Epilepsy in Mowat‐Wilson syndrome: Is it a matter of GABA?

Abstract

We have read with interest the latest advances regarding ZEB2 gene function in neuroembryology and its connections with epilepsy (McKinsey et al., 2013; Van den Berghe et al., 2013). Zinc finger E-box binding homeobox 2 (ZEB2, MIM#60580), also annotated as ZFHX1B and SIP1, is a member of the two-handed zinc finger/homeodomain transcription factors. Its role during development has been confirmed by invalidation in mice, which revealed arrest of embryonic development with severe neural plate and somatogenesis defects, as well as migratory failure of neural crest cells (Van de Putte et al., 2003). In humans, deletions or mutations of ZEB2 cause the Mowat-Wilson syndrome (MWS), which is characterized by a distinctive facial appearance, intellectual disability, and variable other features including agenesis of the corpus callosum and Hirschsprung disease (Mowat et al., 2003). Epilepsy is one of the main features of MWS, with a prevalence of about 70–75%. We recently delineated the electroclinical phenotype of epilepsy in MWS. In these patients, epilepsy is usually characterized by frontal lobe and atypical absence seizures, often preceded by fever-triggered seizures; in addition, we observed an age-dependent electroencephalography (EEG) pattern with frequent diffuse frontal dominant spike and wave discharges during the awake state and a near to continuous spike and wave activity during slow sleep (Cordelli et al., 2013). Some authors suggested that epilepsy in MWS could be the result of cerebral malformations (Engenheiro et al., 2008). Instead, we noticed that MRI did not disclose any cortical malformations clearly associated with epilepsy and that the electroclinical pattern (which was present irrespective of magnetic resonance imaging [MRI] findings) suggested an age-related disorder with a genetic, rather than a structural-malformative, etiology. Meanwhile, McKinsey and Van den Berghe et al. demonstrated the influence of ZEB2 on the neurogenesis of cortical γ-aminobutyric acid (GABA)ergic interneurons. Their studies highlight that the lack of ZEB2 prevents the repression of NKX2-1 homeobox transcription factor, the expression of which provokes the differentiation of the progenitors in striatal interneurons rather than cortical ones. Deficit of GABAergic inhibition is supposed to underlie most forms of seizures, including focal and absence seizures (Yalçın, 2012). However, results of GABAergic inhibition are brain-area and inhibitory-pathway specific. In fact, within one brain region, at a given time of life, some modifications in these circuitries will appear as proepileptic and others as antiepileptic (Bernard et al., 2000). Therefore, the switch between cortical and striatal GABAergic interneurons determined by mutations of ZEB2 could suggest a mechanism for the epilepsy observed in MWS, as proposed by McKinsey and Van den Berghe. From our point of view, that is the one of the clinicians, we strongly support this hypothesis, as the age-related electroclinical pattern we have detected in vivo is reminiscent of the idea of a genetic form of epilepsy and is scarcely influenced by brain macroanatomy. In conclusion, we feel that these observations could be of high importance in understanding how epilepsy is determined in patients with MWS. New interesting scenarios in terms of treatment are now opened. The authors declare no conflict of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.