4 Unanswered Questions in Autism Research Dr. Lynn Waterhouse The College of New Jersey Presented at the 14 th DUTCH NATIONAL AUTISM CONGRESS March 21, 2014 ‘sHertogenbosch, The Netherlands

Question 1: What causes autism social impairment to occur with restricted and repetitive behaviors?

Brunsdon & Happé (2014) theorized social impairment and restricted and repetitive behaviors are each separately caused by separate etiologies, and separate brain dysfunctions.

However, Brunsdon & Happé (2014) are likely to be wrong because autism has so many varied causes There are 200 and 1,000 genes linked to autism (Berg & Geschwind,2012), There are nearly 100 environment causes (Grabruker, 2013; Maramara et al., 2014; Schieve et al., 2014).

The known causes for autism separately cause different brain dysfunctions, and each different brain dysfunction causes some form of social impairment and varied restricted and repetitive behaviors.

Gene causes Single or multiple gene variants Gene X Environmental causes Father’s age Environmental causes Valproate taken by a Mother

Answer to Question 1: Because the hundreds of different causes for autism each cause different brain dysfunctions that cause both social impairment and restricted and repetitive behaviors, these diagnostic symptoms will vary, and therefore the symptoms will not be correlated in large samples.

Question 2: How many different brain dysfunctions cause autism?

Hundreds of varied brain dysfunctions cause autism Bigger brains Smaller brains Missing corpus callosum Cerebellar impairment Amygdala impairment White matter impairment Gray matter impairment As well as Neurotransmitter excess or deficit Protein excess or deficit

One cause of larger heads and brains in autism is the PTEN mutation

Rett syndrome in autism (right image) causes smaller heads and brains

In some with autism the corpus callosum is missing (left image)

Many different gene variants, such as Noonan syndrome and Tuberous sclerosis in autism cause maldevelopment of the cerebellum

Abnormal amygdala size and function affects some with autism

White matter underconnectivity affects some with autism

The brain’s gray matter is denser in some with autism (red line)

Answer to Question 2: There are hundreds of different patterns of brain dysfunction found with autism, thus all single brain dysfunction theories of autism are wrong: no single brain dysfunction is true for autism.

Question 3: Do risk factors for autism cause many non-diagnostic behaviors?

Answer to Question 3: Yes. For example, the risk factor PTEN gene mutation causes autism diagnostic symptoms and non-diagnostic symptoms of epilepsy and an atypically large head (Marchese et al., 2014)

Question 4: Will most idiopathic autism (autism with no known cause) be found to have a cause, and thus become syndromic autism?

Yes, evidence links syndromic autism and idiopathic autism For example, 4 genetically-linked syndromes, each sometimes found with autism— Neurofibromatosis type 1 (NF1) Noonan syndrome Costello syndrome Cardio-facio-cutaneous syndrome Are linked to other non-syndrome causes.

Answer to Question 4: When we have discovered the causes for autism, all autism will have a known cause, therefore, idiopathic autism will not exist.

4 Conclusions 1. Autism symptoms should be studied independently in relation to risk factors. 2. A catalogue of all brain dysfunctions found with autism is needed to advance research. 3. Diagnostic and non-diagnostic symptoms need to be explored together as caused by individual risk factors. 4. Genetic research has demonstrated that the division of idiopathic and syndromic autism is unimportant.