Download Boundary between ASD and the Schizophrenias

Boundary between ASD
and the Schizophrenias
JA R R ET T_BA RNHI LL
UN C S CHOOL OF ME DI CINE
CHA P E L HI L L , N C
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
SchizophreniasHistorically 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 Syndrome22q 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- Catatonia
NMS, related
Nonconvulsive status,
hypermetabolic disorders SCN1a syndrome
Elective mutism
Akinetic mutism
Movement disorders- PD, Severe mood/anxiety
on-off phenomona,
disorder
Complex tics
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 abusefreezing reaction, startle,
autonomic hyperactivity
VGKC, nmda/ampa-r
neuronal antibodies
End stage dementias, tau, ASD- 10-17% prevalence
synucleopathies, TDP 43 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
ConclusionsThe boundary between SCZ spectrum and ASD has an semi-permeable borderneed 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
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