The Triple Hit Hypothesis of Autism

This blog follows one of my previously published ideas stating that autism results from a threshold phenomenon where symptoms manifest themselves  when 3 factors impinge, to various degree, on the developing brain: 1) an environmental exigency, 2) the time window during brain development when the environmental exigency acts, and 3) a genetic vulnerability.  This is the so-called triple hit hypothesis of autism that defines the same as a multifactorial (i.e., a condition resulting from multiple causes) disorder.

Studies suggest the presence of multiple susceptibility and protective genes that modify the risk of developing autism. As in other multifactorial conditions autism appears to involve primarily one organ: the brain. Not surprisingly, the increased risk among first degree relatives falls into the 3%–5% range proposed for other multifactorial conditions. The following is a selective review of the literature that explains some of the data available regarding some of the factors of the triple-hit hypothesis for autism. The review emphasizes the presence of environmental factors such as drugs (e.g., an anticonvulsant known as valproic acid) and how they need to act during defined periods of brain development for autistic symptoms to develop.

It has been noted that in utero exposure to valproic acid and other anticonvulsants increase the risk for manifesting autism or autistic-like traits postnatally. In a study four out of  57 patients prenatally exposed to anticonvulsant were diagnosed with autism.  Of these patients  two had received valproic acid alone and one both valproic acid and phenytoin. Some authors have suggested that the risk for fetal valproate syndrome is dose dependent. This fact has been used to create an animal model (rat) of autism. Prenatal exposure to valproic acid on the 12.5th day of gestation reproduces some of the clinical (e.g, decreased number of social behaviors) and pathological features (e.g, diminished number of Purkinje cells) putatively observed in autism. Another strong association to neuroembryological dysfunction comes from observations that approximately 5% of individuals exposed in utero to thalidomide develop autism. What appears interesting about this observation is that thalidomide patients who manifest autism also exhibit external ear abnormalities and an uncommon form of strabismus (Duane syndrome) but no malformations of their arms or legs (phocomelia). Timing of these“minor” malformations and the supposition that autism may have arisen during the same stage of development suggests a time window of vulnerability early in gestation (20–24 days).

The first trimester is the time of development for multiple congenital anomalies that include autism as one of their manifestations. Among these congenital disorders is Möbius syndrome (facial diplegia). The genesis of Möbius syndrome is disputed.  Theories on causation include genetics, vascular deficits, maternal trauma and the use of certain drugs during pregnancy, for example ergotamine, misoprostol (a drug used for self-induced and planned abortions) and thalidomide. Case series reveal the poor development of various cranial nerve nuclei, focal necrosis and calcification of brainstem tissue. The large variety of  findings in the examined tissue and varied clinical expression suggests that, in terms of the “behavioral” phenotype, timing of the underlying insult may be of equal, if not greater importance, than the anatomical site affected. In other words when considering the developing brain and its orchestrated sequential maturation of neurons, synapses and cortical maps “when is as important as what”.  Sparse clinical data support a vulnerability period for autism during the second and third trimester of gestation. Bleeding and maternal infections during the second trimester have been associated with increased risk for developing autism. Case reports of maternal infections (e.g, cytomegalovirus) during the perinatal period offer less convincing proof in favor of the third trimester of gestation. In effect, patients who have suffered from an infection with cytomegalovirus who later develop an autism phenotype all have damage (i.e., cysts in the germinal zone surrounding the ventricles) suggestive of an early developmental lesion.

The above is just an abbreviated summary of information from the literature suggesting that, for some patients, different environmental factors  and a time window of vulnerability during brain development may play a key role in the pathogenesis of autism.  A genetic component or susceptibility is derived from conditions such as tuberous sclerosis where  17 to 68% of patients have an autism phenotype.  I will talk more about genetics in a future blog.


Casanova MF. The neuropathology of autism. Brain Pathology 14(1):111-118, 2008.

2 responses to “The Triple Hit Hypothesis of Autism

  1. Almost forgotten is the work by Yanei and colleagues in the 1980’s. Yanai’s group found that prenatal exposure to phenobarbital in mice produced a significant and long-lasting loss of cerebellar Purkinje cells and mitochondrial degeneration. Purkinje cell loss is the most frequent finding in human autism autopsy studies. In a follow-up study Yanai’s group reported a GxE effect. Phenobarbital treatment in DBA/1 inbred mice and C57BL/10 inbred mice was compared. DBA/l mice were sharply affected by the drug, while the behavior of C57BL/10 was little altered by phenobarbital administration. Copy number variations can have both risk and protective effects, for example CCL3L1 copy numbers is associated with susceptibility to HIV-1 infection. A lower copy number is associated with an increased risk of HIV-1 infection, while a higher copy number is associated with reduced risk for acquiring HIV-1. GxE mouse models is an area of research that is has been largely neglected and its importance is in prevention strategies that might identify which common genetic variations are associated with increased risk and which common genetic variations are associated with reduced risk.


    • You are correct. In a short exposition such as a blog it is difficult to be comprehensive and provide credit to everybody that is deserving. I was also trying to keep it simple. I will dwell on Purkinje cells in one of my future blogs. Thanks again fro your correspondence.


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