Abstract

Autism biology is present by the first month of pregnancy, and biological differences between profound and mild autism are likewise present at that time. In within-child designs, profound autism biology begins with accelerated and excessive cell proliferation that leads to overgrowth of cortical brain organoids (BCO), cell stress and DNA damage, altered neurogenesis, reduced axon sprouting, deviant cell migration, reduced spontaneous neural activity, reduced synaptogenesis, and reduced complexity of neural firing patterns. These profound autism embryonic differences are statistically correlated with and related to severe social symptom severity; reduced social attention, adaptive behavior level, IQ, language and social neural activity; increased overgrowth of social cortex by about 2 years of age. For example, more embryonic BCO overgrowth is correlated with more the severe social symptoms by age 2. More excess of cells generated is correlated with greater early brain overgrowth by age 2. More reduced the neural firing patterns is correlated with more reduced adaptive behavior abilities. Thus, profound autism is caused by progressive, multi-stage, multi-process pathobiology beginning in the first month of pregnancy and leading to reduced social neural activity, social attention, adaptive behavior and severe social symptoms. This knowledge of profound autism embryonic relationships with outcome clinical and neural patterns has emerged from within-child iPSC research designs. Profound autism is not a mystery, nor is it an intractable hodgepodge of different pathobiologies in different children. Instead, it is knowable and identifiable at early ages when treatment can begin.