Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies

Abstract

Prenatal exposure to valproate (VPA), an antiepileptic drug, has been associated with fetal valproate spectrum disorders (FVSD), a clinical condition including congenital malformations, developmental delay, intellectual disability as well as autism spectrum disorder, together with a distinctive facial appearance. VPA is a known inhibitor of histone deacetylase which regulates the chromatin state. Interestingly, perturbations of this epigenetic balance are associated with chromatinopathies, a heterogeneous group of Mendelian disorders arising from mutations in components of the epigenetic machinery. Patients affected from these disorders display a plethora of clinical signs, mainly neurological deficits and intellectual disability, together with distinctive craniofacial dysmorphisms. Remarkably, critically examining the phenotype of FVSD and chromatinopathies, they shared several overlapping features that can be observed despite the different etiologies of these disorders, suggesting the possible existence of a common perturbed mechanism(s) during embryonic development.

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

“…Lopez-Atalaya et al showed that deficits in the levels of histone H2A and H2B acetylation in lymphoblastoid cell lines derived from two RSTS1-related CREBBP patients were rescued by treatment with TSA [ 175 ]. Furthermore, Parodi et al very recently reviewed the overlap between chromatinopathies and fetal valproate syndrome, highlighting valproic acid as a promising therapeutic approach for RSTS [ 176 ]. However, these results should be confirmed in a therapeutic trial with a large cohort of patients as HDACi represent a therapeutic option for RSTS patients.…”

Measures to Mitigate Sodium Valproate Use in Pregnant Women With Epilepsy

“…Another study demonstrated that valproate use by mothers had produced offspring who demonstrated a significant reduction in performance at school while comparing children who were not exposed to antiepileptic medication and those whose mothers had reported lamotrigine use [27]. Prenatal antiepileptic medication exposure causes retardation of growth in infants in comparison to neonates who are not exposed to medication [28]. Some of the probable mechanisms responsible for the causation of fetal valproate syndrome disorders include programmed cell death and degeneration of neurons seen in the brain of rats (prenatally exposed to valproic acid) during development and increased plasticity of synapses shown in the medial prefrontal cortex of these rats, and reduction in folic acid levels.…”

Valproate Targets Mammalian Gastrulation Impairing Neural Tissue Differentiation and Development of the Placental Source In Vitro

“…On the other hand, VPA is an epigenetic agent, a histone deacetylase inhibitor (HDACi) that acetylates histones and thus affects chromatin state and gene expression [ 4 , 5 ]. Indeed, some chromatinopathies, a heterogeneous group of Mendelian disorders, were found to be phenocopies of FVSD [ 6 ], implying the necessity for further research on epigenetic mechanisms such as posttranslational histone modifications during development. In a seven-day in vitro culture of the mouse gastrulating embryo proper, HDACi VPA downregulated and the other HDACi trichostatin A (TSA) upregulated the expression of pluripotency and the three germ-layer-differentiation genes [ 7 ].…”