Neurological, Neurodevelopmental and Treatment Outcomes in Patients With Pyruvate Dehydrogenase Complex Deficiency.

Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures, affecting 0.5%–1% of the worldwide population (Milligan ; Tellez‐Zenteno et al. ). Patients with epilepsy have an increased risk of co‐morbid disorders and increased premature mortality. Despite the development of new antiseizure medications (ASMs), one third of affected individuals continue to experience seizures. The epilepsies represent a range of conditions including common and rare epilepsies, with the former largely caused by polygenic genetic influences and/or environmental factors, and the latter by pathogenic variants affecting a number of cellular pathways (Van Loo et al. ). More than 900 genes have been associated with epilepsy to date, with more than 90% of genetic epilepsies associated with developmental delay or regression, also known as developmental and epileptic encephalopathies (Oliver et al. ; Scheffer et al. ). Epilepsy can also occur secondary to a neurological insult, such as traumatic or hypoxic brain injury, brain tumors, central nervous system infections, stroke and status epilepticus (SE), resulting in acquired or symptomatic epilepsies (AE). The initial insult is followed by a latent and then chronic phase with recurrent spontaneous seizure activity (Fisher et al. ). Temporal lobe epilepsy (TLE), particularly mesial temporal lobe epilepsy (MTLE), is a common form of acquired epilepsy (Bertram ; Heinemann et al. ). TLE is often drug resistant and can be triggered by insults including hypoxia, infections or tumors, with complex febrile seizures also being a risk factor (Engel Jr. ; Fisher et al. ). The process which transforms the healthy brain into an epileptic brain with a propensity for spontaneous seizures is referred to as epileptogenesis and is accompanied by functional and structural alterations (Pitkänen and Lukasiuk ). Alongside neuronal subpopulations, glial cells including astrocytes have been implicated in epileptogenesis. Astrocytes are the most numerous glial cells in the human central nervous system (CNS) and are key players in many crucial brain functions such as learning and memory (Khakh and Sofroniew ; Sofroniew and Vinters ). Traditionally, astrocytes were thought to be a homogeneous cell population, but recent research has highlighted a remarkable heterogeneity in astrocyte development and function (Holt ). Furthermore, it has been suggested that astrocytes may be matched to neuronal subpopulations to support local circuits. Astrocytic processes ensheath synapses, thus making them part of the synaptic structure alongside pre‐ and postsynaptic elements, known as the tripartite synapse (Semyanov and Verkhratsky ) where they can modulate neuronal activity. They also form part of the innate immune response of the brain, where they become reactive in response to injury and disease (Escartin et al. ) and undergo morphological, molecular and functional changes.