Abstract
Autism spectrum disorders (ASD) are characterized by disconnectivity due to disordered neuronal migration, and by neuronal mitochondrial dysfunction. Different pathways involved in neuronal migration are affected by intrauterine hyperglycemia and hyperinsulinemia, while prolonged neonatal hypoglycemia may cause mitochondrial dysfunction. Our hypothesis was that conditions leading to intrauterine hyperglycemia or neonatal hypoglycemia would influence ASD pathogenesis. In this study, we identified risk factors for ASD by searching PubMed with the MeSH terms “autism spectrum disorder” and “risk factors”. We then analyzed the relationship between the risk factors and glucose abnormalities in the mother and the offspring. The relationship between glucose abnormalities and risk factors such as obesity, excessive maternal weight gain, or diabetes mellitus is evident. For risk factors such as malformations or exposure to selective serotonin reuptake inhibitors, the relationship is speculative. In rodents, for example, intrauterine hyperglycemia is associated with malformations, independent of maternal diabetes. In their turn, selective serotonin reuptake inhibitors reduce the signs of neonatal hypoglycemia. Going undetected, prolonged hypoglycemia may harm the neonatal brain. Importantly, our group demonstrated that either high-carbohydrate diets or physical inactivity the day before delivery may influence neonatal glycemia. In that study, of 158 neonates selected to be screened according to maternal lifestyle risk factors, 48 had hypoglycemia. Of note, five of them had not been identified with current screening programs. Controlled studies are needed to clarify whether maternal interventions aiming at maintaining glycemic control, together with screening programs for neonatal hypoglycemia based on maternal lifestyle risk factors and on exposure to specific prenatal medications can reduce the prevalence of ASD.
Highlights
Impaired reelin cleavage by tissue plasminogen activator (tPA)Another mechanism by which intrauterine hyperglycemia may affect neuronal connectivity involves reelin, a glycoprotein that guides neurons and glial cells from the ventricular zone to the cortex
Autism spectrum disorders (ASD) are characterized by persistent deficits in social communication and social interaction, as well as by restricted, repetitive patterns of behavior, interests or activities[1]
This is because neuroimaging performed later in life identifies only chronic mitochondrial dysfunction, such as those related to ATPase mutations, but not transitory mitochondrial dysfunction due to prolonged neonatal hypoglycemia[15]
Summary
Another mechanism by which intrauterine hyperglycemia may affect neuronal connectivity involves reelin, a glycoprotein that guides neurons and glial cells from the ventricular zone to the cortex. There are reasons to suspect that the prevalence of mitochondrial dysfunction has been underestimated This is because neuroimaging performed later in life identifies only chronic mitochondrial dysfunction, such as those related to ATPase mutations, but not transitory mitochondrial dysfunction due to prolonged neonatal hypoglycemia[15]. This paper reviews how glucose abnormalities could influence the pathogenesis of ASD. It analyzes the relationship between risk factors for ASD and maternal and intrauterine hyperglycemia. It suggests studies to evaluate whether maternal interventions aimed at maintaining glycemic control, along with new screening strategies for neonatal hypoglycemia, can reduce the prevalence of ASD in populations at risk
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