Tuberous sclerosis and autism

This is the first of several blogs describing how a variety of conditions, which manifest autistic symptomatology in a high proportion of cases,  involve the same mechanism: interference with the normal process of divisions of germinal (stem) cells very early on during brain development. Our basic hypothesis for explaining the neuropathology of autism has been explained in previous blogs: “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”. For more information on this hypothesis please see: and/or

The first blog is about a fairly common condition that involves many parts of the body.  It is called tuberous sclerosis or tuberous sclerosis complex. There are 1 to 2 million individuals with the diagnosis living around the world and the condition has an estimated prevalence of 1 out of every 5,000-6,000 births.  A tuber is a modified structure of a plant that is enlarged to store nutrients. In persons with the condition these tubers or outgrowths affect the brain, kidneys, heart, lungs and the skin. Sclerosis means hardening, and it makes reference to the consistency of the tubers upon examination. So the name tuberous sclerosis makes reference to outgrowth in different body parts that are hard to the touch.


Figure: Outgrowths of proliferating tissue in the skin provide for firm, discrete and red or brown  protrusions called adenoma sebaceum. The same is usually located in the nasolabial folds, chin and cheeks. They are not present when the patient is born and in that regards may not be used for an early diagnosis.  They usually appear after 2 years of age.

Research has shown that the condition is due to a mutation of two genes (TSC1 or TSC2) that code for proteins that serve to regulate cell proliferation and differentiation. In this regard the genes are classified as tumor suppressor genes. When either of these proteins is not produced, cells divide out of control producing malformed tissue that on rare occasions may become cancerous.  In approximately two thirds of cases the condition arises from  a sporadic genetic mutation, however, inheritance from offsprings follows an autosomal dominant pattern.  Inheritance of a mutation necessitates a second random mutation (Knudson two hit hypothesis) for the tumors to develop. This phenomenon has been used to explain why despite 100% penetrance tuberous sclerosis has wide expressivity.

In the brain, tuberous sclerosis is associated with nodular lesions in the cortex (wart-like protrusions), clusters of cells (heterotopias) that fail in their migration and get stuck in the white matter or in the periventricular zone. Histological examination reveals jumbled-up cellular elements that may on occasion acquire bizarre conformations. Sometimes these lesions become calcified and are easy to detect using neuroimaging methods.

candle gutterings

Figure: Subependymal clusters of cells that fail to migrate out of the germinal zone form nodules that protrude into the ventricular cavity.  This particular sign of tuberous sclerosis has the descriptive name of “candle-gutterings”. The same abnormality has been reported in a case of idiopathic autism.

subependymal giant cells

Figure: Giant cells with bizarre nuclei define this tumor proper to the subependymal location in patients with tuberous sclerosis. A cluster of smaller (but regular size) cells can be seen in the lower right hand of the image.  The tumor is named subependymal giant cell astrocytoma.

The abnormality in germinal cell division and their migration described in tuberous sclerosis is what we have described in cases of idiopathic autism (see ).  It is therefore not surprising that for conditions that share similarities in terms of their neuropathology (i.e., tuberous sclerosis and autism) also share commonalities as to their clinical presentation. Similarities for both conditions include a high incidence of seizures, mental retardation, large brains, and learning difficulties. The most common seizures disorder observed in tuberous sclerosis are infantile spasms (also called West syndrome). It is noteworthy that infantile spasms are almost always associated with developmental regression as seen in some cases of autism. Behavioral disorders common to both include hyperactivity, self-injurious behaviors, and sleep difficulties.


Figure: The frequency of signs in children with tuberous sclerosis arranged according to age range.

The frequency of autistic symptoms in tuberous sclerosis varies among series from 25 to 50%. Contrariwise, the prevalence of tuberous sclerosis among autism spectrum disorders is 1 to 4%. Neurologic and psychiatric findings in tuberous sclerosis depends on the location, size, and overall growth of the tubers.   Some neuroimaging studies suggest that autistic symptomatology in tuberous sclerosis patients occur when the tubers involve the temporal lobes.

Many other cases of syndromic autism affect the same pathological mechanisms that we have incriminated in idiopathic autism i.e., (heterochornic divisions of germinal cells during brain development).  In future blogs we will describe more of these cases.

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