An approach to etiopathogenetic background of autism
Autism is a developmental disorder clinically expressed in early childhood, characterized by lack of harmonious communication, autistic aloneness, obsessive desire for the preservation of sameness, good cognitive potentialities and frequent manifestations of social and stereotypical behavioral characteristics. Some of the autistic parsons may demonstrate exceptional talents in music, drawing or calculation, despite their functional disability in social performances. There is no general consensus regarding potential etiology of this condition, since the etiopathogenetic background of autism seems to be multifactorial, including morphological alterations of the cortical and subcortical neuronal circuits as well as potential involvement of several neurotransmitters in various areas of the cerebrum and the cerebellum. However, from the broad spectrum of autistic phenomena only a small fraction may be interpreted on the basis of the morphological and neurochemical alterations of the brain. Morphological alterations of the cerebellum such as reduction of Purkinje cells and marked abbreviation of their dendritic arborization in the cortex of the vermis and the hemispheres and variable decrease in granules cells is a rather frequent finding in a substantial number of brains in autism. There is no evidence of reactive gliosis, as a rule, suggesting that the alterations have occurred early in development of the cerebellum. It is worthwhile to mention that changes of the cytoarchitecture in the amygdala, the septum pellucidum, the cingulate gyrus, the hippocampus, the dentate gyrus and the cortex of the frontal lobe, which have been described in autistic children, may be associated with the behavioral changes and the stereotypic phenomena, which dominate in autistic manifestations in the majority of the cases. From the neurochemical point of view, research in autism revealed that in the majority of the cases a variable disequilibrium of the neurotransmitters may play an important role in the etiopathogenesis of this condition. Several studies, focused on serotonergic system, revealed a marked increase of serotonin synthesis, activity, metabolism and serotonin receptors uptake in autistic subjects in the frontal cortex, the thalamus and cerebellum, which might be one of the main pathogenetic factors underlying dysfunction in autism. The serotonergic system is known to modulate mood, emotion, sleep and appetite and thus it may be implicated in numerous behavioural and physiological functions affected in autism. In addition to serotonin changes, other monoamines such as dopamine and norepinephrin seems to contribute substantially in the neurotransmitters' disequilibrium in autism. Elevated homovanillic acid in the cerebrospinal fluid of children suffered from autism suggests increased synthesis of dopamine in the brain. There is a substantial body of evidence that GABA, which plays an important role in neuroinhibition and neuromodulation in cortical and subcortical neuronal circuits, as well as GABA receptors decrease in the hippocampus in a considerable number of autistic children. Nicotin receptors á4 and â2 decrease in the majority of the brains of autistic children. The same receptors are also decreased in many cases of mental retardation. Alterations of the activity of the excitatory amino acids, such as glutamate and aspartate elevations may also play an important role in the speech and behavioural disturbances in autistic children. In addition, reelin mutations may be considered as an etiological factor of the alterations of the cytoarchitecture in autism, because they might cause an abnormal laminar pattern during the development of the cerebral and cerebellar cortices, which might contribute to developmental disorders such as specific learning disorders, since reelin play an crucial role in regulating neuronal migration, during organogenesis of the central nervous system. The amino acid structure of reelin is very similar to that of proteins known to be secreted into the extracellular matrix surrounding neurons. Other neuropeptides, such as substance P and endorphins may also be involved in the unstable balance of the neurotransmitters and signal systems in autism. Although the limited available date suggest that there is no inborn errors in metabolism in autistic children, histidinemia has been reported in some cases. Studies focused on the relationship between autism and autoimmune disorders failed to reveal any autoimmune mechanism contributing to pathogenetic background of autism. Further neuropathological and neurochemical investigations as well as studies of the developmental neurobiologic mechanisms have a critical value in plotting the pathogenetic profile of autism and in developing new therapeutic approaches.
Key words: Autism, neurotransmitters, neuropathology, neurochemistry, ultrastructure.