The Neurobiology of Infantile Autism
by Roland D. Ciaranello, M.D.

Infantile autism is one of the most disabling illnesses of neurologic, emotional and intellectual development. It afflicts about one in every 2,000 children, which makes it as common as cystic fibrosis or fragile X-mental retardation. Boys make up about 75 percent of all autistic individuals. In the San Francisco Bay Area alone, there are nearly 3,000 autistic persons. About 80 percent of autistic children develop signs of the disorder in the first year of life. By three years, the full-blown syndrome is usually present. Autistic children are generally normal in appearance, healthy and attractive; their life expectancy is normal.

The typical signs of autism include: withdrawal, isolation and aloofness; failure to develop language; preoccupation with inanimate objects, such as a spinning top or a light switch; ritualistic behaviors, such as endlessly arranging toys or objects by size, color or shape; repetitive behaviors performed without interruption for extended periods of time, such as hand-flapping or flicking the fingers in front of the eyes; and an intense aversion to the slightest change, so that even the most trivial disruption of an established routine can cause extreme anxiety and emotional turmoil.

There is now quite convincing evidence that genetically regulated disturbances in brain development underlie some, perhaps most, of the cases of infantile autism. In 1971, Michael Rutter and his colleagues showed that autism occurred 50 to 150 times more frequently in families where there was already an autistic member. In monozygotic twins, when one is autistic, the other is also autistic more than 90 percent of the time. Estimates of the heritability of autism derived from both family and twin studies have ranged from 80 to 100 percent. Taken together, these studies provide substantive evidence that a genetic defect in brain development underlies infantile autism.

The human brain is an extraordinarily complex organ, made up of many different structures, each serving a distinct function. The development of the various parts of the brain is regulated by the complex interplay of genetics and environment. One of the most pressing questions scientists have been trying to answer is what part or parts of the brain are damaged in autism? The areas which appear to be prime candidates are the structures of the limbic system and the cerebellum.

The limbic system consists of several different structures. We think the limbic system acts as both an augmentation and a switching center, relaying information between brain areas while simultaneously adding emotional coloration to it. In monkeys, destruction of the amygdala, a part of the limbic system, causes a series of behaviors that closely resemble those of autistic children. Another part of the limbic system, the hippocampus, is known to be involved in the acquisition of recent memory.

Recent autopsy studies from Margaret Bauman and Thomas Kemper's laboratory at Harvard have shown that in both the hippocampus and amygdal there are nerve cells which appear to be immature and which have not migrated to their proper destination in the brains of autistic individuals. This suggests that there may be a defect in the normal developmental migration of these neurons, so that they do not reach their proper destinations, and so cannot establish their normal functions. These same investigators have also shown that there is a selective loss of Purkinje cells in the cerebellum of autistic individuals. This results in a loss of the neurons which make synaptic contacts with the Purkinje cells, ultimately involving many centers in the cerebellum. The significance of this observation is not clear, because the cerebellum's principal role is to aid in coordination of motor function and the position of the limbs and body in space. However, we know that the cerebellum receives extensive connections from the limbic structures and itself sends connections to the cerebral cortex, the major cognitive and information-processing center for the brain. So it is possible that a defect in Purkinje cell development could impede the function of the cerebellum in ways we do not now understand.

What are the implications of all this for infantile autism? We now believe that autism represents a severe developmental disturbance of the brain that most likely occurs at the late or end stages of brain development, during which the final connections between brain cells are established that will define the communication network of the mature brain. We believe that these developmental disturbances giving rise to infantile autism are the result of genetic mutations, occur during the end stages of brain differentiation, and take place in circuits affecting the limbic structures, the temporal cortex and possibly the cerebellum that are responsible for language and information processing, and the emotional coloration that accompanies it. Like any hypothesis, this one must be verified experimentally.

These recent advances in an anatomic understanding of autism have also tied it more closely to another severe developmental disorder, schizophrenia. Schizophrenia is also a disorder of brain development which affects children and adolescents. There are two peak periods of risk for schizophrenia: one occurring about age 7 to 9 years, the second, larger peak, around 19 to 21 years. Schizophrenia is more common than autism, affecting around 1 percent of the population. Like autism, schizophrenia is a highly heritable disorder. For many years, researchers believed autism and schizophrenia were different variants of the same disorder, but epidemiological research showed that the two disorders did not occur more frequently in the same families than would be predicted by chance, so since about 1971, we have taught that they are distinct. However, more recent research suggests they may be related. Work from Patricia Goldman-Rakic's laboratory at Yale, Daniel Weinberger's laboratory at the National Institute of Mental Health, and Edward Jones' laboratory at the University of California, Irvine all implicates maldevelopment of centers in the medial temporal cortex and limbic structures in the pathogenesis of schizophrenia. Moreover, at the cellular level, there is evidence that nerve cells do not mature properly in schizophrenics and that they may also not migrate properly. Thus there appear to be many common threads linking schizophrenia and autism. My own view, at this point unsupported by anything more than informed hunch, is different genes are responsible for schizophrenia and autism (thus explaining why they do not excessively co-occur in families) but that the biochemical function of these genes are highly related, and they may even be members of the same gene family. As more progress is made identifying the genes involved in autism and schizophrenia, we will have the opportunity to examine this hypothesis directly.

Adapted from an article of the same name in The NARSAD Research Newsletter.

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