Fetal Valproate Syndrome: Clinical and Neuro‐developmental Features in Two Sibling Pairs

Abstract

SUMMARY The clinical and neurodevelopmental features are presented of four children–two sibling pairs–who were exposed in utero to valproic acid. One of each pair of children presented for diagnosis and assessment of developmental delay; the other sibling was examined at a later date. Three of the children were globally developmentally delayed with marked speech disability, and had dysmorphic features consistent with fetal valproate syndrome. One also had features of infantile autism. The fourth child had some of the dysmorphic features connected with fetal valproate syndrome, but had normal intellect, with his verbal ability being significantly below his non‐verbal ability. He currently attends a school for learning‐disabled children. RÉSUMÉ Le syndrome foetal du valproate: données cliniques et neuro‐développementales dans deux paires de méme fratrie Les données cliniques et neuro‐développementales de quatrc enfants, deux paires de même fratrie, exposés in uteroá l'acide valproïque, sont présentées. Dans chaque paire, un enfant fut examiné initialement pour le diagnostic et l'évaluation d'un retard de développement; l'autre membre de la fratrie étant examiné ultérieurement. Chez trois des enfants, il fut noté un trouble net du langage, des caractéres dysmorphiques en rapport avec le syndrome foetal du valproate. Un enfant présentait en outre le tableau d'un autisme infantile. Le quatriéme enfant présentait quelques éléments dysmorphiques caractéristiques du syndrome foetal de valproate mais son intelligence était normale, bien que ses capacités verbales aient été manifestement inférieures á ses capacités non verbales. II fréquente actuellement une école pour enfants en difficultés d'apprentissage. ZUSAMMENFASSUNG Valproai‐Embryofelopathie: klinische und entwieklungsneurologische Merkmale bei zwei Zwillingspaaren Es werden die klinischen und entwicklungsneurologischen Merkmale bei vier Kindern—zwei Zwillingspaaren beschrieben, die in utero eine Exposition zu Valproinsaura hatten. Je ein Zwillingskind wurde wegen einer Entwicklungsverzögerung vorgestellt und untersucht, die beiden anderen Kinder wurden zu einem spateren Zeitpunkt untersucht. Drei der Kinder hatten eine globale Entwicklungsverzogerung mit ausgeprägten Sprachschwierigkeiten und Dysmorphiezeichen, die für die Valproat‐Embryofetopathie typisch sind. Ein Kind hatte außerdem Symptome eines infantilen Autismus. Das vierte Kind hatte einige der typischen Dysmorphiezeichen, aber es hatte einen normalen Intellekt, wobei seine verbalen Fähigkeiten signifikant schlechter waren als seine non‐verbalen. Zur Zeit besucht es eine Schule für lernbehinderte Kinder. RESUMEN Sindrome fetal del valproate: caracteristicas clinicas y neuroevolutivas en dos pares de hermanos Se presentan las caracteristicas clinicas y neuroevolutivas de cuatro niños (dos pares de hermanos) que habian sido expuestos in utero a ácido valproico. Uno de cada pareja de hermanos acudieron a la consulta para diagnóstico y evaluatión de un retraso en el desarrollo; el otro hermano fue examinado u...

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

“…There was no significant main effect of Drug on the body weight. As expected males were heavier than females (Sex, F (1,32) =35.511, p < 0.05); adults were heavier than juveniles, (Age, F (1,74) =867.251, p < 0.05). A significant Sex×Drug interaction (F (2,74) =4.266, p < 0.05) was explained because female VPA-treated mice, not males, were heavier than the corresponding controls (F (2,32) =6.232, p < 0.05) in both the VPA-100 and VPA-200 dose conditions (Figure 1).…”

“…Exposure to valproic acid (VPA) in pregnancy is associated with a higher incidence of autism spectrum disorder (ASD) by case reports and population studies [1][2][3][4][5][6][7][8][9]. Rodents exposed to VPA prenatally simulate a number of behavioural traits found in ASD [10,11]; eg.…”

Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism

“…As an animal model of autism, the VPA model seems to be the closest possible insult-based model that allows a systematic study from the synaptic to the behavioral level. Several case studies (Christianson et al, 1994;Williams and Hersh, 1997;Williams et al, 2001), as well as a population study (Moore et al, 2000), reported a link between the administration of the anticonvulsant drug VPA during pregnancy and the risk of giving birth to an autistic child. Although several rodent studies explored and established the teratogenic effects of prolonged VPA administration during pregnancy in general (Vorhees 1987a, b) and in the context of autism (Narita et al, 2002;Wagner et al, 2006), we chose the VPA rat model of autism proposed by Rodier et al (1996).…”

“…VPA is one of the teratogens implicated in causing autism in humans (Christianson et al, 1994;Williams and Hersh, 1997;Moore et al, 2000;Williams et al, 2001;Rasalam et al, 2005), when administered around the critical time period of neural tube closure (embryonic day 20-24; Arndt et al, 2005). In rats, a single intraperitoneal (i.p.)…”

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

“…Rett's syndrome, for example, relates to loss of function of the methyl CpG binding protein 2 (MECP2) that regulates transcriptional repression through its interaction with methylated DNA and HDAC1 and HDAC2 (Samaco and Neul, 2011). Epidemiological studies have also demonstrated teratogen exposure during the first trimester to be significantly correlated with an increased risk of developing ASD (Christianson et al, 1994;Rasalam et al, 2005). The developmental emergence of this condition has been associated with abnormal synapse remodelling arising from dysregulation of synaptic development proteins, including cell adhesion molecule function and glycosylation state Pinto et al, 2010;), that inexorably gives rise to an array of neuroanatomical malformations (Courchesne et al, 2011).…”