The Cause of Autism: Part 1 Introduction

I know that it is presumptious to write an article about what may be the cause of autism. There are many individuals that have their own take on this particular and, although offering polarizing views, their opinions are usually sustained with some type of data. This blog will deal with my own ideas as to causation, those derived from work in my laboratory. It is based on what I consider the core neuropathology of autism for which I have been extremely biased in terms of reviewing the literature. For those interested I have had several previous blogs discussing why some reported findings on the pathology of autism may be misleading and what may be regarded as true abnormalities (see and also ).

Let’s start by saying that it is widely acknowledged that the clinical presentation of autism is highly variable or heterogeneous. Patients vary among themselves in terms of, among others, types of symptoms, severity, onset, and comorbidities. It is said that once you have met an autistic individual you have met “one” autistic individual. Robert Schultz once made the analogy of autistic individuals to snowflakes, no two are alike. It is therefore not surprising that some investigators have renamed the condition Autisms as opposed to Autism. This has been dealt extensively in two very well written books: “The Autisms” (by Mary Coleman and Christopher Gillberg) and “Rethinking Autism” (by Lynn Waterhouse).

It is believed that the clinical heterogeneity of autism supposes an equally diverse group of etiologies. Researchers aplty quote the large number of risk genes in autism (close to 5,000). These genes vary in terms of their participation in extremely different biochemical pathways. From this perspective autism stands as a syndrome with many possible causes.


When discussing causation, I stand at the opposite end of the spectrum along with a limited number of supporters. Instead at looking at the variability of expression I examine commonalities among the different offending agents. In terms of pathology this entails looking at what has been called a locus minoris resistentiae or path of least resistance. The search entails looking for some type of abnormality that all or a majority of causative agents have in common. In Alzheimer’s disease, for example, it has been said that the hippocampus (a certain region of the brain) stands as a locus minoris resistentiae for the condition. What is meant is that every single case of Alzheimer’s disease bears degenerative changes in this brain region. Furthermore, a particular area of the hippocampus called the entorhinal cortex appears to exhibit the earliest changes in Alzheimer’s disease. Neurodegenerative changes seem to proliferate out of this brain region to invade other areas of the cerebral cortex. The question that I would like to address in this blog is the presence of a similar abnormality in autism… whether autism has an area similarly affected as the hippocampus in Alzheimer’s disease?

In autism, the vast majority of cases seem to lack a verifiable cause. These cases are called «idiopathic». A significant minority of cases, however, have a definable cause and are called «syndromic». As an example of syndromic autism, a significant number of patients (30-50%) with tuberous sclerosis express autistic symptoms. Similarly, individuals born with extreme prematurity, Ehrler-Danlos syndrome, and those exposed to certain viruses (e.g., cytomegalovirus) or toxins (e.g., cocaine) during pregnancy can manifest syndromic autism. My concern is what brain alteration(s) do these syndromic cases have in common and whether similar ones can be seen in the idiopathic cases?

My own research has led me to believe that there is a locus minoris resistentiae in autism, this being the germinal cells that give rise to both the cerebral cortex and different nuclei of the brainstem. It is my belief that in genetically susceptible individuals these cells are prompted to divide by an environmental exigency. Because these cells are forced to divide at an inopportune time, the structures that they are meant to generate (e.g., cerebral cortex) are malformed (also called dysplastic). Cells migrating to affected areas are therefore uncoordinated in their maturation with those already inhabiting the same thus providing for symptomatology. Variability in the genetic susceptibility of the individual and timing/severity of the environmental exigency (time during brain development) could all account for variability in expression of symptoms. Furthermore, the proposed neuropathology of autism would squarely place the same as a neurodevelopmental condition, something with an onset way before the person is born. Lastly, the same mechanism may help explain both abnormalities of the cortex and of the brainstem (see ).


Figure: Germinal cells surround the ventricle. These cells divide to provide different (non germinal) types of cells.  In this particular example germinal cells divide and their progeny migrates along a radial glia scaffolding to reach the mantle where the cerebral cortex will be formed.

In future blogs I will detail the fingerprint of this germinal cell pathology. Insults to the brain leave a fingerprint or tombstone as to their presence that allow us to reconstruct the pathology. The future blog will therefore describe some of the evidence for germinal pathology and migratory abnormalities in autism.

Addendum: Please read the continuation of this blog at

11 Respuestas a “The Cause of Autism: Part 1 Introduction

  1. I’m not sure I understand some of the things you are saying. I guess by germinal cells, you mean undifferentiated stem cells and these are technically not neurons or glia yet. I thought it was well known that neurons don’t divide when fully differentiated though I guess glial cells (and other non nerve cells) divide when fully developed and differentiated. This is why brain cancer involves glia and not neurons. I’m not sure by cells if you mean neurons, glia or both, but i guess probably neurons. If these are neurons, do you mean undifferentiated during fetal development? Von Economo cells can develop until age 4 and they might be involved in autism and they exist in prefrontal cortex which I think was one of the areas of minocolumn abnormalities that you found. So I guess you mean undifferentiated stem cells which may become neurons, but I’m not sure and I guess according to your theory this would mean ASD’s could only devrelop early in fetqal development and not postnatally

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  2. You understood well. The germinal (stem) cells provide for several precursors which will differentiate among different lines, both glia and neurons. I think I will have to start my next blog by illustrating this process in order to make it clear. Thanks for helping me clarify this point.

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  3. Pingback: Guest Post by Dr. Manuel Casanova: “Enlargement of the Brain Ventricles in Preterm Infants and Autism: An Ultrasound Study” | Science Over a Cuppa·

  4. Patients with asperger syndrome can have an absence of some gross abnormalities of the you mentioned, no doubt we have gray and white matter volume abnormalities and folding difference, which may be the brain adapting to autism in some cases and not the autism itself. Is the minicolumn difference the root of what makes it autism and not just some other intellectual disability or epilepsy without autism? What about the lack of autophagy they have found and lack of difference in gene expression in the frontal and temporal cortex, whence do they come from migrational difficulties?

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    • I agree. There is a spectrum of these abnormalities. In my case report on Asperger I said that the «pathology» differed in severity not in kind. I do not believe Aspergers have prominent heterotopias or cortical abnormalities. These are more common for people with seizures. As you said the increased folding and some other findings may be the way the brain adapts itself to more minicolumns.

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