beta2-Adrenergic Receptor Activation and Genetic Polymorphisms in Autism: Data from Dizygotic Twins

Abstract and Introduction

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 β₂-adrenergic receptor in dizygotic twins who were exposed to terbutaline, a selective β₂-adrenergic receptor agonist used to treat premature labor, as a gestational factor. As a possible genetic mechanism, we studied two β₂-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 β₂-adrenergic receptor by terbutaline or by increased signaling of genetic polymorphisms of the β₂-adrenergic receptor that have diminished desensitization can affect cellular responses and developmental programs in the fetal brain, leading to autism.

The neurobiologic mechanisms underlying autism are in place before birth. Neuroanatomic studies of postmortem autism brain have documented abnormalities in structures that are well established by the second trimester of gestation,^[1,2,3,4] and high levels of several neuropeptides have been found in blood collected at birth in children who later developed symptoms of autism.^[5] In addition to the unknown molecular and genetic pathways underlying autism, there might also be gestational influences that affect brain development. In our clinical experience, we observed children with autism spectrum disorders whose mothers had been treated with terbutaline to arrest premature labor. Terbutaline, a selective β₂-adrenergic receptor agonist, easily crosses the placental and blood-brain barriers^[6,7] and is often used to arrest premature labor during the second or third trimester,^[8] although its use is no longer officially recommended.^[9] In this report, we investigate the possibility that aberrant in utero activation of β₂-adrenergic receptor signaling contributes to the development of autism.

The β₂-adrenergic receptor is an essential part of the catecholamine system. Stimulation of this receptor by its ligands, norepinephrine and epinephrine, generates cyclic adenosine monophosphate and protein kinase A^[10] as second messengers and increases intracellular calcium.^[11] Continued stimulation of the mature β₂-adrenergic receptor (but not the immature receptor) results in decreased signaling (desensitization) and decreased receptor numbers on the cell surface (down-regulation).

The catecholamines are among the earliest-appearing neurotransmitters in mammalian central and peripheral nervous system development^[12,13,14] and act as growth factors at early stages. They are required for normal nervous system development and for the function of both neural and non-neural tissues in the adult. Thus, abnormalities in this system could account for both developmental and ongoing functional deficits seen in autistic individuals.

Animal studies have shown that overstimulation of the β₂-adrenergic receptor during gestation has detrimental effects on the development of the brain and peripheral nervous system. Pulse doses of terbutaline administered to pregnant rats during the second trimester of gestation result in delays in synaptogenesis, especially in the cerebellum,^[15] deficiencies in cerebellar Purkinje cell numbers, and abnormalities in somatosensory cortex and hippocampal development,^[16] as well as interference with the central and peripheral nervous systems and tissue maturation in prenatally exposed offspring.^[17,18,19] Many of these observed differences in rats are gender selective, favoring males,^[16,20] analogous to the male predominance in autism. Thus, we hypothesized that unusually high levels of prenatal stimulation of the β₂-adrenergic receptor by terbutaline (or other environmental factors) might contribute to the pathogenesis of autism.

Preterm labor occurs frequently in multiple birth pregnancies and increases the risk of exposure to β₂-adrenergic receptor agonists for tocolysis. Consequently, as a preliminary investigation of our hypothesis, we studied dizygotic twins (who are genetically distinct yet share the same uterine environment) with at least one of the pair affected with an autism spectrum diagnosis. There is sufficient frequency of exposure to terbutaline for tocolysis in this group to examine the relative risk of autism as reflected in concordance rates among pairs in which one or both of the twins is affected with autism, using a small sample size.

In addition to environmental factors, such as terbutaline exposure, prenatal overstimulation of the β₂-adrenergic receptor could be driven by genetic factors. We explored one potential genetic influence on the receptor, polymorphisms of the β₂-adrenergic receptor gene, within this framework. We sequenced two polymorphic sites (codons 16 and 27) previously shown to alter β₂-adrenergic receptor function; both glycine at codon 16 (16G) and glutamic acid at codon 27 (27E) confer increased receptor activity (diminished or delayed desensitization or down-regulation) in vivo after β₂ receptor agonist infusion.^[21,22] If present in the fetus, these "more active" polymorphisms could create susceptibility to premature overstimulation by agents such as terbutaline. Thus, we further hypothesized that these more active genetic polymorphisms of the β₂-adrenergic receptor would be more common in affected twins compared with nonautistic controls and might increase prenatal susceptibility to the effects of terbutaline exposure.

J Child Neurol. 2005;20(11):876-884. © 2005 BC Decker, Inc.

Cite this: beta2-Adrenergic Receptor Activation and Genetic Polymorphisms in Autism: Data from Dizygotic Twins - Medscape - Nov 01, 2005.