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Boundary between ASD and the Schizophrenias - NADD

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Boundary between ASD and the Schizophrenias
Jarrett_BarnhillUNC School of MedicineChapel Hill, NC
Goals
We are on a journey into the world of boundary violations,Autism Spectrum Disorders and Schizophrenia Spectrum Disorders, especially Childhood onset or Very Early onset Schizophrenia overlap but then diverge during childhoodHigh Functioning ASD, Multiple Complex Developmental Disorder (subset of PDD) may converge in adulthoodGWAS note shared risks with epilepsy, ASD, SCZ, learning disability, ADHD22q11.2-d13.2, 15q11.2 duplication, catatonia are our foci.
Psychosis: Core Symptoms
Hallucinations- spectrum of symptomsDelusions – obsessive pre-occupations, fixed ideasThought disorder – illogical or disorders of associationBehaviors- “bizarre” is in the eye of the beholderVariations due variability of ID
Intellectual Disability and Psychosis
Genetic vulnerability exacerbated by decreased adaptive skillsHigher rates of comorbid neurodevelopmental disordersGreater vulnerability to stress-induced psychotic symptomsDisorganizing effects of mood and anxiety disorders, SUDs, iatrogenic disorders
Schizophrenias-
Historically diagnosis based on clinically observable symptomsSeveral subpopulations- simple, paranoid, catatonic and hebephreniaCurrently classified as a subset of psychoses associated with primary symptoms of psychosis (hallucinations, delusions, cognitive, emotional and behavioral disorganization) based on positive and negative symptoms, age of onset, severity markers (duration of symptoms, degree if functional impairment but exclusion neurological and other etiological features of psychosis.Research suggests it is a heterogeneous neurodevelopmental disorder
Schizophrenias
Syndrome with several phenocopies - possible final common pathwaySpectrum of disorders - dimensional relationship to schizotypal personalitySubtypes with differing neurobiology - paranoid versus nonparanoidPositive versus negative symptoms
General Features
Premorbid findings - LD, asociality, attention deficitsAge of onset variables - gender differencesProdromal - mood disturbance, schizotypal symptomsAcute psychotic phase - positive symptomsRelapsing and progressive course - negative symptoms
What exactly are spectrum disorders?
Mistaken assumption that psychiatric disorders are discrete syndromes- how to avoid the pessimism of dimensional complex neuropsychiatric disordersASD is classified as a Neurodevelopmental Disorders, Schizophrenia is not- most evidence towards both as highly heritable, complex genetic disorders, but developmental trajectory of gene-environment interactionsDimensions can vary from age of onset, clinical course, and phenomenology; neurobiology; overlapping brain-behavior, neuropharmacological profiles
Autism Spectrum Disorders
Classified based on early age of onset, deficits in social communication and proneness to restrictive and repetitive cognitions and behaviorsTiming of gene expression, neuronal maturation, synaptic integrity and central coherence- 2ndtrimester, over-populated by immature neurons without stable interconnectionsHeritability, simplex v multiplex, inherited v gene mutations- gender effects, age of onset, severity and association with ID22q 11-13 deletions, 15q13 duplications, MCP2; multiple genes involved
ASD: Neuropsychiatric Comorbidities
Intellectual disability is present in most (70%) and shapes symptomatology and risk for symptomatic or secondary autismsSeizure disorders more common with DDMood disorders, including a suggested links link between Asperger’s and bipolar disorderMultiplex/ASD- affective, cognitive, behavioral instability, VCFS and psychosis
ASD- Core Features
70% of those with ASD have ID, severity of ID and ASD interrelated, SZDO/EEG abnormalitiesAdaptive functions are generally more impaired relative to cognitive functionsThree super families: relatedness to other autosomal neurodevelopmental syndromes; polygenic form related to a broader phenotype; disintegrative/late regressive
Fundamental differences
If both are spectrum disorders, then what characterizes the split- hallucinations, delusions, thought disorder, and progressive functional impairmentASD excludes these positive symptoms but 10 % may go on to develop AVH, delusions; the problem may be recognition; Very early onset Schizophrenia overlap with ASD.ASD with communication/repetitive behaviors as most prominent findings diagnosed quite early, male female 4-8:1; peak age of onset 20 for M; mid-late 20’s females; 1:1 gender ratio, appears to be a long prodrome, waxing/waning course;
Fundamental Differences- cont’d
Pattern of neurogenesis, migration, maturation and stability of dendrites, myelination, maturation of excitatory/inhibitory networksGenetic risks- polygenic. MZ>DZ, VEOS- genetic loading for SCZ; ASD two subtype- hereditary/spontaneous mutation- higher risk of ID in ASD mutation group; higher M:F ratio in hereditary ASD. SZ disorderVEOS resemble PDD, motor incoordination up to around age 3, transition to schizophrenia between 5-7. (+/-) symptoms; behavioral disorganization in SPID/ASDProdrome, attenuated symptoms, onset schizophrenia (early 20’s in M: late 20’s in females; negative symptoms- outcome
