Evaluating Genetic Risk Factors for Childhood-Onset Schizophrenia

A study of children and adolescents with very early onset by age 12 (COS) of DSM-III-R defined schizophrenia is examining the clinical, neurobiological, early neurodevelopmental, genetic, and clinical drug response characteristics of these cases, under Protocols 97-M-0126 and 03-M-0035. Earlier studies have documented the continuity between COS and adult-onset cases. The focus has now shifted to increasing the sample size and evaluation of familial risk factors including: psychiatric diagnoses of family members; neuropsychological testing, anatomic and functional brain imaging, and obtaining blood and fibroblasts for cell lines for genetic studies. A study of obstetrical records of COS probands indicated no increase in adverse pre or perinatal events for these cases compared with obstetrical records of their well siblings. In contrast, several findings point to increased genetic risk for these probands. The study of first-degree relatives of these very rare cases addresses the hypothesis that risk factors, most probably genetic, are increased in immediate family members relative both to community controls and to the relatives of patients with chronic, treatment resistant, adult-onset schizophrenia (AOS). A second hypothesis is that COS familial risk factors include similar forms of the developmental delays/abnormalities being observed in the COS probands. Preliminary data suggests greater abnormalities of frontal-parietal circuits for early onset patients and their relatives than seen in adult onset illness. We will examine brain development in unrelated healthy volunteers and siblings of our COS probands by combining resting- and task-related magnetic resonance imaging (MRI) and magnetoencephalography (MEG) imaging. Imaging studies may lead to greater understanding of the course, mechanisms, and influences on brain development of high-risk siblings and may lead to improved understanding of the risk factors, early identification, and optimization of brain maturation. For more than 20 years, imaging has been done under a separate protocol (89-M-0006); however, we now plan to incorporate these imaging studies into this protocol (as well as into our main patient screening and follow-up protocol (03-M-0035) by previously submitted amendment).