GABAergic Interneurons in Severe Early Epileptic Encephalopathy with a Suppression-Burst Pattern: A Continuum of Pathology

Abstract

Early infantile epileptic encephalopathy (EIEE) and early myoclonic encephalopathy (EME) are catastrophic epilepsies starting in the neonatal period. The International League Against Epilepsy classifies both of them as generalized symptomatic epilepsies of nonspecific etiology, characterized by early onset, presence of burst-suppression EEG pattern and serious prognosis. The critical difference lies in their presumed etiologies and the prevailing clinical seizure type at onset: EIEE (known as Ohtahara syndrome) usually manifests with tonic seizures, while EME is mainly associated with myoclonic seizures. However, the distinction between those two pathologies is not always easy due to clinical and etiological overlap. Both mutations in the ARX gene for EIEE (OMIM 308350) and disruption in the neuregulin receptor ErbB4 for EME (OMIM 609304) impair interneuron migration and alter the number of GABAergic interneurons in the postnatal cortex. These findings could explain the occurrence of severe epileptic encephalopathy with a burst-suppression pattern and represent a continuum of progressive pathology. In the present chapter we review the genes involved in EIEE and EME including their possible mechanisms of action, particularly via GABAegic interneurons. Their clinical manifestations are myoclonic or tonic seizures, which represent the expression of the underlying pathology and correlate with degree of brain damage.

From nephron to neuron: an exciting journey in search of a cure for epilepsy

“…In recent years, the idea is gaining strength that impairment of the inhibitory systems could be at the root of epileptic seizures [1]. More specifically, a crucial role has been proposed for interneurons secreting γ-Aminobutyric acid (GABA) as their primary neurotransmitter [2][3][4]. GABA amino acid neurotransmitter is responsible for most of the fast-inhibitory neurotransmission in the brain by acting on its putative ionotropic receptors type A (GABA A R).…”