You probably know by now that in the gene name KCNQ2, K is for potassium and CN is for channel. But what about Q2 (and 1, 3, 4, and 5)? You might want to go to Italy to find out! The KCNQ family (aka Kv7) will have a sort of “reunion” this week at the International Kv7 Channel Symposium in Naples. Researchers from the across Europe, the United States (hello, Dr. Ed Cooper!), Australia, and China will gather to focus on their common ties and the ways they can help each other out for the benefit of many.
Download powerpoint slides for the meeting here!
Dr. Maurizio Taglialatela, MD, PhD, professor of pharmacology at the University of Naples Federico II and member of the medical advisory board for the Jack Pribaz Foundation, will host his colleagues in his hometown. “We hope to merge together in this meeting the best work done in the areas of neuroscience, cardiac, and muscle,” Taglialatela says, “so that cross-fertilization among disciplines might help in promoting better research and therapeutic opportunities for our patients.”
Recently Gina Pribaz Vozenilek interviewed Dr. Maurizio Taglialatela by email about the goals of the conference and the importance of considering the Kv7 genes together.
GPV: Can you explain the family of Kv7 genes and how they are related to one another?
MT: Among ~ 80 potassium channel genes found in humans, those belonging to the Kv7 family regulate the activity of cells in many organs including brain, heart and muscle. The five known Kv7 family members (Kv7.1-5 or KCNQ1-5) show distinct cellular and subcellular localization in each cell and often cooperate functionally with each other. For instance, KCNQ1 is mainly found in the heart whereas KCNQ2 and KCNQ3 are more abundant in the brain. Alteration of their function can cause diseases such as epilepsy, cardiac arrhythmias, or deafness, depending on their tissue- and time-specific expression pattern. KCNQs show a similar structure and function, and have peculiar regulatory properties, distinct from those of most other potassium channels.
GPV:What is the potential value of looking at all the Kv7 genes together synergistically in terms of helping understand KCNQ2 encephalopathy?
MT: At least in specific cell types and at distinct developmental stages, some members of the Kv7/KCNQ family, namely KCNQ3 and KCNQ5, are found in the brain, where they can work together with KCNQ2 and modulate its function. Mutations in KCNQ3 and, more recently, KCNQ5 have been shown to cause neurological diseases with features partially-overlapping KCNQ2 encephalopathy, although gene- and even mutation-dependent phenotypes are also emerging. Therefore, understanding structural and functional similarities and differences among KCNQ family members may potentially provide new strategies for the treatment of KCNQ2 encephalopathy; in fact, available Kv7-acting drugs all have serious limitations, including poor selectivity among Kv7 family members. For instance, information on specific pharmacological properties of cardiac Kv7.1 channels might facilitate the development of “brain” Kv7.2-specific drugs without the potential negative side effects that cause arrhythmias.
GPV:Conversely, how have advances in KCNQ2 research improved knowledge in the study of other KCNQ illnesses?
MT: As said before, despite the previously-mentioned similarities in functional characteristics and structure among members of Kv7/KCNQ family, each of them plays a different functional role at distinct sites in the human body; thus, the knowledge generated from KCNQ2 studies could provide the opportunity to target diseases completely distinct from KCNQ2-related diseases, such as hypertension, urinary dysfunction, pain, arrhythmias, and GI disorders.
GPV: What are your hopes for this conference?
MT: The goal of this conference is to facilitate the sharing of knowledge and ideas among scientists working in different fields in which the Kv7 channels play a relevant functional role; we hope that such cross-fertilizing experience will deepen our understanding of KCNQ-related illnesses and reveal emerging and yet under-explored areas in which Kv7 channels are involved, such as (just to mention a few …) cancer, depression, anxiety, and autism-related disorders. The meeting will also strengthen existing collaborative research networks and create new ones, further enhancing the opportunity for young scientists to train in prestigious labs around the world. Furthermore, given the participation of several pharmaceutical companies, the meeting will provide a unique opportunity to share results between academy and industry to speed the pace toward finding a cure for KCNQ-related illnesses.
Boston genetic counselor Lacey Smith, MS, CGC, shares the most common questions she hears from families.
I have been a genetic counselor in the Epilepsy Genetics Program at Boston Children’s Hospital for about three years. During my time here, I have met with many families who have received a genetic diagnosis for their child’s epilepsy, including KCNQ2-related epilepsy. Getting such a diagnosis can be overwhelming for families, as there is often a lot of information coming in at once. My hope is to provide you with answers to some of the questions I am most often asked by families when they first hear that their child has KCNQ2-related epilepsy. Even though your child has this diagnosis, each individual is unique so your experiences may be different from those of other families you may have met who also have a child with KCNQ2-related epilepsy.
