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Autism Flashcards

1
Q

What is autism?

A

Autism is a neurodevelopmental disorder resulting from impairment of growth and development of the cerebrum

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2
Q

When was autism first identified as a condition?

A

Leo Kanner in 1943 studied 11 children diagnosed with schizophrenia with the same key symptoms. These were aloneness, bizarre repetitive routines, muteness and abnormal speech which he termed the children autistic.

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3
Q

How is the diagnosis of autism made?

A

Diagnostic and Statistical manual of Mental Disorders- V (DSM-V) characterises the disorder with two criteria; the patient must exhibit deficits in social communication & interaction and a restricted & repetitive behaviour.

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4
Q

Epidemiology of Autism

A

1 in every 100 people in the UK has ASD (NHS, 2016). There has been a 600% increase in the prevalence of autism in the last 20 years and at least 25% can be attributed to the change in diagnosis criteria set.

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5
Q

Cost of Autism and effect on work

A

Huge cost and only 16% of autistic adults in the UK are in full-time paid employment, and only 32% are in some kind of paid work (National Autistic Society, 2016).

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6
Q

Aims of the essay - 3 choices

A

Syndromic autism acts as a gateway to explore the genetic aetiology of the disease which allows the potential to identify risks and treatment strategies.
Animal models have provided valuable insight into the genetic basis of autism and its treatments
ASD has a multifactorial inheritance with environmental factors playing a influential part, I will look into some of the common factors associated with ASD

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7
Q

Name the three genetic diseases associated with autism risk

A

Tuberous Sclerosis Complex
Fragile X syndrome
16p11.2 deletion syndrome

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8
Q

What is TSC and how common is it?

A

Tuberous Sclerosis complex is an autosomal dominant disease affecting 1 in 6,000 people.

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9
Q

What did Curatolo et al., 2015 state about TSC?

What are the symptoms and other signs seen in TSC?

A

It is caused by mutations in either the TSC1 gene on c9 or the TSC2 gene on c16 which encode for hamartin and tuberin respectively.
Involved in the mammalian target or rapamycin (mTOR) signalling pathway as tumour suppressors, mutation of these genes lead to hyperactivation of the mTOR pathway.
The symptoms are caused by this hyperactivity which causes abnormal cell growth, proliferation and tumorigenesis.
In the CNS, cortical tubers grow which displace neural tissues. Other symptoms include adenoma sebaceum and in more than 80% of cases epilepsy begins in the first 3 years of life

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10
Q

How common is autism in TSC? Who stated this and what did it show in development?

A

Spurling et al. (2014)

A longitudinal cohort study studied infants up to 3 years of age with TSC. Twenty-two of 40 children (55%) with TSC met criteria for ASD.

At 6 months, TSC group showing delays in NVIQ (both FM and VR domains). By age 9 months, infants with TSC exhibited delays in all developmental domains.
Impaired visual tracking, disengagement of attention, and anticipatory responses.

Significant decline in Non Verbal IQ between 12 and 36 months while the non-ASD group showed gains in both full Developmental Quotient and Visual IQ between 12 and 36 months

It was speculated that early visual perception impairment leads to an increase risk decreased social function.

A larger sample size in the first year will enable earlier prediction of ASD however this study does show domain specific decline which could lead to better intervention put in place.

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11
Q

What animal models have been used in TSC and autism?

A

Rat Model
Eker rats carry a spontaneously occurring germline inactivation of rat orthologue of TSC2

Walterait et al. (2011)

Studied both TSC genotype and developmental epilepsy on social behaviours in TSC2+/- (Eker) and WT rats between 3-6 months.
They found that TSC+/- rats displayed autistic-like deficits such as reduced novel object, environmental and social exploration behaviours in Eker (TSC+/-) rats compared to WT rats
Increased social evade and reduced contact time levels in Eker and WT rats induced with status epilepticus.
Only measured social interaction, one part of diagnostic domain of ASD.
In literature elsewhere, such as in Curatolo et al. (2008), it is known that intellectual deficit in TSC is associated with prolonged seizures and a limitation in this current study regarding the discrepancy is that the kainic acid induced epilepsy may not have been sufficient in duration or intensity, P7-14 is later in development than seizures during the first year of life. This would be an important area to modify in future studies.

