What We Have Learned about Autism Spectrum Disorder from Valproic Acid

Hindawi Publishing Corporation Pathology Research International Volume 2013, Article ID 712758, 8 pages http://dx.doi.org/10.1155/2013/712758 Review Article What We Have Learned about Autism Spectrum Disorder from Valproic Acid Taylor Chomiak, Nathanael Turner, and Bin Hu Department of Clinical Neurosciences, Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, Canada T2N 4N1 Correspondence should be addressed to Taylor Chomiak; Received 9 July 2013; Revised 16 October 2013; Accepted 17 October 2013 Academic Editor: Piero Tosi Copyright © 2013 Taylor Chomiak et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Two recent epidemiological investigations in children exposed to valproic acid (VPA) treatment in utero have reported a significant risk associated with neurodevelopmental disorders and autism spectrum disorder (ASD) in particular. Parallel to this work, there is a growing body of animal research literature using VPA as an animal model of ASD. In this focused review we first summarize the epidemiological evidence linking VPA to ASD and then comment on two important neurobiological findings linking VPA to ASD clinicopathology, namely, accelerated or early brain overgrowth and hyperexcitable networks. Improving our understanding of how the drug VPA can alter early development of neurological systems will ultimately improve our understanding of ASD. 1. Introduction The core clinicopathology of autism spectrum disorder (ASD) is currently thought to be characterized by accelerated or early brain tissue overgrowth in regions involved in emotional, social, and communication functions [1–6]. Although much of the earlier evidence regarding accelerated or early brain overgrowth was based on head circumference measurements which may not be as robust as previously thought [7] (but see [8]), more recent longitudinal brain imaging studies have provided further evidence of this abnormal pattern of brain growth in ASD [3, 6]. In fact, abnormal pathological overgrowth in ASD may even persist into adulthood in certain brain regions [9]. Exposure to exogenous chemicals during pregnancy can interfere with cortical development and the maturation of offspring. One such exogenous chemical is the short chain fatty acid valproic acid (VPA). VPA is a drug used in humans primarily for epilepsy and seizure control, although it has been used in many nonepileptic conditions as well [10]. Based on several case studies and small-scale populationbased studies in humans [11–16], in addition to mounting experimental evidence in animals [17–32], VPA has known teratogenicity and has long been suspected as a risk factor for ASD. This year, however, both a prospective study and a large-scale population-based study were published providing the most substantial evidence to date linking prenatal VPA exposure to an increased risk of ASD [33, 34]. Thus, in this paper we will review epidemiological evidence linking VPA to ASD and will discuss two promising leads in the study of ASD in light of human clinical findings and the valproic acid animal model of ASD. 2. Valproic Acid and ASD: Epidemiological Evidence Previous links between the antiepileptic drug VPA and ASD have been found and explored in several case studies and retrospective studies. VPA has long been known to cause physical malformations and developmental disabilities, features of the clinical entity termed fetal valproate syndrome (FVS). Laegreid and colleagues in a 1993 study examined seven children with FVS, two of which were also exposed to benzodiazepines. Two of the seven cases showed autistic traits, with 2 more showing marked developmental delays [16]. The next year Christianson et al. published a case 2 study describing two sibling pairs, all having FVS to various degrees, with one having been diagnosed with infantile autism [11]. A second case of a boy with FVS and ASD was reported by Williams et al. in 1997, followed up with 5 more cases described by the same authors in 2001 [12, 13]. Several larger retrospective studies have also been published providing further support that in utero VPA exposure and fetal valproate syndrome may be linked to an increased risk of ASD, where, for example, it has been reported that the rate of ASD in the children of VPA-treated mothers may be roughly eight times larger than that of the general population [14, 15, 35]. Nevertheless, many of these studies had mentioned the need for future study to confirm the association between VPA and ASD. A recently published prospective cohort study by Bromley et al. [33] explored the relationship between prenatal exposure to anti-epileptic drugs (including VPA) and the risk of neurodevelopmental disorders such as ASD, ADHD, and Dyspraxia. They performed an 11-year study, observing the physical and cognitive development of 415 children born to mothers with epilepsy and nonepileptic controls, with a final outcome of neurodevelopmental diagnosis by 6 years of age. Their results showed a significant increase in the risk of neurodevelopmental disorders in those women taking VPA during pregnancy, with autism being the most frequent diagnosis. The researchers also suspected a dose-dependent mechanism of VPA action but were not able to show it with significance in the study due to low numbers of mothers taking VPA. Although this study had a fairly small cohort and a relatively early endpoint (the average age of diagnosis of ASD in the UK is 5–11 years of age), it was the first prospective study to explore the relationship of VPA to ASD [33]. A much larger and detailed population-based study by Christensen et al. [34] that focused more on ASD than other neurodevelopmental disorders was also published this year. The large sample (655,615 children) and thorough control of the study provide the strongest evidence to date on the relationship between VPA and ASD. Data were from children born in Denmark from 1996 through 2006 over 14 years until the end of 2010. In their analysis they controlled for other known risk factors of ASD and potential confounders such as parental psychiatric disease, parental age at conception, congenital malformations, and maternal epilepsy. They divided the outcomes as Autism Spectrum Disorder (ASD) or childhood autism (the most severe diagnosis, simply referred to as “autism”) and reported absolute risks over the 14 years and hazard ratios (HR) for each. The absolute risks for all children studied for ASD and autism were 1.53% and 0.48%, respectively, whereas for those exposed to VPA in utero, the risks were 4.42% (HR 2.9) and 2.5% (HR 5.2). In fact, even when looking at all stratifications and controls, it was concluded that there was a significantly increased risk of children developing either ASD or autism in women taking (...truncated)