Identification of the embryonic stage when injury can cause autism has led to the insight that the disorder is initiated by changes in the developing brain stem. The shortening of the hindbrain and loss of cranial nerve neurons in an animal mode of the insult and a human cause of autism resemble features of the Hox-1 transgenic knockout mouse. Thus, it is now possible to suggest a unifying hypothesis regarding the multiple etiologies of autism. We propose that teratogens and genetic defects lead to similar developmental changes in the brain stem because mutations of early developmental genes are the cause of familial cases and the teratogens which cause the disease act by interfering with function of the same genes. The new finding that one of the candidate genes is abnormal in some cases autism supports this hypothesis. This project will continue our attempt to identify genetic causes of autism based on data about the developmental origin and neuroanatomical phenotype responsible for some causes of the disease. We shall examine early developmental genes for mutation in cases of autism, Asperger's syndrome, Moebius syndrome, developmental language disorder with semantic-pragmatic features, and normal controls. It is our hypothesis that these syndromes are related to autism not only behaviorally, but etiologically, as well. Minor physical anomalies and neurological symptoms which have fixed the time of injury in some cases of autism will be investigated in all groups to determine whether there is evidence for the same time of origin in the related disorders. Behaviors affected in autism, including language, emotion, and cognition, will be described in each patient, and the data from biological markers and behavioral descriptions will be used to searched for clusters of cases related in phenotype or etiology. By evaluating the characteristics of all these groups with the same measures, we hope to define relationships that expand or refine the definition of autism. The goal of these studies is to produce biological markers for human causes of autism and provide genetic constructs for animal models of genetically- induced autism. The models will be created in Project I and tested behaviorally in Project II.
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