Shared risk factors
Parental age, timing of prenatal insults, intrauterine infectionsMaternal autoimmune disordersNeurotoxin exposure- timing during gestationASD and SCZ have a variety of symptomatic endophenotypes- epilepsy, neurodegenerative disorders, metabolic disordersBoth involve time sensitive changes in neuronal maturation, overlapping genetic markers associated with neuronal migration, maturation, synaptic integrity, neurotransmitter functions, glial cell maturation
Specific gap closers- convergence
Problems arise with severe/profound ID, more common in ASD but often precludes the diagnosis of SCZ. Psychosis in ASD- higher functioning group, F>MRates of SZDOs- SPIDD, gene markers, increase the risk for SZ in ASD and more complex forms of epilepsy, emerge during adolescence . Schizophrenia-like Psychosis (SLP) more common in CPSCatatonia22q deletion syndromes- Velocardiofacial syndrome15 q13.2 duplicationsMultiple Complex Developmental Disorders- Asperger’s +
More differences- the Paradox of Childhood onset SCZ
1970’s both were segregated from Childhood schizophrenia, both were very rare (4/10,000); ASD underdx; VEOS, extremely rare40% of Childhood SCZ may had a PDD.NOS diagnosis prior to the onset of psychotic featuresHigher genetic loading for SCZ- 1st degree relatives with many of the neurophysiological deficits; ASD subtypes, expanded behavioral phenotype; role of co-occurring IDShared alleles (SNPs/CNVs) with epilepsy, ID, learning disabilities but different frequencies in parental pedigrees
Velo-cardio-facial Syndrome-22q 11.2-13.3 del
Genetic disorder with highly diverse morphological anomaliesPresent with ID, ADHD, expressive language disorders, poor verbal memory ASD-like symptomsDepending on the size of the deletion, SHANK3, COMT, PDOH affected, immunological- T-cells- associated with autoimmune disorders, platelet issue, recurring infectious diseases, ? Responses to SGAPDHigh for SCZ- 1/3 may develop symptoms later than SCZ, fewer negative symptoms in spite of COMT, delusions/disorganization,
15 q 11.2-13.1 duplications
Two subtypes, interstitial duplication (maternal) is most problematicASD, ID, Ataxia, SZ (complex),developmental delays, SCZ, MERRF (inverted duplication)Cholinergic Receptor nicotine a7 affected, P50 (gating), GLUT/DA signalingRelationship of psychosis to complex epilepsyRelationship to PWS/Angleman’s- defect in GABA inter-neuron receptorsProgressive changes possibly related to MERFF like syndrome
Catatonia
Origins in SCZ but now considered a complex behavioral syndrome with multiple etiologiesASD high rates (10%) tends to underdiagnosed- passive subtypes may be at greatest riskFreezing, mood disorders, movement disorders, metabolic/genetic /CNS lesions; medications side effects (APD-induced), confused with delirium, serotonin syndrome, malignant forms severe mania; stuporous formsCurrently conceptualized as an imbalance between excitatory/inhibitory pathways, endophenotypes of ASD and SCZRelationship to trauma-
Catatonia
Complex neuropsychiatric disorder, multidimensional etiologyCore symptoms: immobility, de-/increased speech output, stupor >1 day; and one of the following: catalepsy, automatic obedience, posturingCriteria B: bradykinesia, akinesia/abulia; imitation/environmental dependency, freezing, stereotypies and movement disordersRush-Frances Catatonia Rating Scale-
Etiology- Catatonia
Multiple Complex Developmental Disorder
Defines a subgroup, mainly PDD.NOS or Asperger’s (ASD, Mild v Social Communication pragmatic Disorder) with increased risk for late onset SLP; 78% -At Risk Mental State for SCZ- high degree of overlapAffect dysregulation with chronic anxiety; impairment is social relatedness (empathy over the distress of others), cognitive processing, confusion between reality-fantasy -over identification with Anime characters); paranoia/referential thought (nonsystematized); poor motor control; ODD like behaviors towards commands/daily living needsGenerally, no family history of SCZ, questionable subtype ASD (symptomatic v familial); Aendophenotypeof SCZ/ASD
Conclusions-
The boundary between SCZ spectrum and ASD has an semi-permeable border- need for endophenotyping; avoided boundary issues between OCD and related syndromes and both for another time.PDD.NOS has a boundary Childhood onset SCZ- divergenceMultiplex Dev Disorder, VCFS, 15q duplication- convergenceGWAS note overlap in genes making small contributions in epilepsy, SCZ, ASD, Language disorder, ADHDCatatonia- a final common pathway that overlaps movement disorders, metabolic, immunological, neuro-pharmacological, Mood disorders, “PTSD”, SCZ and ASD
Thank youIf you want a copy of slides, email meJarrett_Barnhill@med.unc.edu

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Boundary between ASD and the Schizophrenias - NADD