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12
Q

What treatment have been used in TSC?

A

mTOR Inhibitor Treatment

The first mTOR inhibitor was rapamycin which binds to cytosolic protein which inhibits the pathway by direct competition.

Schneider et al. (2016)

Investigated the effects of Everolimus, a second generation mTOR inhibitor, using Walterait et al. (2011) study methods.
Everolimus was shown to reverse the autistic phenotype in social behaviour deficit as measured by social exploration and recognition memory Eker rats.
The limitation to this study is that no control data was taken for either drug induced epilepsy WT rats and Eker rats naïve for induced seizures which would allow more conclusions to be drawn about mTOR inhibitor treatment.
No mechanistic data was taken on the Everolimus treatment and reassessment of social behaviour after washout of Everolimus would identify duration of effect. This is a potential area of further study currently being researched to understand the efficacy of the drug relating with autism.

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13
Q

What is 16p11.2 Deletion Syndrome?

What is the mutation frequenct and how common is it associated with autism?

A

16p11.2 deletion syndrome is due to de novo recurrent microdeletions which span 500kb

Kumar et al., 2008

A combined frequency of 0.6% of ASD patients, representing the most common recurrent genomic disorder associated with autism. De novo CNVs in patients with autism but not in several of their affected sibs suggests 16p11.2 microdeletion may represent a susceptibility variant

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14
Q

What are the molecular and phenotypic characteristics in 16p11.2 deletion syndrome?

A

Patients with 16p11.2 mutations showed significant speech and cognitive impairment whilst the deletion group had statistically significant macrocephaly compared to control groups with a broad forehead, flat midface indicative of the disease.
Autism was seen in 20% of deletion cases indicating a clear genetic basis for ASD

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15
Q

What animal models are available for studying 16p11.2 deletion syndrome?

A

Zebrafish and Mice model

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16
Q

What zebrafish models have been used and why?

What have they shown in 16p11.2 syndrome?

A

Golzio et al. (2012)

Studied the expression KCTD13 gene in the 16p11.2 deletion syndrome.
A splice blocking morpholino, short antisense oligonucleotides, against KCTD13 reduced expression in the zebrafish and significantly increased macrocephaly due to impaired regulation of early neurogenesis.
Importantly, measurement of the somitic trunk length of scored embryos showed no differences in length, indicating that the head size differences are unlikely to be driven by gross developmental delay.
The data used does not exclude any other loci important or whether all phenotypes are driven by KCTD13.
These findings are associated with human phenotype of both 16p11.2 deletion syndrome and autism which provides valuable insight into the genetic basis of the disease.

17
Q

What mice models have been used in 16p11.2 and why?

What have they shown in autism?

A

Able to analyse social and cognitive phenotypes within 16p11.2 deletion syndrome mice models using social housing environment.

Portmann et al. (2014)

Replicated 16p11.2 deletion syndrome by deleting the 7F3 orthologue in mice.
The mice show defects in smooth motor movements similar to the highly prevalent motor delay described for 16p11.2 patients.
Defects in habituation to familiar objects are reminiscent of behavioural inflexibility reported in ASD which show mouse models may provide insight into the basis of ASD

There are differences however, 16p11.2 patients tend to be obese compared to the smaller mice phenotype. The reduced weight can be removed by reducing competition which shows it is not due to physiological mechanisms, rather social conditions.

18
Q

What other mouse models in 16p11.2 have been used?

