Boundary between ASD and the SchizophreniasJARRETT_BARNHILL

UNC SCHOOL OF MEDICINE

CHAPEL 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 childhood

High Functioning ASD, Multiple Complex Developmental Disorder (subset of PDD) may converge in adulthood

GWAS note shared risks with epilepsy, ASD, SCZ, learning disability, ADHD

22q11.2-d13.2, 15q11.2 duplication, catatonia are our foci.

Psychosis: Core Symptoms Hallucinations- spectrum of symptoms

Delusions – obsessive pre-occupations, fixed ideas

Thought disorder – illogical or disorders of association

Behaviors- “bizarre” is in the eye of the beholder

Variations due variability of ID

Intellectual Disability and Psychosis Genetic vulnerability exacerbated by decreased adaptive skills

Higher rates of comorbid neurodevelopmental disorders

Greater vulnerability to stress-induced psychotic symptoms

Disorganizing effects of mood and anxiety disorders, SUDs, iatrogenic disorders

Schizophrenias- Historically diagnosis based on clinically observable symptoms

Several subpopulations- simple, paranoid, catatonic and hebephrenia

Currently 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 pathway

Spectrum of disorders - dimensional relationship to schizotypal personality

Subtypes with differing neurobiology - paranoid versus nonparanoid

Positive versus negative symptoms

General Features

Premorbid findings - LD, asociality, attention deficits

Age of onset variables - gender differences

Prodromal - mood disturbance, schizotypal symptoms

Acute psychotic phase - positive symptoms

Relapsing 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 disorders

ASD 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 interactions

Dimensions 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 behaviors

Timing of gene expression, neuronal maturation, synaptic integrity and central coherence- 2nd trimester, over-populated by immature neurons without stable interconnections

Heritability, simplex v multiplex, inherited v gene mutations- gender effects, age of onset, severity and association with ID

22q 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 autisms

Seizure disorders more common with DD

Mood disorders, including a suggested links link between Asperger’s and bipolar disorder

Multiplex/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 abnormalities

Adaptive functions are generally more impaired relative to cognitive functions

Three 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 impairment

ASD 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 networks

Genetic 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 disorder

VEOS resemble PDD, motor incoordination up to around age 3, transition to schizophrenia between 5-7. (+/-) symptoms; behavioral disorganization in SPID/ASD

Prodrome, 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 infections

Maternal autoimmune disorders

Neurotoxin exposure- timing during gestation

ASD and SCZ have a variety of symptomatic endophenotypes- epilepsy, neurodegenerative disorders, metabolic disorders

Both 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>M

Rates 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 CPS

Catatonia

22q deletion syndromes- Velocardiofacial syndrome

15 q13.2 duplications

Multiple 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 rare

40% of Childhood SCZ may had a PDD.NOS diagnosis prior to the onset of psychotic features

Higher genetic loading for SCZ- 1st degree relatives with many of the neurophysiological deficits; ASD subtypes, expanded behavioral phenotype; role of co-occurring ID

Shared 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 anomalies

Present with ID, ADHD, expressive language disorders, poor verbal memory ASD-like symptoms

Depending on the size of the deletion, SHANK3, COMT, PDOH affected, immunological- T-cells- associated with autoimmune disorders, platelet issue, recurring infectious diseases, ? Responses to SGAPD

High 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 problematic

ASD, ID, Ataxia, SZ (complex),developmental delays, SCZ, MERRF (inverted duplication)

Cholinergic Receptor nicotine a7 affected, P50 (gating), GLUT/DA signaling

Relationship of psychosis to complex epilepsy

Relationship to PWS/Angleman’s- defect in GABA inter-neuron receptors

Progressive changes possibly related to MERFF like syndrome

Catatonia Origins in SCZ but now considered a complex behavioral syndrome with multiple etiologies

ASD high rates (10%) tends to underdiagnosed- passive subtypes may be at greatest risk

Freezing, mood disorders, movement disorders, metabolic/genetic /CNS lesions; medications side effects (APD-induced), confused with delirium, serotonin syndrome, malignant forms severe mania; stuporous forms

Currently conceptualized as an imbalance between excitatory/inhibitory pathways, endophenotypes of ASD and SCZ

Relationship to trauma-

Catatonia

Complex neuropsychiatric disorder, multidimensional etiology

Core symptoms: immobility, de-/increased speech output, stupor >1 day; and one of the following: catalepsy, automatic obedience, posturing

Criteria B: bradykinesia, akinesia/abulia; imitation/environmental dependency, freezing, stereotypies and movement disorders

Rush-Frances Catatonia Rating Scale-

Etiology- CatatoniaNMS, related hypermetabolic disorders

Nonconvulsive status, SCN1a syndrome

Elective mutism

Akinetic mutism Movement disorders- PD, on-off phenomona, Complex tics

Severe mood/anxiety disorder

Locked in syndrome CVA- biparietal, bifrontal, ant cerebral artery

Substance Abuse withdrawal, Wernicke’s

Stiff persons (GAD-25 antibodies

Delirium – multiple etiologies, PCP/ketamine

Physical/sexual abuse- freezing reaction, startle, autonomic hyperactivity

VGKC, nmda/ampa-r neuronal antibodies

End stage dementias, tau, synucleopathies, TDP 43

ASD- 10-17% prevalence rates, passive subtype

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 overlap

Affect 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 needs

Generally, no family history of SCZ, questionable subtype ASD (symptomatic v familial); A endophenotype of 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- divergence

Multiplex Dev Disorder, VCFS, 15q duplication- convergence

GWAS note overlap in genes making small contributions in epilepsy, SCZ, ASD, Language disorder, ADHD

Catatonia- a final common pathway that overlaps movement disorders, metabolic, immunological, neuro-pharmacological, Mood disorders, “PTSD”, SCZ and ASD

Thank you

If you want a copy of slides, email meJarrett_Barnhill@med.unc.edu