Mechanisms underlying GRIN2D-associated DEEs and search for an effective treatment

Developmental and epileptic encephalopathies (DEEs) are a group of devastating disorders that comprise global developmental delay and intractable epilepsy. Symptoms include a wide range of cognitive and motoric impairments, severe epileptiform abnormalities, and a shortened life expectancy. Many variants have been identified in association with DEEs; including a de-novo point, missense mutation in an N-methyl D-aspartate glutamatergic receptor (NMDAR) subunit GRIN2D. NMDARs play a key role in synaptic long-term plasticity and excitatory transmission, indicating the severity of the pathology and thus, these individuals exhibit severe symptoms including early onset epilepsy, hypotonia and intellectual disabilities. Insufficient therapeutic technologies exist to treat this disorder, and those that are available, bear great heterogeneity in patient’s response profiles, thus, our aim is to identify a therapy that treats the DEE phenotypes, both developmental and epileptic, while in turn, leaving function brain activity intact. Our research focuses on multiple different aspects in parallel, using a cellular model, a mouse model, and a molecular dynamics model in order to understand the mechanism behind the DEE pathology and the search for a suitable therapy to treat the resulting comorbidities. We are currently analysing the effect of a cholesterol hydroxylase inhibitor on the pathologic phenotype of a mouse model that mimics the human phenotype and have found that this inhibitor results in prolonged survival and the rescue of motor impairments.