A

Yang et al. (2015)
Novel object recognition deficits were replicated as in the study by Portman et al. (2014) further deficits such as location memory were seen.
In three-chambered analysis, a mouse is introduced to one side and the test mouse is observed, a novel second mouse is introduced opposite and behaviour is observed - 16p11.2 mice models showed decreased interest in novel mouse.
When raised with the same genotype of mice, the deficits were not seen so mixed genotype housing leads to the smaller heterozygotes becoming subordinate animals.
Highlights home-cage environment as a possible factor in phenotypic changes in some genetic mouse models of human disorders, a key area of further research into phenotypes of ASD in humans.

19
Q

What is Fragile X syndrome? How common? Why are women less affected than men with the condition?What are the clinical features?

A

The most prevalent monogenic cause of ASD which affects 1 in 4000 males and 1 in 6000 females.
The absence of FMRP on the X chromosome which results in the inability to form connections between neurones.
It is an X-linked recessive disorder and shows increased penetrance with males more severely affected due to X inactivation in females leading to mosaicism which produces a mixture of healthy and mutant cells and a less severe phenotype.
Clinical features include learning disabilities and cognitive impairment
Long and narrow face, large ears, prominent jaw and forehead and macroorchidism.
1/3 have ASD features
Diagnosis is made by CGG repeat length within the FMRP gene using a southern blot analysis

20
Q

What mice models have been used and what did it show about ASD and FXS?

A

Previous studies have identified a de novomicrodeletion in SHANK2 in autism spectrum disorder (ASD)

Tse, 2012

Generated transgenic mice that carried the same mutation as the human microdeletion. These mutant mice (Shank2−/−mice) showed autistic-like impairments in social interaction and in learning and memory.
Intraperitoneal injection of D-cycloserine (a partial NMDAR agonist) improved social interaction of Shank2−/− mice - showing the underlying mechanism.

21
Q

What drosophilia models have been used in FXS? What did they show in relation to social behaviours?

A

Drosophila has a single gene (dfmr1) with similar properties with the FMR/FXR protein family

Dockendorff et al. (2002)

Dfmr1 mutant males displayed reduced overall courtship activity toward two independent targets, virgin females and immature males, which are anatomically distinct and have different pheromonal profiles.
The results have similarities to behavioural phenotypes observed in patients with fragile X syndrome which indicate the model is suitable for comparison.

22
Q

What is the mGluR theory in FXS?? What animal model has been used?

A

Excessive protein synthesis of synaptic plasticity-gating proteins occurs in response to metabotropic glutamate receptor (mGluR) activation in the absence of FMRP.
The excessive production of these proteins is proposed to underpin aberrant neuronal function in FXS.

(Michalon et al., 2012)

Used the novel and selective mGlu5 inhibitor - CTEP to address this issue in the Fmr1 knockout mouse.
Chronic treatment that inhibits mGlu5 rescues cognitive deficits with treatment starting in young adulthood.
Results from mice model of mGlu5 inhibition supports that mGlu5 inhibitors might have the ability to change the developmental trajectory of FXS patients and thus could hold the potential for disease modification.
With the high incidence of ASD in these patients, the ability to reverse phenotypes may benefit treatment in ASD cases.

However clinical trials on human using mGlu5 antagonists showed no improvement in phenotype in humans and highlights caution when applying animal models to humans.

23
Q

What environmental factors are implicated in autism?

A

Cerebellar Injury
Purkinje Cell Loss
Valproate Exposure

24
Q

What are the relative risks of identical twins, cerebellar injury, valproate exposure in ASD?

A

Wang et al., 2014

  • Calculated the risks of getting autism in different environment and genetic factors
  • Identical Twins = 84x
  • Cerebellar injury = 43x – replicated in further studies and shown to be the single most non-inheritable risk
  • Valproate Exposure – 6x
25
Q

Describe cerebellar injury and it’s association with ASD

A
  • Foetal brain development is affect by ASD and an early disruption in cerebellar circuitry has shown to positively correlate with autism
  • Limperopoulos et al., 2007
  • A retrospective, case-control showed preterm infants with cerebellar haemorrhagic injury
    are at significantly increased risk for subsequent neurodevelopmental disabilities when compared with preterm infants in the control group.
    Over 90% of neuropathological studies in persons with autism have shown well-defined cerebellar anatomic abnormalities which showed high prevalence of significant deficits in cognition, communication (both receptive and expressive), and social-behavioural function
  • Longitudinal follow-up studies are needed to establish whether these deficits are enduring
  • The apparent association between CHI and autism spectrum risk is of great interest, the tests for autism risk were screening tools, and data from more specific and diagnostic testing instruments are required to confirm this association
26
Q

