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ß 2-Adrenergic Receptor Activation and Genetic Polymorphisms in Autism: Data from Dizygotic Twins

Department of Neurology and Developmental Medicine Kennedy Krieger Institute, Baltimore, MD

Dorothy E. Crowell

Department of Neurology and Developmental Medicine Kennedy Krieger Institute, Baltimore, MD

Charles G. Eberhart, MD, PhD

Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD

Joshua Copeland

Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD

Craig J. Newschaffer, PhD

Department of Epidemiology Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD

Sarah J. Spence, MD, PhD

Departments of Psychiatry and Pediatrics David Geffen School of Medicine at UCLA, Los Angeles, CA

Andrew W. Zimmerman, MD

Department of Neurology and Developmental Medicine Kennedy Krieger Institute, Baltimore, MD, zimmerman{at}kennedykrieger.org.

Gestational and genetic factors can contribute to autism during infancy and early childhood through their effects on fetal brain development. Previous twin studies have shown strong genetic components for the development of autism, a disorder that can have multiple causes. We investigated the effects of prenatal overstimulation of the ß₂-adrenergic receptor in dizygotic twins who were exposed to terbutaline, a selective ß₂-adrenergic receptor agonist used to treat premature labor, as a gestational factor. As a possible genetic mechanism, we studied two ß₂-adrenergic receptor polymorphisms in twins from whom DNA was available: glycine substitution at codon 16 (16G) and glutamic acid substitution at codon 27 (27E), which show diminished desensitization in vivo compared with the wild-type receptor. Continuous terbutaline exposure for 2 weeks or longer was associated with increased concordance for autism spectrum disorders in dizygotic twins (relative risk = 2.0), with a further increase in the risk for male twins with no other affected siblings (relative risk = 4.4). A significant association was found between the presence of 16G and 27E polymorphisms in autistic patients compared with population controls (P = .006). Prenatal overstimulation of the ß₂-adrenergic receptor by terbutaline or by increased signaling of genetic polymorphisms of the ß₂-adrenergic receptor that have diminished desensitization can affect cellular responses and developmental programs in the fetal brain, leading to autism. (J Child Neurol 2005;20:876—884).

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