How RIKEE helped treat a KCNQ2 patient

Photograph courtesy of the Arkansas Children’s Hospital

Building a collaborative network

It’s a two-way street. The Rational Intervention for KCNQ2 Epileptic Encephalopathy (RIKEE) patient registry both provides valuable information and accepts the input of new data from volunteers, creating a powerful collaborative resource to help families, physicians, and researchers. Just ask Dr. Sarah Mulkey. Dr. Mulkey is an Assistant Professor in the Department of Pediatrics, Section of Neurology, at the University of Arkansas for Medical Sciences. She was caring for a newborn whose clinical presentation was like none she’d seen before, and RIKEE came to the rescue. The parents of Dr. Mulkey’s young patient later agreed to have their child participate in the RIKEE registry, a decision that set in motion a detailed reexamination of the histories of patients with similar stories diagnosed around the world.

Thank you, Dr. Mulkey, for sharing your insights with KCNQ2 Perspectives.

Searching for answers

Just after birth, a baby was having movements that looked like seizures. The infant was brought to our neonatal intensive care unit, where I work as a neonatal neurologist. The baby appeared ill, but brain imaging did not reveal a reason. Although the brain wave test (or EEG) was far from normal, it showed that the baby’s movements were not caused by seizures–in fact I could find no real seizures at all. This was a highly unusual pattern. Although I suspected there might be an underlying genetic cause for the baby’s illness, the combination of symptoms and test results was different from any patient that I had previously encountered. I decided to email Dr. Phillip Pearl in Boston, a renown expert in genetic metabolic epilepsy in children, to seek his advice.

Learn all about RIKEE and how to get involved at www.rikee.org

Suspecting a genetic-related epilepsy and possibly KCNQ2, Dr. Pearl put me in contact with neurologists Dr. Ed Cooper in Houston and Dr. Roberta Cilio in San Francisco. Genetic testing indeed revealed a KCNQ2 variant. The RIKEE database also informed us that there were several other families and treating physicians participating in research that had referred children with the very same variant as found in my patient. As permitted under the RIKEE research protocol, we contacted all the treating physicians and all agreed to form a new, international collaborative team. Although the research is ongoing, overall we have learned that the patients have many similarities with each other and are different in important respects from patients with some other KCNQ2 variants. We believe this new understanding will help us design new treatment strategies, which in this instance would be tailored to not only to KCNQ2, but to an individual KCNQ2 variant.

“…it is important to build such networks of colleagues for rare illnesses so that we can combine our knowledge…” –SM

Only the existence of the RIKEE database and its contributing network of families, scientists and physicians allowed me to gain a real understanding of my patient’s situation. This experience showed me that it is important to build such networks of colleagues for rare illnesses so that we can combine our knowledge and advance science to provide the best care.

Adding to the registry

I also recently took care of another newborn whose history fit with the definition of benign familial neonatal epilepsy (BFNE). Like most other babies with BFNE, my patient had neonatal seizures that were easily controlled with medicine, and the baby showed normal developmental progress. Because KCNQ2 variants are the most frequent cause of BFNE, it was not a great surprise when testing revealed a KCNQ2 variant. Based on research conducted by the RIKEE team, Dr. Cooper explained that, because of the location of the variant within KCNQ2, additional specialized genetic testing might be warranted. I contacted the genetic testing service and requested the additional analysis be performed, leading to a revised diagnosis. This provides another example of how the RIKEE database can increase understanding of these variants and improve care for individuals and their families.

Sharing what we learn

As a result of this fruitful collaboration, Dr. Cooper invited me to attend the KCNQ2 investigators’ meeting at AES (read a recap of that meeting in the Q2 News). I was able to share my experience in caring for these patients with other researchers that are working on different aspects of KCNQ2. It was inspiring to spend a day with other dedicated clinicians and neuroscientists focused in KCNQ2-related epilepsy research. I believe it is multi-disciplinary collaborations like this that will be able to make pivotal discoveries and improve the lives of patients with genetic epilepsies. I look forward to continuing these team efforts on KCNQ2.

Register in RIKEE to advance KCNQ2 research and speed the path to better treatments.

Sarah Mulkey, MD, PhD, graduated with her medical degree at the Florida State University College of Medicine and completed her child neurology residency training at the University of Arkansas for Medical Sciences. She focuses her clinical work on caring for newborns with different types of neurologic conditions. She has a PhD in clinical research and works to find treatments for newborn brain injury and improve neurologic outcomes for babies. Outside of work, she keeps busy with her three young children ages 2, 4, and 7.

