Before the cardiologist goes nuclear w/ stress #AHA17

Measuring troponin in CAD patients before embarking on stress testing may provide Read more

Virus hunting season open

Previously unknown viruses, identified by Winship + UCSF scientists, come from a patient with a melanoma that had metastasized to the Read more

#AHA17 highlight: cardiac pacemaker cells

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NMDA receptor

Nerve gas, angel dust and genetic epilepsy

Last week, Lab Land noticed similarities between two independent lines of research from the Escayg and Traynelis/Yuan labs at Emory. Both were published recently and deal with rare forms of genetic epilepsy, in which molecular understanding of the cause leads to individualized treatment, albeit with limited benefit.

Both conditions are linked to an excess of neuronal excitation, and both can be addressed using medications that have also been tested for Alzheimer’s. A critical difference is that memantine is FDA-approved for Alzheimer’s, but huperzine A is not.

What condition? Dravet syndrome/GEFS+ Epilepsy-aphasia syndrome
What gene is mutated? SCN1A – sodium ion channel GRIN2A – NMDA receptor subunit
What is the beneficial drug? Huperzine A Memantine
How does the drug work? Acetylcholinesterase inhibitor NMDA receptor antagonist
Other drugs that use the same mechanism Alzheimer’s medications such as donepezil

Irreversible + stronger: insecticides, nerve gas

Ketamine, phencyclidine (aka PCP)
Posted on by Quinn Eastman in Neuro Leave a comment

NMDA receptors: triple-quadruple axel

NMDA receptors are saddled with an unwieldy name, but they are some of the most important* signaling molecules in the brain, both for learning and memory and in neurological and psychiatric diseases.

Kasper Hansen, a postdoc from Stephen Traynelis’ lab who is establishing his own at the University of Montana, is lead author on a recent paper in Neuron, which could spur research on NMDA receptors’ pharmacological properties.

The NMDA receptors in the brain are actually mix-and-match assemblies of four subunits, and most of the time in the brain, three different proteins come together to make one receptor, the authors explain. In the laboratory, it has been easier to study simpler, more homogenous, but also more artificial constructs. Hansen and his colleagues developed a way to build replicas of the more complicated NMDA receptors found in the brain and probe their distinct responses to drugs. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Personalized molecular medicine part 3

This is a continuation of previous posts on individualized treatment for infantile-onset epilepsy, made possible by Emory scientists Stephen Traynelis and Hongjie Yuan’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 Alzheimer’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. Read more

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Personalized molecular medicine part 2

This is a continuation of the post from last week on the early-onset epilepsy patient, whom doctors were able to devise an individualized treatment for. The treatment was based on Emory research on the molecular effects of a mutation in the patient’s GRIN2A gene, discovered through whole exome sequencing.*

For this patient, investigators were able to find the Ray Ban Baratas cause for a previously difficult to diagnose case, and then use a medication usually used for Alzheimer’s disease (memantine) to reduce his seizure frequency.

Last week, I posed the question: how often do we move from a disease-causing mutation to tailored treatment? Read more

Posted on by Quinn Eastman in Cancer, Neuro Leave a comment

True personalized medicine: from mutation to treatment

Stephen Traynelis and Hongjie Yuan

Stephen Traynelis, PhD and Hongjie Yuan, MD, PhD

How often can doctors go from encountering a patient with a mysterious disease, to finding a mutation in a gene that causes that disease, to developing a treatment crafted for that mutation?

This is true personalized molecular medicine, but it’s quite rare.

How rare this is, I’d like to explore more, but first I should explain the basics.

At Emory, Stephen Traynelis and Hongjie Yuan have been working with Tyler Pierson, David Adams, William Gahl, Cornelius Boerkoel and doctors at the National Institutes of Health’s Undiagnosed Diseases Program (UDP) to investigate the effects of mutations in the GRIN2A gene.

Their report on the molecular effects of one such mutation, which caused early-onset epilepsy and intractable seizures in a UDP patient, was recently published in Nature Communications.

With that information in hand, UDP investigators were able to repurpose an Alzheimer’s medication as an anticonvulsant that was effective in reducing seizure frequency in that patient. [The details on that are still unpublished but coming soon.]

Read more

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