Key Concept: Abnormal micro-RNA programming disrupts early brain development causing autistic spectrum disorder, characterized by delays, plateaus and spurts of brain development. Similar abnormal micro-RNA programming disrupts brain development during adolescence causing schizophrenia, characterized by positive and negative symptoms. The degree of micro-RNA abnormality determines the time of onset, severity, and duration of symptoms in both disorders.
The theory presented in this essay is that autism spectrum disorder and schizophrenia are caused by abnormal micro-RNA, the non-coding part of the genome that directs the development of the brain. It is based upon two key clinical observations: (1) the nature of their symptoms, and (2) their clinical course.
Edward R. Ritvo, MD
Let’s first consider what clues their symptoms can give us as to their cause. In autistic spectrum disorder, symptoms usually appear first during the earliest years of life when the brain is developing rapidly.
What we observe are delays in onset, prolonged phases, and spurts of development of language, social relatedness, and sensory-motor modulation. This tells us that the normal rate and coordination of brain development is disrupted, and different parts of the brain are developing at different rates.
In schizophrenia, symptoms usually first appear during late adolescence when there is a rapid period of brain development. The classical “positive” and “negative” symptoms of schizophrenia indicate that the normal development of the coordination of thoughts, feelings, and sensations occurring at this time are disrupted (This is the observation that led Bleuler to coin the term schizophrenia: “Schizo” for splitting – and “phrenia” for psyche).
Thus, the symptoms we observe in both disorders express abnormal brain development.
Second, let’s consider what their clinical courses suggest as to their cause. In both disorders it is well known that symptoms wax and wane and in some cases they can remit completely. This tells us that the underlying brain pathology is not static, but the brain development is able to pause and restart. For this to happen, there must be “on” and “off” switches in the genome which normally orchestrate brain development, but do not function properly in these two disorders.
These two key observations lead us to ask, “Where in the genome are these “on” and “off” switches located, and what causes them to malfunction?”
The answer to these questions requires some speculation. The most likely answer to the first one, concerning location, is that the “noncoding micro-RNA” part of the genome contains the instructions for the development of the brain and all other parts of the body. Typically, DNA instructions code for building specific proteins. Micro-RNA instructions, on the other hand, appear to contain timing, placing, and sequencing instruction such as “put it here,” “put it there,” “deliver it now,” and “deliver it when XYZ happens in the future.” Abnormal functioning of such instructions can explain the developmental delays, plateaus, spurts, separation of brain functions, and changing clinical picture of both autism spectrum disorders and schizophrenia.
Now we come to the crucial question, what could cause micro-RNA to malfunction? Unfortunately, tools to study RNA directly are just being developed, and no direct evidence is available so far. However, with regard to other possible causes, it is important to note that no specific or unique environmental factors or abnormal brain structures or nerve cells have yet been found in either disorder. This, in spite of extensive efforts on our part and at research centers throughout the world. The search continues, and hopefully will bear fruit.
On a more positive note, however, there is some evidence from family studies that is consistent with our theory that abnormal micro-RNA plays a causative role. Both disorders, to put it in the vernacular, tend to “run in families.” In autistic spectrum disorder we showed many years ago that if a couple has an affected child, the chances of each following pregnancy producing an affected child is ten percent. We also observed that autistic parents had many more than expected autistic children, and that in pairs of identical twins, almost always both were affected. Similarly, with schizophrenia, there is a higher probability that affected parents will have affected children. These observations are consistent with the theory that abnormal micro-RNA could be a crucial link in the cause of autistic spectrum disorder and schizophrenia.
You might be wondering, “Can the abnormal micro-RNA account for the different clinical types of autism spectrum disorder and schizophrenia, and if so, how?” The answer to the first part is yes, and here’s how. The time of onset and clinical course varies in each individual depending upon exact segments of micro-RNA that are involved and their degree of abnormality.
To explain this further, lets first look at severe, or “classical autism.” Here the degree of abnormal micro-RNA is most severe, has its earliest, and its most pathological effects. These infants exhibit developmental delays from the earliest months of life. They do not gaze at their mothers, do not have smiling responses, remain mute, and are unable to modulate sensations (they appear deaf – then hypersensitive to sounds, do not react to painful stimuli – then become sensitive to the slight pressure of their clothes, etc.). They may not begin speaking until age four or five, or even later. Fortunately, in the majority of these cases, development recommences and they show later spurts of development.
In clinically defined “mild” or “high functioning” autism, speech and language may begin on time but develop slowly, and social relatedness and sensory motor modulation may be only slightly delayed. Here we postulate a milder degree of abnormality in their micro-RNA, with a greater chance of remission with age.
In the mildest form of autism, called Asperger’s Disorder, speech and language and sensory-motor modulation usually develop on schedule, and are minimally affected. However, social relatedness lags and is prominent. “Social blindness” is the term we use to describe this main symptom. Here, we postulate that the abnormal micro-RNA developmental disturbance is the mildest and impairs primarily just the parts of the brain that are involved in social relatedness.
In schizophrenia, as we pointed out before, a developmental spurt normally occurs in the frontal lobes during late adolescence. This is when abnormal micro-RNA does its damage. Instead of orchestrating normal growth and organization of the brain, the “on” and “off” switches malfunction, and the classic “positive” and “negative” symptoms of schizophrenia appear. For example, feelings may get blunted (“flattening of affect”), or misplaced (“inappropriate affect”), and sounds may be heard and body sensations felt when there are no external sources (“auditory and somatic hallucinations”). Also, internally generated optical sensations (“visual hallucinations”), and faulty reality testing (“psychosis”) may occur. Attempts by such stricken individuals to explain these strange phenomena arising from within their brains would be interpreted as symptoms of madness.
As in autistic spectrum disorder, the severity of the micro-RNA abnormality determines the severity of the symptoms. If only mild disruption occurs, the clinical picture is called “schizo-affective” disorder. More serious disruption would lead to classic “paranoid”, “hebephrenic”, or “simple” types, and extremely abnormal micro-RNA could lead to the “catatonic” and “deteriorating” types.
Both autistic spectrum disorder and schizophrenia are known as “remittent” disorders because their natural history may show spontaneous improvements in certain cases. For example, it is well known that the majority of autistic children improve with age, and one third of schizophrenia patients are known to have only one episode and never relapse. This, we suggest, is due to the fact that developmental changes which get “switched off” can get “switched on” to re-establish normal developmental and coordination of developmental pathways.
Summary
To sum things up, we propose the following theory: The symptoms of autistic spectrum disorder and schizophrenia express abnormal development of the brain. This abnormal development is caused by abnormal micro-RNA programming. The degree of severity and clinical course of the disorders is determined by the segments of micro-RNA involved and their degree of abnormality.
Suggestions for Further Reading:
- Ritvo, E. Understanding the Nature of Autism and Asperger’s Disorder: Forty years of clinical practice and pioneering research. Jessica Kingsley Pub. London, 2006
- John S Mattick, The hidden genetic program of complex organisms, Scientific American, Sept. 2004
- Gregory Mauszek and Zohreh Talebizadeh, autism genetic database including autism susceptibility gene-cnv’s integrated with known noncoding RNA’s and fragile sites, BMC Medical Genetics, 2009. 10.102
- Ritvo, R, Ritvo, E, Ritvo, M, Clinical Evidence that Asperger’s Disorder is a Mild Form or Autism, Comprehensive Psychiatry, Volume 49, issue 1, Jan 2008 pp 1-5