The spectrum of features associated with KCNQ2-related epilepsy is quite vast and the genetics aspect is often unique to each family, so my answers may be a little vague and may not touch upon your specific needs or experiences. As such, I am also providing suggestions of whom to contact to gather additional information specific to your child. You can also use this information as a guide in coming up with questions to ask your child’s neurologist.
What does a diagnosis of “KCNQ2-related epilepsy” mean?
This means that your child has an alteration (also called a “variant”) in a gene called KCNQ2, and that variant has likely caused your child to develop seizures or epilepsy. It may also explain any developmental challenges your child may have.
Knowing the underlying genetic cause of your child’s epilepsy could be beneficial in a number of ways. First of all, it provides an answer or a reason as to why your child developed seizures. Having a diagnosis can allow your child’s doctor to provide you with more information regarding prognosis and potential treatment options than they would have been able to without knowing the underlying cause. It can prevent your child from undergoing additional unnecessary tests to rule out other conditions or medical complications. It can provide insight into family history if there are any other family members who have/had seizures and it can provide information regarding the likelihood of having another child with similar symptoms.
What does this diagnosis mean for my child’s prognosis?
Knowing that your child has a variation in the KCNQ2 gene can allow your child’s doctor to have a better idea of how your child’s symptoms may progress over time, based on what is already known about other children who have KCNQ2-related epilepsy. There are two general categories of symptoms. Children usually fall somewhere along a spectrum from Benign Familial Neonatal Epilepsy (BFNE) on the mild end to an epileptic encephalopathy. In the world of epilepsy, “benign” usually means that seizures are expected to resolve over time or the child may “grow out” of their seizures. An epileptic encephalopathy is a term that is used when a child has seizures, and in addition, the electrical activity of the brain both during and between seizures can also cause developmental delays and cognitive challenges.
So how does one know where along the spectrum their child will be? Unfortunately, this is difficult to know. Currently, this isn’t enough information available to predict exactly what symptoms a child will develop based solely on the results of the genetic test. Even among individuals who have the same KCNQ2 variant, each individual can have different symptoms. There are likely other factors (such as other genes) that are modifying the effects of the KCNQ2 variation. Researchers are trying to learn more about these contributing factors. In the meantime, your child is going to tell his or her own story. Most often, the best predictor for how your child will do is how your child has done/is doing. This can be difficult when the diagnosis comes at a very young age and there is little developmental history to look back on.
…your child is going to tell his or her own story. –LS
Over time, researchers will hopefully gain a better understanding of features associated KCNQ2-related epilepsy. By gathering information from many individuals who have been diagnosed, they can begin to analyze patterns including the spectrum of symptoms and look for any associated modifiers to be able to better predict a child’s prognosis. One of the ways in which researchers can collect this information is through a patient registry. A registry gathers and keeps information about people who have a certain condition to support and encourage research into that condition. Individuals may sign up or enroll in a patient registry to have their information included and available to researchers. The RIKEE Project is one patient registry that is targeted specifically to KCNQ2-related epilepsy.
Register your child in RIKEE to connect with the international team of KCNQ2 researchers and advance understanding of KCNQ2-related epilepsy.
How does this diagnosis affect management/treatment for my child?
This diagnosis may not lead to a drastic change in management. For example, if your child has been experiencing some delays in development and has been receiving services to help with development, then he or she would continue to receive those services. If your child is on target for all milestones, then you will know to be on the lookout for any delays moving forward and intervene right away with evaluations and/or services if needed.
You may find that your child’s doctor may not recommend any medication changes based on this diagnosis, especially if your child’s seizures are well-controlled. Targeted treatments for genetic forms of epilepsy is a very big topic in research right now– being able to treat the exact cause of seizures based on the underlying genetic cause is on the horizon and new advancements are happening quite frequently. This is true for KCNQ2-related epilepsy. Because the field is evolving so rapidly, it is best to discuss medication management with your child’s doctor in order to have the most up-to- date information.
If this is “genetic,” does it mean that one of us parents passed this on to our child?
Not necessarily. Just because a condition is considered “genetic” does not necessarily mean it was inherited. Genetic variations can be passed through families, or these variations can arise for the first time in a child (these are called “de novo” variants). De novo variants are likely produced by a spontaneous event during the formation of the sperm or the egg cell. Some individuals can have the KCNQ2 variant but never develop any symptoms, so it is possible for a child to inherit the variant from a seemingly unaffected parent. You can determine whether your child has an inherited variant or a de novo variant by testing both parents. Your child’s doctor can help facilitate such testing.
What does this mean for my other child/children? Can I test them?
If you have another child who also has seizures, then it is possible that they could also have the same KCNQ2 variant and it would be possible for this child to have genetic testing. In general, it is not routinely recommended that unaffected children (children who do not show any features of the condition) undergo testing. Rather, that child could make the decision to undergo testing on their own when they are of suitable age.
