 10 other children that presented to Dr. Kanner with of the core features of schizophrenia, “detachment from reality” similar symptoms, he published a paper called Autistic (Autos, in Latin means “he himself”) Disturbances of Affective Contact • Invented the category of early infantile autism, borrowing the o Dementia Praecox oder Gruppe der Schizophrenien, in Anschaffenburg, G. ed., Handbuch der Psychiatrie (1911) term from schizophrenia from decades prior • As a result, autism was identified as a term of psychiatry and psychoanalysis • Note that at that time, psychological ≠ biological Leo Kanner, 1938 • Donald T., 5-year-old • “…happiest when he was alone… drawing into a shell and living within himself… oblivious to everything around him.” – Donald’s father • “Autistic Disturbances of Affective Contact,” Nervous Child 1943; 2:217-50 • Kanner invented a new category: Early Infantile Autism, borrowing the term “autism” from Bleuler • Autism Spectrum Disorders Autism is referred to as a “spectrum disorder” because the symptoms and characteristics of autism can present themselves in a variety of combinations and degrees of severity, ranging from mild to severe. • The word spectrum is accurate Common traits of autism include: • 1-5 involve social communication, 6-7 social interaction, 8-11 repetitiveness • Unusual use or lack of communication skills • Difficulty with back-and-forth social interactions • Reduced appreciation of others’ interests or emotions • Unusual use or lack of eye contact • Unusual use or understanding of body language • Challenges in developing, maintaining, and understanding relationships • Insistence on sameness and routines • Fixated interests often in unusual topics and objects • Difficulty with large and small transitions • Over- or under-responsiveness to sensory input • Unusual focus on specific sensory aspects of the environment (e.g., background sounds, reflections, etc.) • Language impairment has been de-shaded from the blue and off to the gray • We see that mood, anxiety and hyperactivity are commonly associated (perhaps due to sensitivity) • When we look at the interactions of associated issues, we can see that it’s very easy for comorbid disorders to manifest 2 Autism Spectrum Disorder, DSM V Diagnostic Criteria A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text). 1. Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions. 2. Deficits in nonverbal communicative behaviours used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication. 3. Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties adjusting behaviour to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers. Severity specified: e.g., Level 1-3, mild to severe B. Restricted, repetitive patterns of behaviour, interests or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive, see text). 1. Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypes, lining up toys or flipping objects, echolalia, idiosyncratic phrases). 2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal-nonverbal behaviour (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat food every day). 3. Highly restricted, fixated interests that are abnormal in intensity or focus (e.g., strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interest). 4. Hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment (e.g., apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement). Severity specified: e.g., Level 1-3, mild to severe C. Symptoms must be present in the early developmental period (but may not • We don’t used the disorder fast and loose, it become fully manifest until social demands exceed limited capacities, or involves an impairment in the ability to live and may be masked by learned strategies in later life). thrive in today’s society D. Symptoms cause clinically significant impairment in social, occupational, or • Many potential factors that go into it when we other important areas of current functioning. consider whether something is a disorder or not E. These disturbances are not better explained by intellectual disability • Some symptoms can manifest themselves in many different ways (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level. Specify if: With or without accompanying intellectual impairment With or without accompanying language impairment Associated with a known medical or genetic condition or environmental factor 3 Autism Spectrum Disorder: Common Impairments • Social deficits and repetitive behaviours The Spectrum of Behaviours • In terms of social deficits, where do we draw the line between shyness, social Where should the disorder threshold be placed? anxiety, other factors such as language barriers, etc.? What else does the placement of disorder threshold depend on? • Often, the mark on the spectrum can be fairly narrow – such that not much of a shift can get you past the threshold from disordered to not disordered – makes sense if the brain is influenced by the environment Is There a Better Way to Diagnose a Brain-Based Disorder? • Research is easier at the extremes of the spectrum, specifically in behavioural neuroscience • Currently, diagnosis in mental disorder (including ASD) is based on clinical observation and patients’ • Aside from behavioural symptoms, we can