Veronika Borbélyová, MSc., PhD.

borbelyova.veronika88@gmail.com

History • Eugen Bleuler

• autism (from the Greek words autos = self, ismus = orientation, status)

• the patient reduces the contact with the outside and he drifts into his own world (Bleuler, 1911)

• Leo Kanner • “early infantile autism” • the inability of the child to relate to people and objects

in an appropriate manner

• lack of social relatedness = “extreme autistic aloneness”

• difficulties in adapting to changes in routines, the desire for sameness, impaired speech, limited spontaneous activity and abnormal reactions to some common stimuli from the environment (Kanner, 1943).

History

• Hans Asperger

• children with impaired social interaction, motor stereotypies and clumsiness, stereotyped interests and impaired communication

• well-developed language and high intelligence (Asperger, 1944)

History

Autism Spectrum Disorder (ASD)

Survaillance year Number of ADDM

Sites Reporting Prevalence/

10 000 children

This is about 1 in X children

[year of publication]

2000 6 67 1 z 150 [2007]

2002 14 66 1 z 150 [2007]

2004 8 80 1 z 125 [2009]

2006 11 90 1 z 110 [2009]

2008 14 113 1 z 88 [2012]

2010 11 147 1 z 68 [2014]

2012 11 146 1 z 68 [2014]

Autism and Developmental Disabilities Monitoring (ADDM) Network

>

1 z 45

Prevalence of autism spectrum disorder (ASD) (ADDM Network: 2000 – 2012)

What is the exact cause of the higher rates of ASD?

• Still not clear

•different methodologies used across studies •different screening and diagnostic instruments •the ever-changing diagnostic criteria for the disorder •the increased public awareness and increased availability of educational services •inaccurate diagnoses •geographical location (rural or urban area) • variations in the size and type of the target population

How is ASD diagnosed?

• No medical test that can diagnose autism

• autism-specific behavioral evaluations - specially trained physicians and psychologists

• parents notice the first signs of unusual behaviors

How is ASD diagnosed? • The most overt symptoms tend to emerge 6 months

after birth

• However, some studies suggest that differences in development can be observed around 2 to 12 months of age

• “red flags” (signs that appear by 12 months of age in typically developing children)

• ICD-10

• DSM-V

Screening tools

• CHAT (Checklist for Autism in Toddlers)

• M-CHAT (Modified Checklist for Autism in Toddlers)

• STAT (Screening Tool for Autism in Toddlers and Young Children)

• SCQ (Social Communication Questionnaire) ASSQ (Autism Spectrum Screening Questionnaire) CAST (Childhood Autism Spectrum Test)

ARCA (Academic Research Center for Autism) - 2013

• Prof. Ostatníková et al.

• Clinical Servis • Education • Research

https://vyskum-autizmu.webnode.sk/

Etiology

• The specific cause of ASD is still unknown

• Multifactorial disease :

– Psychological

– Environmental (non-genetic)

– Genetic

Psychological factors

• Theory of mind: expresses the ability to infer the

mental states of other people by observing their behavior

• Theory of executive dysfunction: executive function -

mechanisms that allow us to focus our attention and control impulsive reactions

• Weak central coherence theory: basic deficit in autistic

children is the inability to integrate information into coherent or meaningful wholes

• Empathizing-systemizing theory

• Measuring the strength of interest in empathy (E)

• Measuring the strength of interest in systems (S)

• 5 groups of people

Psychological factors

S – ♂

E – ♀

• Sex differences in E and S (experience and socialization ) • fetal testosterone

• fetal testosterone concentration positively correlates with

systemizing ability and negatively correlates with empathizing ability

• The extreme male brain theory : ↑ fetal testosterone concentrations ↑ autistic phenotype.

