Ion channels and brain malformations. When the “channelopathy” concept first emerged – the idea that dysfunction of neuronal ion channels leads to neurological disease including epilepsy – it seemed implausible that such dysfunction could lead to malformations of cortical development. However, recent research has suggested that ion channel dysfunction may indeed be linked with brain malformations. In 2017, we saw convincing evidence that germline de novo variants in GRIN2B can cause malformations of cortical development. Some suggestive, but less conclusive, evidence has also linked SCN1A and SCN2A to brain malformations. Now Fry and collaborators demonstrate that de novo pathogenic variants in GRIN1 can also cause significant polymicrogyria, expanding the phenotypic spectrum of GRIN1-related disorders. As a disclaimer, I am also a co-author on the publication by Fry and collaborators. Continue reading
Category Archives: GRIN1
The genetic sibling of NMDA receptor encephalitis
GRIN1 encephalopathy. In the early 2000s Dalmau and collaborators observed a condition in women with ovarian teratoma who presented with psychosis or memory problems and rapidly progressing neurological deficits that required prolonged intensive care support. Auto-antibodies against the NR1 subunit of the NMDA receptor were found to be the causative agent. The clinical spectrum of anti-NMDA-receptor encephalitis has since expanded significantly and this initial discovery fueled the discovery of an entirely disease mechanism, the concept of the autoimmune encephalitis. In a recent publication in Neurology, we describe a novel neurodevelopmental syndrome affecting the gene for the NR1 receptor, the genetic sibling of NMDAR encephalitis. This blog post is about the unexpected overlap of autoimmune disorders with the genetic epilepsies and the spectrum of GRIN1-related genetic encephalopathies. Continue reading
