Lecture 17: Autism

Question 1

Describe autism as defined by Leo Kanner

Answer 1

In 1943, he identified 11 children with hypersensitivity to stimuli, anguish for changes, echoing words, food problems yet good intellectual potential.

Question 2

What is infantile autism?

Answer 2

the innate inability of certain children to relate to other people.

Question 3

What is classic autism?

Answer 3

-impaired social interaction and communication.
-inflexible ritualistic attachment to objects/routines (OCD tendencies).
-delay or lack of spoken language
-one-sided conversations
-repetitive motor mannerisms
-lack of spontaneous social play (more withdrawn).

Question 4

What is Asperger’s syndrome?

Answer 4

Asperger’s syndrome is a milder form of autism and is commonly known as “little professors” because it is common among professors for some reason.
Defined by:
-lack of empathy
-inability to form friendships
-one-sided conversations
-intense absorption in special interest
-clumsy movement
In 2013, Asperger’s syndrome was reclassified as part of “Autism spectrum disorders” (ASD) with ratings from mild to severe.

Question 5

Describe the cost/difficulties of ASD to families

Answer 5

The cost is very immense
This includes:
-speech and occupational therapy, special education, home care and medicine for associated chronic disease.
Families earn 28% less
Mothers 56% less
Total annual cost: $137 billion in the US

Question 6

Why is the diagnosis of ASD on the rise?

Answer 6

Doctors are better at diagnosing it
Environmental toxins (potentially)
Stats:
4 boys to every 1 girl (more prevalent among boys)
1 in 44 children as of 2018

Question 7

What other factors could be contributing to the rise of ASD?

Answer 7

It could be the definition.
The DSM (Diagnostic and Statistical Manual of Mental Disorders) was designed to enable a more systematic psychiatric diagnosis of “insanity” post WWII
The way the DSM classifies autism could also contribute to its rising rate of diagnosis.

Question 8

What type of birth trauma is a risk factor for autism

Answer 8

We don’t know if these are symptoms of autism or if these cause autism.
Recent meta-analysis tentatively identified birth complications that increase the risk of autism.
-Anemia 8 times
-Inhaled Meconium 7 times (meconium = waste from baby inhaled in lungs).
-Weak crying after birth 5 times

Question 9

Describe Andrew Wakefield’s false claims regarding Autism and MMR vaccines

Answer 9

MMR: is the measles, mumps, and rubella three in one vaccination.
Andrew Wakefield studied 12 kids who received the MMR vaccine and claimed that they got gastrointestinal illness and became autistic.
Termed this “autistic enterocolitis” which was associated with gastrointestinal disease and developmental regression in previously normal children.
His findings were published in the Lancet paper however it was later found that there were no controls in these study and it was very poorly designed. Furthermore, the data had been fabricated.
As a result this paper is now redacted from the journal but the resulting damage has launched a campaign of anti-vaxxers who have stopped providing vaccines to their children.

Question 10

Describe the importance of the MMR vaccine

Answer 10

It saves lives!
Measeles was on the path of being eradicated before this vaccine.
But because of this “study” there has been a spike in cases.
1 in 1000 children with measles die in the developed world, 1 in 3 in developing
Fijian epidemic of 1875 2/3 of population killed.

Question 11

What is the “refrigerator theory” of autism

Answer 11

This theory claims that parents of autistic children just happen to defrost enough to produce a child. Basically calling the parents bad parents and being mean to their children resulting in their child having autism. (This is completely false and a hurtful assertion).

Question 12

Explain how genetic factors in autism are very strong.

Answer 12

-Autism is highly heritable as shown by the high concordance in monozygotic (identical) twins (70-90%).
(Complex heritability)
- one sibling with disease increases likelihood by 25 fold.
- paternal and grand paternal age at conception increase risk (2 fold) presumably due to accumulated spontaneous mutations.
(Age-related mutations)
(Parent genes can have a strong effect on future generations).

Question 13

Autism is a complex genetic trait: some causes are caused by ____ genes some by ____

Answer 13

1) single gene
2) multiple genes/chromosomal

Question 14

Explain the causes of autism

Answer 14

-Single gene, Mendelian
Inheriting a bad gene or 2 recessive copies.
-Cytogenetic
Changes in genes such as imprinting (change in parent genes).
Paternal mutation
older dads are more likely to have autistic kids
-Common Autism (multiple gene, environment).

Question 14

Describe ASD conditions that arise from single gene dysfunction

Answer 14

-Rett Syndrome
-Fragile X Syndrome
-Timothy Syndrome

Question 15

What is Rett syndrome?

Answer 15

hand wringing, no verbal skills, DSM-V has now separated from autism spectrum disorders
Symptoms overlap a lot.
Can still be studied to reveal neuronal pathways that can be compared to autism.

Question 16

What is Fragile X syndrome?

Answer 16

Retardation in most, autism like symptoms in some.

Question 17

What is Timothy syndrome?

Answer 17

heart arrhythmia and autism symptoms.

Question 18

Give more stats/info regarding Rett syndrome

Answer 18

-Prevalence is 1 in 10,000 (rare but not that rare).
- loss of speech =, stereotyped movement
- mostly girls (boys may die very early, usually at birth).
- linked to mutations in the MeCP2 gene, a transcription factor that regulates many other genes and is expressed in brain cells.
Could act in multiple gene types
These genes are identified from pedigrees usually and genetic technology.

Question 19

Describe a model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells.

Answer 19

-involves differentiating cells into neurons
- examining different properties
-Rett syndrome neurons have reduced neuronal activity.
MECP2 is a loss of function mutation

Question 20

What happens to Rett syndrome when gain of function mutation experiments are used and when loss of function mutation experiments are used

Answer 20

Gain of Function:
-Normal version is put into cells resulting in the regaining of a lot of function.
MECP2 is a loss of function mutation
Loss of Function:
Reduce MECP2
This resulted in similar symptoms/worse symptoms.

Question 21

What drug discovery was made using patient iPSC cells?

Answer 21

Gentamicin a common antibiotic is also toxic to certain mammalian sensory cells such as hair cells in the inner ear (caused hearing loss in many children).
Gentamicin enhances the translation of MECP2 protein.
Gentamicin restores synapse density along dendrite of neurons derived from Rett patient iPS cells.

Question 22

Provide more info about Timothy syndrome

Answer 22

Discovered in 2004
irregular heartbeat
fused digits (due to lack of apoptosis)
developmental delay and autism
mutations I CACNA1C a subunit of the voltage gated calcium channel CAv1.2

Question 23

What was discovered when iPSC derived neurons were used to uncover phenotypes associated with Timothy syndrome?

Answer 23

Action potentials in patient derived neurons are abnormally long lasting (4 ms instead of normal 3ms).
The drug nimodipine is a calcium channel blocker that corrects the abnormally long action potentials in patient derived neurons.
May help with cardiac and autism aspects.

Question 24

What is the summary of this lecture?

Answer 24

-Autism spectrum disorder spans a wide range of severity and symptoms.
-The genetics are complex with no singular cause.
-iPS cells taken from autism patients are opening new avenues for drug discovery.