(Baron-Cohen a kol., 2005)

Environmental factors

• BEFORE CONCEPTION/PRENATAL RISK FACTORS:

– Parental age

– Maternal physical health (bleeding, and mother infection during

pregnancy)

– Maternal mental health (depression, anxiety)

– Maternal prenatal medication use

(valproate, thalidomide)

Environmental factors

• NATAL RISK FACTORS

• preterm (<35 weeks) and postterm pregnancy (>42 weeks

• bleeding during pregnancy

• fetal complications (umbilical-cord complications and cesarean delivery (26% increased risk of autism) – hypoxia

Environmental factors

• POSTNATAL RISK FACTORS

– Low birth weight (<2500g)

– Jaundice

– Postnatal infection

Genetic factors

• ASD – a gene-based disorder • monozygotic twins – (60-90%) • dizygotic twins – (10%)

• genetic research - to identify candidate genes of ASD • the number of ASD-implicated genes: 200 – 1000

• many of these genes are also associated with other

neurodevelopmental disorders (epilepsy and schizophrenia)

Risk genes for ASD

Genetic syndromes associated with ASD

• Fragile X syndrome (FXS)

• Down syndrome (DS)

• Tuberous sclerosis

• Neurofibromatosis

• Phenylketonuria

Syndromic and non-syndromic autism

• predominantly ‘non-syndromic’ or ‘idiopathic’ autism

• autism coincides with a genetic syndromes (FXS, DS etc.) - ‘syndromic’ autism

What differentiates individuals with syndromic autism from those with FXS or DS in isolation?

What differentiates individuals with syndromic autism from those with FXS or DS in isolation?

Animal models of autism

1. Animal models based on lesions in specific areas of the brain

2. Animal models based on modifications of the genome – use either transgenic animals (mainly knockout mice) or spontaneous mutants

3. Microtine model – Montane vole model

SHANK 3 gene

• SH3 and multiple ankyrin repeat domains 3

• Cytogenetic Location: 22q13.33

SHANK 3 protein

• scaffold protein at excitatory synapses

• functioning of synapses (cell to cell communication)

• formation and maturation of dendritic spines (transmission of nerve impulses)

SHANK 3 and ASD

• ~ 43 SHANK3 gene mutations:

1. disruption of the function of the SHANK3 protein

2. prevention of the the protein production

disruption in cell to cell communication

ASD

SHANK proteins – mice

• Encoded by SHANK1,2,3 genes

• Shank1 gene – mouse chromosome 7B4

• Shank2 gene – mouse chromosome 7F5

• Shank3 gene – mouse chromosome 15E3

CNS expression • SHANK1 – cortex, thalamus, amygdala, hippocampus

(CA1 and CA3), cerebellum

• SHANK2 – cortex, thalamus, hippocampus (CA1 and CA3), dentate gyrus, cerebellum, (kidney and liver)

• SHANK3 – heart, spleen, cortex, thalamus, striatum, hippocampus (more in CA3 than in CA1), dentate gyrus, cerebellum

SHANK3 isoforms expression in the brain

The link between SHANK genes and ASD

• ASD – etiologically heterogenous

• mutations or disruptions in the SHANK gene family account for ~1% of all patients with ASD

• correlation between SHANK1–3 mutations and the degree of cognitive impairment

• difference in impairment severity - expression pattern of the mutated SHANK gene

• Is autism reversible in adulthood?

• re-expression of the Shank3 gene in adult mice:

– improvements in synaptic protein composition, spine density and neural function in the striatum

– social interaction deficit and repetitive grooming behavior - rescued

– anxiety and motor coordination deficit - not recovered

3 HIT model

1. Genetic factor (Cntnap2-/-)

2. Environmental factor (LPS-MIA)

3. Sex (male mice)

autism

Science at IMBM

• IMBM is not a standard research institute focusing on one molecule in one pathomechanism

• Different research background of people in our labs

ecDNA

• The extracellular DNA (plasma) • Measuring the activity of the enzyme that cleaves this DNA -

deoxyribonuclease (DNase)

• The exogenous application of this enzyme is protective in sepsis, liver and kidney injury

• Any inflammation leads to an increase of extracellular DNA - IS activation

• We try to uncover the details of its role in sepsis, colitis and periodontitis in both, animal experiments and clinical studies

Inflammation and autism

Prenatal testosterone and ASD

Metabolic syndrome

Steroid hormones

Acute and chronic kidney injury

borbelyova.veronika88@gmail.com

www.imbm.sk