Thursday, March 6, 2014

In the early access view of the journal, Annals of Neurology, Doctors Lemke and colleagues, representing a large consortium of investigators, sought to evaluate 357 patients comprising a vast spectrum of epilepsy disorders for genes known to contribute to epilepsy and/or intellectual disability (ID).

  • The investigators found de novo mutations in genes named GRIN2B encoding the NR2B subunit of the NMDA receptor in two individuals with West syndrome and severe developmental delay, as well as one individual with ID and focal epilepsy.

  • The patient with ID and focal epilepsy had a mutation in the extracellular gluten binding domain, whereas both West syndrome patients carried mutations within the NR2B ion channel-forming re-entrant loop.

  • Subsequent screening of 47 patients with unexplained infantile spasms did not reveal additional de novo mutations but detected a carrier of novel inherited GRIN2B splice site variants in close proximity.

  • Mutations found resulted in reduced magnesium block and a higher calcium permeability, leading to a dramatically increased calcium influx; whereas other mutations cause less severe disturbance of channel function corresponding to the milder patient presentation.

  • The authors conclude that GRIN2B gain of function mutations is one of the causes of West syndrome with severe developmental delay, as well as of ID with childhood onset focal epilepsy. Severely disturbed channel function in the NMDA receptor led to severe clinical epilepsy and ID.  

Authored by: Joseph I. Sirven MD on 3/2014