Atypical Neurodevelopment PDF

Atypical Neurodevelopment Two Examples of Atypical Neurodevelopment 1. Autism Spectrum Disorder 2. Williams Syndrome  Occurs 1 in 68 births – debate on incidence Autism 2 symptoms for diagnosis (in DSM*-5) Spectrum 1. Reduced capacity for social interaction and Disorder com...

Atypical Neurodevelopment Two Examples of Atypical Neurodevelopment 1. Autism Spectrum Disorder 2. Williams Syndrome  Occurs 1 in 68 births – debate on incidence Autism 2 symptoms for diagnosis (in DSM*-5) Spectrum 1. Reduced capacity for social interaction and Disorder communication 2. Restricted and repetitive patterns of behavior, interests or activities Other frequent non-diagnostic co-symptoms ▪ 75% are males ▪ Many suffer from intellectual of learning disability ▪ Many suffer from epilepsy *Diagnostic and Statistical Manual of Mental Disorders From: California Department of Developmental Services  Frombonne et al. (2006). Pediatrics, 118: 139. https://doi.org/10.1542/peds.2005-2993 Prevalence of ASD in Canada, 2019 Why an ▪ Environmental factor? increase in prevalence of ▪ Better early identification/diagnosis? ASD? ▪ Better awareness? Penn State University From: California Department of Developmental Services Apr 2003   Pre-COVID Post-lockdown Lockdown   Frombonne et al. (2006). Pediatrics, 118: 139. https://doi.org/10.1542/peds.2005-2993  ▪ Environmental factor? Why an Possibly, but not vaccines increase in prevalence of ▪ Better early identification/diagnosis? ASD? (2) Change in diagnostic criteria from DSM- III → DSM-IV → DSM-V ▪ Better awareness? More people seeking diagnosis for themselves/their children Self-advocacy Autism has recently (2013) been re-defined DSM IV DSM V DSM: Diagnostic and Statistical Manual of Mental Disorders  ▪ A highly heterogeneous disorder Features of ▪ Functions can be: impaired, normal, or Autism improved Spectrum ▪ Even those with with severe intellectual Disorder disability normally preserve: rote memory, musical and artistic abilities, the ability to solve jigsaw puzzles.  Heterogeneity in ASD: Savants ▪ Autistic Savants (about 10-30% of people with ASD) ▪ Savant: persons with intellectual disability who display amazing and specific cognitive or artistic abilities ▪ Some examples: o Naming the day of the week for any past or future date o Identifying prime numbers o Drawing o Playing musical instruments o Feat memory By a 5-year-old child with ASD  Neurobiological Bases of Autism Spectrum Disorder  Some genetic factors: Evidence for ▪ It runs in families (5% chances that a sibling Genetic of a child with ASD will also have ASD). Component of ▪ If one monozygotic twin has ASD, 60% ASD chance that the other has ASD too ▪ Approximately 5% of cases of ASD explained by a single genetic mutation What does this mean? → genetic factors interact with the environment in triggering autism Results from the Autism Genome Project Some chromosomes: Strong evidence for loci on chromosomes 7 and 17 Possibly also loci on chromosomes 2, 5, 11, 15, 16 and X Some genes: 1. Serotonin transporter on chromosome 17 2. A transcription factor (EN2) on chromosome 7 3. Several genes associated with glutamate action 4. Neurexin 1 on chromosome 11 For more information, see full list of AGP publications. Results from the Autism Genome Project (image 1) Among the hundreds, a functional network of mutations  Results from the Autism Genome Project (image 2) Many genes that are active during early to mid development Greater mutation load in females with ASD Many are de novo mutations – not present in family members Results from the Autism Genome Project: Functional Families of Genes 159 genes with de novo mutations fall into 4 clusters: 1. Chromatin/DNA modification/regulation 2. Postsynaptic density (critical for excitatory synapses functioning) 3. Neuronal signaling/cytoskeleton 4. Activity of many ion channels  ▪ One known environmental factor: thalidomide ▪ Prescribed for morning sickness → birth defects, cognitive effects, including ASD Morning sickness → First few weeks of Thalidomide pregnancy/prenatal development Frances Kelsey (1914-2015), the Canadian doctor who protected the Americans from thalidomide  ASD Neurological Phenotype ▪ Impaired face recognition o Increased risk of prosopagnosia o Difficulties recognizing emotions from faces o Reduced activation of the fusiform face area o Abnormal amygdala activation ▪ Reduced activation of the mirror neuron system o When looking at others performing actions (understanding others’ actions) 4 Phases of Brain Growth in ASD 1. Slight prenatal brain undergrowth “…the brain may be creating 2. Rapid and large brain abnormal connections that overgrowth at age 6-14 months make it very hard for autistic (predicts severity of ASD) children to make sense of the 3. Overall slow down in brain world they live in” growth rate at age 1-5 (Courchesne et al., 2003). 