use physical abnormalities, or some kind of biological or genetic differences, neuroimaging scans, phenomenological symptom reports developmental/network/neurotransmitter differences o This is the basis of the DSM used by clinicians • Apparently, psychiatry and psychology treatments for disorders aren’t • How could these diagnoses in mental disorders be helpful because they aren’t exhaustive – but neither is medicine… improved? • What is missing in this information? Research Domain Criteria (RDoC) • Current diagnoses are mostly NOT informed by recent breakthroughs • Looks at genetic and biological factors, at the moment, in genetics, molecular, cellular, and systems neuroscience specific to research • We recognized that most, if not all, brain-based disorders are NOT • Many of the syndromes and conditions that we recognize unitary; rather variable in symptoms and severity and diagnose have significant overlap in their biological • Recognized syndromes are very likely comprised of distinct mechanisms • Goal is to determine the source or origin of these disorders subgroups, likely comprising of clusters of complex behaviours and conditions, in order to better inform diagnosis and • RDoC is intended as a framework to guide classification of patients specific treatment for research studies, not (yet) as an immediately useful clinical tool • Currently, criteria are based on behaviours and self reports • Goal might be to eventually use biological criteria to help with • RDoC tries to consolidate categories and constructs of diagnoses, and inform more specific treatment behaviours into five families that capture just about everything • This is a work in progress, so they may shift around • Diagnoses do become checklists • Using this matrix, we can see where the biological issues lie – at the level of the network, cells, molecules, or genes 4 MMR Vaccine Does NOT Cause ASD Findings: Onset… associated by parents with the MMR vaccine (8 children). 9 diagnosed with autism. Immediate Criticism of the Paper “This anecdotal reporting of a biased sample is poor science and has no place in a peer-reviewed journal. … considerable evidence has been collected by others to suggest that it does not exist. … Children are being put at risk form potentially lethal infectious diseases not by new reliable evidence but by media coverage of another badly designed study by this group.” – DR Walker; The Lancet, Volume 351, Issue 9112, Page 1355. Allegations of fraud related to the article: • AJ Wakefield was subsequently found to be receiving payments form lawyers of a group who organized the 12 families to sue the vaccine manufacturer • Investigation revealed over $500,000 in payments • Later revealed that AJ Wakefield was part of a group developing a rival MMR vaccine ASD Not Associated with MMR Vaccine Large population-based epidemiological studies have shown no association • We need to move forward from this, because children are not being vaccinated and are duing between MMR and autism. • There are children who can’t be vaccinated for various • Finland: 3 million vaccinations, 31 developed intestinal side effects. Of reasons, but are protected by herd immunity because the those, none had autism, 10 years later. rest of us are vaccinated o No evidence for measles, mumps, and rubella vaccine- • If children aren’t vaccinated when they should be, they associated inflammatory bowel disease or autism in a 14-year face a higher chance of death prospective study. Peltola H, Patja A, Leinikki P, Valle M, Davidkin I, Paunio M. Lancet 1998; 351:1327-8 • Five cohort studies involving 1,256,407 children, and five case-control studies involving 9,920 children were included in this analysis. The data reveal no relationship between vaccination and autism. o Vaccines are not associated with autism: An evidence-based meta-analysis of case-control and cohort studies. Luke E. Taylor, Amy L. Swerdfeger, Guy D. Eslick 5 Environmental Causes of ASD This is an interesting area, and difficult to take associations and convert them to Gestational associations (small epidemiological studies): causations. • Maternal rubella infection • ASD diagnosis is not uncommon – more than 1 in 100 children • Ethanol (alcoholism) • Misoprostal (anti-ulcer) • There doesn’t seem to be hot spots, so environmental causes are a little difficult to ascertain • Thalidomide • Evidence points to the most vulnerable period as being very early in gestation • Valproic acid (anti-convulsant) when the neural tube is closing and there is rapid development of the nervous • Evidence that environmental insults are most system damaging during weeks 3 and 4 of gestation (neural tube closure) • Range of affected offspring: 5-25% • For VPA, high-functioning ASD or Asperger’s Genetic Causes of ASD • It’s not 100%, so there must be something else other than genes that’s • ASD concordance identical twins: 60-90% contributing to the incidence and prevalence of ASD • ASD concordance fraternal twins or siblings: 0-30% • Within families of someone diagnosed with autism, some of the behavioural • Siblings and parents are more likely to show some symptoms do manifest in parents and siblings • Genetic factors account for at least 38-90% of phenotypic variances typical cognitive