This is a continuation of previous posts on individualized treatment for infantile-onset epilepsy, made possible by Emory scientists Stephen Traynelis and Hongjie Yuanâ€™s collaboration with the NIH Undiagnosed Diseases Program. A companion paper containing some clinical details was recently published in Annals of Clinical and Translational Neurology.

Memantine, which was found to be effective for this particular child, is normally used to treat symptoms of Alzheimerâ€™s disease. He has a mutation in a gene encoding a NMDA receptor, an important signaling molecule in the brain, which hyperactivates the receptor. Treatment with memantine reduced his seizure frequency from 11 per week to three per week, and eliminated one type of seizure, myoclonic jerks. It allowed doctors to taper off conventional anticonvulsant drugs, which were having little effect anyway. His cognitive ability has remained unchanged.

The team also discovered that the compound dextromethorphan, found in many over-the-counter cough medicines, was effective in the laboratory in counteracting the effects of a GRIN2A mutation found in another patient. However, these effects were mutually exclusive, because the molecular effects of the mutations are different; memantine helps L812M, while dextromethorphan helps N615K.

Yuan and Traynelis report they have an Fake Oakleys ongoing collaboration with UDP investigators to analyze the effects of mutations in NMDA receptor genes. That means more intriguing case reports are coming, they say.

Tyler Pierson, MD, PhD, lead author of the clinical paper who is now at Cedars-Sinai Medical Center in Los Angeles, and David Adams, MD, PhD, senior staff clinician at NIH, provided some additional information on the patient in the study, shown here in a Q + A format.

How old is the child now? 9-10 years old

How much of the familyâ€™s genomes did you need to sequence to pinpoint the GRIN2A mutation as critical? [Adams] Our discovery techniques rely on starting with exomes from the entire family. This allows us to filter out variants that do not segregate with disease. For new dominant mutations, each site can be tested to see if it shows up in the parents or unaffected siblings. We do use a variety of databases to look for common variants that are too frequent to be consistent with a severe early-onset illness.

Explain the rationale behind the choices of memantine and dextromorphan. These compounds are FDA-approved, and are known to bind to the NMDA receptor and decrease its activity. Memantine had been tested in children previously and also had been tested for epilepsy in animal models.

GRIN2A mutations have been identified in other cases of early-onset epileptic encephalopathy, as well as a less severe epilepsy-aphasia syndrome. Do your results suggest that memantine or dextromorphan may be beneficial for any of those cases (depending on the precise mutation)? Yes, but each case would likely need to have specific testing as we did with this family. Likely cases where it could work would be ones with a similar single amino acid change causing increased activity. Cases where the mutation does not allow for Foakleys On sale expression of the mutated NMDA receptor subunit would be much less likely to respond to memantine.

Can you describe the impact that the reduction in seizure frequency has for the patient and his caregivers? Are they relieved to discover the cause of his condition? Are they disappointed that memantine did not have more of an effect, even if that expectation may be unrealistic? Your paper suggests that earlier diagnosis may have allowed more to be achieved.

[Pierson] The family are close friends of mine and the father and I often trade barbs over our rival football teams (him: Giants; me: Eagles). They are quite thankful to discover the cause and that it is a de novo mutation, since they worried about the risks their other children could have with having children; it turns out there is pretty much no chance of this. Getting a genetic answer also has a psychological effect of taking away the worry from the parents that they might have done “something wrong” and brought this on their child. This is a VERY common feeling among families with children who have rare neurogenetic disorders.

The reduction of seizure number and subsequently the number of drugs he had to take has allowed them to take life a little easier. They are extremely pleased with this result and we were very clear with the family that the goal was to reduce the number of seizures and it was very unlikely that his cognition or development would improve.

One of the ideas is that his poor development was the result of uncontrolled seizure activity (hence the term “epileptic encephalopathy”) and perhaps if memantine was available it might have made a significant impact when he was a neonate.