Meet a KCNQ2 Researcher

KCNQ2, KCNQ2, research

Li Li, MD, PhD

Bringing KCNQ2 to a big stage

Do you ever wonder what it really means to “support research” for KCNQ2? In our first blog, we are happy to introduce you to a special person whose work was one of our earliest investments in KCNQ2 research.

Her abstract, “KCNQ2 encephalopathy: novel single amino acid deletion variants strongly suppress currents and are responsive to SF0034” was selected for platform presentation at the Pediatric Epilepsy Highlights Session at the American Epilepsy Society (AES) meeting in Philadelphia.

JPF: Please tell us a little bit about what motivates you in your research.

LL: Mutations in the potassium channel gene KCNQ2 cause medically refractory neonatal-onset epilepsy, global developmental delay, and autism. Increasing numbers of clinical cases of KCNQ2 encephalopathy in children have been found in the past couple of years. These cases encourage me to join KCNQ2 study groups.

As a mother to two boys, nothing makes me happier than seeing them smile, watching them laugh, play and grow up healthy. So I understand how hard it is when parents have to face something as hard as watching their child struggle in their development. Being a mother encourages me and gives importance to my goal: To discover good treatments for kids’ diseases using my knowledge and techniques.

JPF: Can you please summarize your abstract in lay terms?

LL: Our lab and collaborators have established an international registry of KCNQ2 cases from patients. To date, we have collected around 120 KCNQ2 encephalopathy missense variants and two interesting examples of single amino acid deletion. One is a unique variant (found in one case), the other in 6 children. My goal was to clarify whether these deletion variants were likely to be the cause of the seizures and impaired development seen in patients.

This diagram shows the location in the KCNQ2 protein of the two newly discovered single amino acid deletions (dots in red) and the 120 previously characterized missense mutations (dots in blue). A missense mutation is a point mutation in which a single nucleotide change results in a codon (a triplet of nucleotides) that codes for a different amino acid. A single amino acid deletion occurs when an entire codon is lost and the rest of the sequence is shifted. Dr. Li’s paper was the first to show that a single amino acid lost, not changed, can induce encephalopathic epilepsy.

JPF: Why do you think your abstract was selected as a highlight? What about your discovery is most valuable in advancing KCNQ2 (or epilepsy) research?

LL: I think my abstract was selected because it is the first time deletion variants have been shown to induce KCNQ2 encephalopathy. I detected strongly reduced channel function and showed a drug could reverse some of the effects of the variant on the channel.

JPF: When did you find out your abstract was selected for special presentation, and how did you prepare for the talk?

LL: In June, I submitted my abstract to the AES annual meeting. After 3 months, in September, I got an email from 2015 the AES scientific program committee. My abstract was selected for a Pediatric Epilepsy Highlights presentation. To prepare, Dr. Cooper and my coworkers gave a lot of valuable advice. It took around a month to organize our clinical and electrophysiological data, and I practiced many times before the presentation.

JPF: Describe your experience of presenting the work. What kind of feedback or questions did you get?

LL: About a thousand people attended my presentation. Most of the audience were doctors. They were very interested in the mechanism and drug treatment. Most of the questions I received were about drug side effects and rules to use drugs to treat encephalopathy, since I presented a new drug (SF0034) that showed similar effects as ezogabine (an FDA approved drug to treat seizures) but which may be less likely to cause the side effects of blue skin discoloration.

JPF: What are you working on next?

LL: I will try to complete these deletion variant studies and publish a paper in the near future. Also I will study other variants in KCNQ2 encephalopathy.

Left to right: Baouyen Tran, a PhD student, Li Li, and Jacquenae Mays, a post-Bac student. Jacquenae and Bao are Li’s collaborators and she thanks them for tirelessly helping her in preparation and rehearsal of her talk.

A native of Dalian, China, Dr. Li Li received her PhD in Department of Pharmacology and Neurobiology at Tokyo Medical and Dental University and her Medical Bachelor degree at Dalian Medical University in Dalian, Liaoning, China. She has studied ion channels for 10 years and joined Dr. Ed Cooper’s Lab at Baylor College of Medicine in 2012 as a postdoctoral research fellow. Her focus is to clarify the mechanisms underlying potassium and calcium channel diseases and develop new drug treatments to cure them

research

Gina Vozenilek

January 18, 2016