Describe Purkinje Cell Loss and it’s association with ASD

A
  • Purkinje cells (PCs) are a class of GABAergic neurones located within the Purkinje layer in the cerebellum. They send inhibitory projections to the deep cerebellar nuclei
  • Schumann & Nordahl, 2011
  • 30 postmortem cases of autism in which the cerebellum has been studied, 22 (or 73%) cases showed lower density of Purkinje cells, particularly in the more lateral regions of the structure
  • Others have reported no difference in the density of Purkinje cells in the cerebellum.
  • Although a comprehensive stereological study of the actual number of Purkinje neurons in the whole cerebellum has yet to be carried out
  • Skefos et al., 2014
  • Used a systematic sampling technique that significantly reduces experimenter bias and variance to estimate PC densities in the postmortem brains of eight clinically well-documented individuals with autism and age and gender controls.
  • PC density was lower in the cases with autism as compared to controls, an effect that was most prominent in crus I and II and lobule X had a lower density in males only
  • Limited by a small sample size with fewer female cases than ideal
  • Due to the age range of our study, it was not possible to assess the early developmental processes that are believed to be crucial in understanding autism
27
Q

Describe Valproate exposure and it’s association with ASD

A
  • Valproate is a broad spectrum anti-convulsant used primarily to treat epilepsy and bipolar disorder.
  • Valproate causes birth defects upon exposure during pregnancy such as Fetal Valproate Syndrome.
  • Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, shallow philtrum and small downturned mouth.
  • Rasalam et al., 2005
  • The study examined long-term effects of prenatal exposure to AEDs in 260 children (122 males, 138 females). Of these, 26 (16 males) were reported by parents to have social or behavioural difficulties. Sodium valproate was the drug most commonly associated with autistic disorder, five of 56 (8.9%) of the study children exposed to sodium valproate alone had either autistic disorder or AS
  • It was concluded that prenatal exposure to anticonvulsant medication is a risk factor for the development of an ASD
  • Bromley et al., 2008
  • Found that a seven-fold increase in ASD diagnoses when exposed to VPA monotherapy in utero. The features found were reduced language, lack of attention, social difficulties and restricted interests
28
Q

Describe the MMR vaccine have associations with austim?

A

Wakefield et al., 1998

  • Suggested MMR predisposes to behavioural regression and pervasive development disorders
  • Limitations – small sample size, uncontrolled design, speculative conclusions
  • WITHDRAWN – however caused a huge uproar and meant many children were not vaccinated and thus Herd immunity was compromised
29
Q

Why study zebrafish models in 16p11.2 deletion syndrome?

A

Zebrafish have been used as models for human disease as they reach maturity in 3 months and are easy to breed and manipulate the genome. Screening is possible due to the ability to place early zebrafish larvae in multi-well plates.
To model human disease, zebrafish have 71% orthologues to human proteins and 84% of human 16p11.2 core genes, making it ideal to study 16p11.2 in relation to ASD.

30
Q

Name the papers in the TSC disorder essay

A

Curatolo 2015
Spurling 2014
Walterait 2011
Schneider 2016

31
Q

Name the papers in the 16p11.2 deletion syndrome essay

A

Kumar 2008
Golzio 2012
Portmann 2014
Yang 2015

32
Q

Name the papers in the FXS essay

A

Tse 2012
Dockendorff 2002
Michalon 2012

33
Q

Name the papers involved in the environmental factor essay

A 
Wang 2014
Limperolous 2007
Schumann & Nordahl 2011
Skefos 2014
Rasalam 2005
Bromley 2008

Autism (3 decks)

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