Autism spectrum disorder and epileptic encephalopathy: common causes, many questions

Abstract

Epileptic encephalopathies represent a particularly severe form of epilepsy, associated with cognitive and behavioral deficits, including impaired social-communication and restricted, repetitive behaviors that are the hallmarks of autism spectrum disorder (ASD). With the advent of next-generation sequencing, the genetic landscape of epileptic encephalopathies is growing and demonstrates overlap with genes separately implicated in ASD. However, many questions remain about this connection, including whether epileptiform activity itself contributes to the development of ASD symptomatology. In this review, we compiled a database of genes associated with both epileptic encephalopathy and ASD, limiting our purview to Mendelian disorders not including inborn errors of metabolism, and we focused on the connection between ASD and epileptic encephalopathy rather than epilepsy broadly. Our review has four goals: to (1) discuss the overlapping presentations of ASD and monogenic epileptic encephalopathies; (2) examine the impact of the epilepsy itself on neurocognitive features, including ASD, in monogenic epileptic encephalopathies; (3) outline many of the genetic causes responsible for both ASD and epileptic encephalopathy; (4) provide an illustrative example of a final common pathway that may be implicated in both ASD and epileptic encephalopathy. We demonstrate that autistic features are a common association with monogenic epileptic encephalopathies. Certain epileptic encephalopathy syndromes, like infantile spasms, are especially linked to the development of ASD. The connection between seizures themselves and neurobehavioral deficits in these monogenic encephalopathies remains open to debate. Finally, advances in genetics have revealed many genes that overlap in ties to both ASD and epileptic encephalopathy and that play a role in diverse central nervous system processes. Increased attention to the autistic features of monogenic epileptic encephalopathies is warranted for both researchers and clinicians alike.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-017-9202-0) contains supplementary material, which is available to authorized users.

Contribution of Transferrin and Ceruloplasmin Neurotransmission and Oxidant/Antioxidant Status to the Effects of Everolimus: A Case Series

“…Her EEG recording indicated high voltage, irregular slow waves intermixed with spikes and polyspikes (hypsarrhythmia) (Figure 1). The presence of such epileptogenic lesions represents epileptiform discharges [11], which are brief abnormalities that stand out from the EEG background, usually due to a peak or sharp appearance, including hypsarrhythmia.…”

“…As mTOR regulates neuronal excitability in established neural circuits, mTOR hyperactivation enhances neural excitability related to seizures [1], inducing epileptiform discharges (referred to as spikes) on electroencephalograms (EEGs) and may contribute to progressive brain dysfunction, including autistic symptoms [11].…”

Comorbidity between epilepsy and autism from the point of view of ontogenesis

“…Из известных на сегодня 62 генов, ответственных за эпилептические энцефалопатии, 34 также являются фактором риска для развития аутизма. Этот набор генов включает как идиопатический аутизм (когда РАС -основное состояние), так и синдромальный (сочетается с другими клиническими симптомами и синдромами) [74]. Из генетических мутаций, связанных с эпилептическими энцефалопатиями и наи более часто являющихся причиной РАС, выделяют повреждения в гене SCN2A.…”

Colors of Autism Spectrum: A Single Paradigm Explains the Heterogeneity in Autism Spectrum Disorder

“…As such, it is fragile in many ways, including Seizures may be due to high excitation/inhibition ratios, which are also one of the main theoretical routes proposed in autism models (Rubenstein and Merzenich, 2003). In turn, a high degree of genetic overlap can be expected, and indeed, ASD and epileptic encephalopathy seem to have many common genetic causes (Srivastava and Sahin, 2017). Restricting particular features, autismepilepsy phenotypes with macrocephaly may lead to the separation of relevant subtypes and to improved genetic screening, as suggested by Marchese et al (2014).…”

“…The quest to discover causality relations, including the necessary and sufficient conditions, is difficult. However, the cited genetic study (Srivastava and Sahin, 2017) indicates that the genes involved in comorbid disorders have undergone more purifying selection than the genes unique to ASD.…”