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 http://bit.ly/12qrJsD and also http://bit.ly/UoWFuQ ).

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 http://bit.ly/10FY4x6 ).

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 http://bit.ly/18iI4pw