HCN1 epilepsy: From genetics and mechanisms to precision therapies

We describe how mouse models have furthered our understanding of the phenotype of, and efficacious treatment options for, HCN1 epilepsy, and we explore the next steps needed to advance our knowledge of this devastating disease. AbstractPathogenic variation inHCN1 is now an established cause of epilepsy and intellectual disability. Variation inHCN1 causes a spectrum of disease with a genotype –phenotype relationship emerging. De novo pathogenic variants that occur in the transmembrane domains of the channel typically cause a cation ‘leak’ that associates with severe developmental and epileptic encephalopathy (DEE). Genotype–phenotype associations for variants that fall outside of the transmembrane domains are less well established but do include milder forms of epilepsy that can be either de novo or inherited.HCN1 DEE mouse models have been generated which recapitulate the seizures and learning difficulties seen in human patients. These mice have also acted as powerful preclinical models which share pharmacoresponsiveness with humanHCN1 DEE patients. Data from these mouse models support the conclusion that anti-seizure medications with sodium channel block as their primary mechanism of action should be used with caution inHCN1 DEE. Other comorbidities ofHCN1 DEE including retinal dysfunction have also been modelled inHCN1 DEE mice, suggestingHCN1 variants can cause a dramatically reduced sensitivity to light with limited ability to process temporal information. Our und...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: REVIEW Source Type: research