Abstract
Neurodevelopmental disorders can be caused by mutations in neuronal genes fundamental to brain development. These disorders have severe symptoms ranging from intellectually disability, social and cognitive impairments, and a subset are strongly linked with epilepsy. In this review, we focus on those neurodevelopmental disorders that are frequently characterized by the presence of epilepsy (NDD + E). We loosely group the genes linked to NDD + E with different neuronal functions: transcriptional regulation, intrinsic excitability and synaptic transmission. All these genes have in common a pivotal role in defining the brain architecture and function during early development, and when their function is altered, symptoms can present in the first stages of human life. The relationship with epilepsy is complex. In some NDD + E, epilepsy is a comorbidity and in others seizures appear to be the main cause of the pathology, suggesting that either structural changes (NDD) or neuronal communication (E) can lead to these disorders. Furthermore, grouping the genes that cause NDD + E, we review the uses and limitations of current models of the different disorders, and how different gene therapy strategies are being developed to treat them. We highlight where gene replacement may not be a treatment option, and where innovative therapeutic tools, such as CRISPR‐based gene editing, and new avenues of delivery are required. In general this group of genetically defined disorders, supported increasing knowledge of the mechanisms leading to neurological dysfunction serve as an excellent collection for illustrating the translational potential of gene therapy, including newly emerging tools.
Highlights
Autism spectrum disorder Benign familial neonatal/infantile seizures Calcium-activated potassium channels Cyclin-dependent kinase-like 5 (CDKL5)-deficiency disorder Central nervous system Dravet syndrome Epilepsy Epilepsy-aphasia spectrum Epileptic encephalopathy Epilepsy of infancy with migrating focal seizures Febrile seizure plus Fragile X syndrome Generalized epilepsy with febrile seizure plus Gain-of-function Human cortical spheroids Human embryonic stem cell Human induced pluripotent stem cell Human subpallial spheroids Intellectual disability Knock-out Loss-of-function Neurodevelopmental disorders Neurodevelopmental disorders with epilepsy NMDA receptor Paroxysmal kinesigenic dyskinesia Paroxysmal kinesigenic dyskinesia with infantile convulsions Protein truncating variant Pentylenetetrazole Parvalbumin-positive Rett syndrome
Epileptic encephalopathies (EEs) are a broad group of syndromes characterized by early-onset epilepsies that are often comorbid with Neurodevelopmental disorders (NDDs) (McTague et al 2016)
In this review we will use the general term neurodevelopmental disorders with epilepsy (NDD+E), which includes any disorder affecting the development of the brain associated with some level of epileptic activity, regardless of whether epilepsy is seen as a primary pathological process or a comorbidity
Summary
Recent advances in gene therapy for neurodevelopmental disorders with epilepsy Thomas James Turner1*, Clara Zourray1,2*, Stephanie Schorge, Gabriele Lignani. Keywords (up to 6): Neurodevelopmental, Epilepsy, Gene therapy, ion channels, synaptic proteins, disease models
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