Mutations could lead to energy depletion during development, or to neuronal dysfunction and cell death [26]. The ARX VX-809 cell line gene plays a role in regulating neuronal differentiation and proliferation, as well as the migration of neuron progenitors to the developing cortex [26], [34] and [35]. Mutations of the ARX gene have been associated with structural abnormalities such as hypoplastic corpus callosum, small basal ganglia and hippocampi, a defect of the cavum

septum pellucidum, and cerebral atrophy [30], [31] and [32]. Dysfunctional differentiation may also lead to a deficiency of inhibitory interneurons, partly accounting for the intractable seizures observed in these patients [34]. The STXBP1 gene is involved Enzalutamide supplier in the regulation of synaptic vesicle release, and thus, like ARX, also plays a role in neuronal progenitor cell differentiation and migration, because the release of γ-aminobutyric acid and glutamate are important for these functions [26] and [35]. Moreover, mutations of STXBP1 may lead to brainstem abnormalities. Widespread cell death in the

brainstem has been observed in STXBP1 null mice [34]. Brainstem dysfunction was previously implicated in Ohtahara syndrome because the tonic seizures that are prevalent in the syndrome are thought to be generated in the brainstem, and brainstem abnormalities are frequently reported in autopsies of patients with Ohtahara Dolichyl-phosphate-mannose-protein mannosyltransferase syndrome [36]. Interestingly, brainstem dysfunction is also thought to contribute to the development of hypsarrhythmia in infantile spasms [37], and may play a role in the transition from Ohtahara syndrome to West syndrome. Similar to

Ohtahara syndrome, the pathogenesis of early myoclonic encephalopathy is variable, with structural, metabolic, and genetic abnormalities all playing a role. The overall picture in early myoclonic encephalopathy seems to involve a diffuse process particularly involving the brainstem and white matter, possibly leading to deafferentation and hyperexcitability of the cortex. Unlike Ohtahara syndrome, focal structural abnormalities are not frequently observed in early myoclonic encephalopathy. However, progressive, diffuse cortical atrophy has been reported in most cases [12]. Once again, this finding is suggestive of an underlying metabolic or degenerative disorder [9]. Associated metabolic abnormalities are frequently described. In particular, nonketotic hyperglycinemia has been associated with a large number of cases [38], [39] and [40], and this entity was suggested to constitute the most common etiology of early myoclonic encephalopathy [41]. Cases have also been reported in association with d-glyceric acidemia, propionic aciduria, molybdenum cofactor deficiency, pyridoxine deficiency, methylmalonic acidemia, sulfite oxidase deficiency, Menkes disease, and Zellweger syndrome [39], [40], [41], [42], [43] and [44].