Shared Etiology in Autism Spectrum Disorder and Epilepsy with Functional Disability

Abstract

Autism spectrum disorders and epilepsies are heterogeneous human disorders that have miscellaneous etiologies and pathophysiology. There is considerable risk of frequent epilepsy in autism that facilitates amplified morbidity and mortality. Several biological pathways appear to be involved in disease progression, including gene transcription regulation, cellular growth, synaptic channel function, and maintenance of synaptic structure. Here, abnormalities in excitatory/inhibitory (E/I) balance ratio are reviewed along with part of an epileptiform activity that may drive both overconnectivity and genetic disorders where autism spectrum disorders and epilepsy frequently co-occur. The most current ideas concerning common etiological and molecular mechanisms for co-occurrence of both autism spectrum disorders and epilepsy are discussed along with the powerful pharmacological therapies that protect the cognition and behavior of patients. Better understanding is necessary to identify a biological mechanism that might lead to possible treatments for these neurological disorders.

Figure 1

Genetic pathologies linked with epilepsy and ASD. Synaptic plasticity can be altered by epilepsy or seizures in an early phase of infantile development leading to ASD. Anomalies in neural plasticity can be a result of malfunctioning neurotrophins, signaling molecules, or receptors, resulting in a 30% reduction in dendritic spine density in hippocampus (Cornu Ammonis) CA3 neurons and a 40% reduction in prefrontal cortex (PFC) neurons. Several genes involved in autism and epilepsy pathogenesis have been linked to this biochemical pathway critical in brain development and function.

Figure 2

PI3K/AKT/mTOR pathway. Receptor tyrosine kinase activates the mTOR pathway. Hyperactivation of mTOR1 occurs due to TSC1/2 mutations. Downstream signaling pathway results in lipid and protein synthesis, ribosome biosynthesize, and autophagy. Similarly, mTOR2 downstream signals to lipid and glucose metabolism and cytoskeleton organization which accelerated cell division, proliferation, and irregular gene expression that exemplify TSC; RTKs: receptor tyrosine kinase; PDGFR: plate-let-derived growth factor receptor; KIT: protooncogene receptor; IGFR: insulin-like growth factor receptor; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homologue deleted on chromosome 10; RHEB: Ras homologue a small GTP-binding protein enriched in the brain; TSC: tuberous sclerosis.

Figure 3

Significant characteristics in TSC. This demonstrates the correlation between phenotypic characteristics and predictive risk factors in patients with TSC.