or behavioural features • Genetic factors account for at least 38-90% of the o Percentage of variance that can be accounted for by genetics phenotypic variance o A lot is also not accounted for my genetics • There are several X-linked syndromes that have ASD symptoms There are X-linked syndromes with ASD symptoms: • Fragile X (FMR1) • Rett’s syndrome (MECP2) Many Genetic Syndromes Have Associated ASD Symptoms • Some are very high and some not as high • When you add all of these together, they add up to a very low percentage of the total autism cases • Well known genetic cases don’t add up to a large percentage to the causes of autism • These are all recognized disorders and have concordance or autism symptoms ASD Genetics 1. First genetic link for autism: Xp22.3 genetic locus deleted in There are cases where it’s just autism without comorbid disorders. several ASD females • Pair of siblings with autism had mutation in neuroligin-3 2. Neuroligin-3 (R451C mutation found in one Swedish pair of o Gene had single point mutation in codon siblings with ASD); only human ASD with this mutation o Gene is 451 3. Neuroligin-4 mutation found in one Swedish pair of siblings; o Mutation in codon changed arginine to cysteine (R and C) • Many polymorphisms found in NLGN4 – high penetrance many polymorphisms now found, very high penetrance o Seems to have a high risk factor for autism X-linked gene mutations affect males more than females. o Relatively few families • All are X-linked mutations (lower penetrance in heterozygote • So far, individual genes associated with ASD have been state) identified in very few families, so what is causing the rest? 6 R451C: Single Nucleotide Polymorphism • Natural variants, individual nucleotides that are different between individuals – these Single nucleotide polymorphism (SNP): simplest type of genetic variation is a substitution of one are polymorphisms base for another at a single site • There are 10 million SNPs between any two individuals o Vast majority don’t cause protein changes (happen in introns, not exons) • 10 million known SNPs in the human genome o Result from copying errors of DNA during mitosis • R541C – codon coded for cysteine instead or arginine o Most don’t cause protein sequence changes or disease • SNPs result from copying errors of DNA during the process of cell division New and Powerful Tools Now Being Used to Map ASD-Related Genes “Truth is stranger than fiction, but it is because fiction is obliged to stick to possibilities; truth isn’t.” – Mark Twain Genetic Variances in ASD An individual has, on average, 3,000,000 (0.1%) genetic variants… • CNV deletion, then copy number would be zero • CNV insertion can be anywhere from two to many • Single nucleotide variants (polymorphisms, SNPs) • Variability is the rule, not the exception • Short insertions or deletions (copy number variants, CNVs) • Most of the time, variance doesn’t outright cause a disorder or Most (95%) are very common (shared with > 5% of people). Every disease, but might alter the risk one of us carries 40-100 disease-associated variants; variants are the o Accumulation of many variants can increase risk even more, with synergistic effects rule, not the exception. • Very few variants have high risk (e.g., sickle cell anemia, cystic • Most variants alter risk of a disease fibrosis) • Most disease variants are low penetrance (low risk, need many variants to develop a disease) • Very few are high penetrance (high risk, one variant  disease) o E.g., neuroligin • Less than 1% of variants are very rare or unique Copy Number Variants • Sequencing DNA looking for genes, it’s been impossible Copy number variants (CNVs): insertions and deletions of chunks of DNA to tell how many copies there are sequence • Now, through various techniques like microarrays, you can measure how strong the signal is and infer the • SNP array signal intensities; can measure copy number differences number of copies of sequences between samples E.g., an 11kb deletion on chromosome 8 revealed by ultra-high resolution CGH. Blue lines: individuals with two copies; red lines: individuals with zero copies. 7 Autism Genome Project Consortium (AGPC) • Trying to look for genetic differences between controls and autism Staring in 2002, 137 researchers from 8 countries formed the Autism Genome Project. • Led in Canada by Stephen Scherer, Hospital for Sick Children and Dr. Peter Szatmari of the Offord Centre for Child Studies, McMaster University • Scientists from 50 centres in North America and Europe collecting 1,496 ASD families with two or more children with autism (7,917 family members) for this study AGPC Phase 1 Results Mapping autism risk loci using genetic linkage and • Phase 1 produced no results – no glaring disease gene that was responsible for many cases of autism chromosomal rearrangements (AGPC, Nature Genetics 2007). • Amongst these individuals with autism, there are many many different genes that are at play, so there’s not a strong enough signal from any one gene • Linkage analysis only produced one strong disease loci that’s coming up over the others • Suggests a different cause in each family, perhaps • Each family might have a unique cause
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