4. By adolescence brain size is no different from that of average healthy brains ASD and local brain connectivity ASD: short- and long-range hyperconnectivity Oxytocin and ASD 1. Children with ASD were shown to have reduced levels of plasma oxytocin 2. Children with ASD were shown to have a mutated form of the peptide. 3. Studies with OT administration show improvements in social domain: emotion recognition, eye contact, stereotypy, socialization, and communication. 4. Limited effect on other core symptoms, not currently viable as a single treatment. See: Aishworiya et al., 2022; Preti et al., 2014  Occurs 1 in 7500 people ▪ Intellectual disability → very low IQ (~55) Williams ▪ Amazing language abilities – very good use of voice intonation in acting out a story, very Syndrome talkative ▪ Very poor spatial and drawing skills ▪ Sociable, highly empathetic ▪ Very good at recognizing faces ▪ Preoccupation with a single subject/activity ▪ Musical talent  1. “Elfin” features Diagnostic Indicators of 2. Severe impairment in spatial cognition Williams 3. Many health problems, mostly cardiac Syndrome 4. Emotional immaturity (overreactions) Spatial vs. Language Abilities "And what an elephant is, it is one of the animals. And what the elephant does, it lives in the jungle. It can also live in the zoo. And what it has, it has long gray ears, fan ears, ears that can blow in the wind. It has a long trunk that can pick up grass, or pick up hay… If they are in a bad mood it can be terrible…If the elephant gets mad it could stomp; it could charge. Sometimes elephants can charge. They have big long tusks. They can damage a car… It could be dangerous. When they’re in a pinch, when they’re in a bad mood it can be terrible. You don’t want an elephant as a pet. You want a cat or a dog or a bird…"  ▪ Considered a genetic disorder ▪ The cardiac problems helped identify the major Genetic Causes genetic factor causing Williams syndrome of Williams ▪ A deletion in chromosome 7 involving 25+ genes Syndrome ▪ Gene for elastin, a protein that gives elasticity to organs and tissues ▪ 95% of people with Williams Syndrome lack the gene ▪ A blood test for elastin is now a good diagnostic test for Williams Syndrome Anatomical Anomalies Associated with Williams Syndrome ▪ Small occipital and parietal cortex May explain poor spatial abilities ▪ Normal frontal and temporal cortex May explain good speech capabilities ▪ Changes in the limbic system May explain high emotionality What can we learn from comparing the neurobiology of ASD and Williams Syndrome? AUTISM SPECTRUM DISORDER WILLIAMS SYNDROME ▪ Sometimes an intellectual disability ▪ Always an intellectual disability ▪ Multiple genes linked, mostly de novo ▪ Gene(s) on chromosome 7 mutations ▪ Typically socially avoidant ▪ High sociability ▪ Excellent spatial abilities ▪ Poor spatial abilities ▪ Preoccupation with a single ▪ Preoccupation with a single subject/activity subject/activity ▪ Musical talent ▪ Musical talent ▪ Emotional reactivity ▪ Emotional reactivity Genes and Environment: The case of “Genie” Highlights the critical importance of experience, but… Stories about children like Genie seldom give the full story.  28. Frombonne et al. (2006). Pediatrics, 118: 139. https://doi.org/10.1542/peds.2005-2993 29. Nevison & Zahorodny (2019). Figure 3. J. Autism Dev. Disord., 49: Image 4721. https://doi.org/10.1007/s10803-019-04188-6 30. Public Health Agency of Canada (2022). Figure 1. Autism References Spectrum Disorder: Highlights from the 2019 Canadian Health Survey on Children and Youth. https://www.canada.ca/en/public- health/services/publications/diseases-conditions/autism-spectrum- (cont’d) disorder-canadian-health-survey-children-youth-2019.html 31. Solmi et al. (2022). Figure 2. Mol Psychiatry 27: 4172. https://doi.org/10.1038/s41380-022-01630-7 32. Lord (2011). Figure 1. Cell, 147: 24. https://doi.org/10.1016/j.cell.2011.09.017 33. Chang et al. (2015). Figure 1. Nature Neurosci., 18: 191. https://doi.org/10.1038/nn.3907 34. Krishnan et al. (2016). Figure 3. Nature Neurosci., 19: 1454. https://doi.org/10.1038/nn.4353 35. Keown et al. (2013). Cell Reports, 5: 567. https://doi.org/10.1016/j.celrep.2013.10.003 36. Supekar et al. (2013). Cell Reports, 5: 738. https://doi.org/10.1016/j.celrep.2013.10.001