What are the chances of having another child with this condition? Can I reduce the chances?
The likelihood of having another child that has the KCNQ2 variant depends on whether this was an inherited variant or a de novo variant. If the KCNQ2 variant was inherited from a parent, then there would be a 50% (1 in 2) chance that each conception would also inherit the KCNQ2 variant. If the KCNQ2 variant was de novo, then the chances are much smaller although not zero. This is because there is some residual chance to have another child with the same variant due to something called “gonadal mosaicism.” Gonadal mosaicism is not something that is routinely tested for in the clinical setting. For some families, during the parental testing process, the KCNQ2 variant is detected in some, but not all, of the cells in one of the parents. This is another form of mosaicism. For those families, it is also possible for future pregnancies to also have the KCNQ2 variant.
Regardless of inheritance of the variant it is possible to test future pregnancies to see if the KCNQ2 variant is present. For more information regarding prenatal testing options, you can speak with a genetics specialist when you are considering having additional children.
It is also important to remember that individuals with KCNQ2 variants or KCNQ2-related epilepsy may show different symptoms, even when they have the same variant. While it is possible to test pregnancies for the KCNQ2 variant, one cannot predict with certainty the severity of symptoms an individual may present with. Future children who have the KCNQ2 variant may have symptoms that are less severe or more severe than those of your child.
Who else can I talk to?
It is important to find a neurologist or epileptologist with whom you/your child feel comfortable. Don’t be afraid to ask for a second opinion, or more! If you have concerns regarding your child’s development, you could have your child evaluated by a neuropsychologist. A neuropsychologist is a doctor who, through a series of tests, can identify your child’s strengths and weaknesses in learning, emotions and behavior. From there, recommendations for services specific to your child’s needs can be made.
It may be helpful to speak with someone who has specific training with genetic conditions, whether it be specifically genetic forms of epilepsy or more general genetic conditions. This could be a geneticist and/or a genetic counselor. Healthcare providers who are specially trained in genetics can provide information regarding inheritance patterns, identifying family members who could be tested and options for testing future pregnancies, if desired. You may consider asking your child’s doctor to refer you to a genetics specialist in your area. You or your child’s provider can also find a genetic counselor through the National Society of Genetic Counselors website at www.NSGC.org, and navigate to the “Find a Genetic Counselor” link. You can identify genetic counselors in your area and genetic counselors that specialize in epilepsy or neurogenetics.
Lacey Smith, MS, CGC
Lacey Smith, MS, CGC, is a genetic counselor in the Epilepsy Genetics Program at Boston Children’s Hospital. She has roles in both the clinic and in research. In the clinic, she works closely with epileptologists in meeting with children who either have, or are presumed to have, a genetic form of epilepsy. She reviews all aspects of genetic testing, discusses potential implications for other family members and future children, and helps families understand their child’s diagnosis. In the research world, her team is trying to better understand the genetic contributions to epilepsy. Specifically, they are trying to identify new genes associated with epilepsy, determine how variations in these genes cause epilepsy, and develop more targeted therapies for children who have epilepsy caused by variations in these genes. Lacey is also a member of EpiGC, a consortium of genetic counselors whose mission is to promote access to quality genetics services for patients and families affected by epilepsy through research, public policy/advocacy, education and outreach activities.
By all accounts, KCNQ2 is getting serious attention. On New Year’s Eve 2015, Dr. Ingo Helbig, one of the authors of the blog Beyond the Ion Channel, recapped his top ten posts for the year (hopefully while wearing a party hat and sipping a little bubbly). KCNQ2 came in at #10, and he wrote that KCNQ2 “may be the most common genetic cause of neonatal epileptic encephalopathies.” For any family who has ever felt alone with a KCNQ2 diagnosis, that’s a pretty incredible thing to read. It spurred me to ask for Dr. Helbig’s perspective for KCNQ2 Perspectives, and he has graciously obliged.
You have invented this new term, Epilepsiome. Please tell us what the Epilepsiome is and how researchers and clinicians can use it.
The Epilepsiome is the community-based gene curation effort of the epilepsy world. Basically, the Epilepsiome project aims to review and curate data on all relevant epilepsy genes, especially involving scientists and clinicians who work on the particular genes. The goal is to provide you with an up-to-date overview that will then link out to the other resource such as ClinGen, ClinVar, GeneReviews, or OMIM. However, in contrast to these resources (which are used widely in genetic studies), the Epilepsiome will have a clear focus on epilepsy and will put the current findings and controversies into context. My vision was to carry some blogging atmosphere over to a gene curation project, which typically engages the community more than a static page that is only updated infrequently.
The Epilepsiome is growing. We are building expert groups for particular genes and we are very fortunate to have a dedicated group of scientists and clinicians on board to add to our gene curation. We aim to have the main genes for genetic epilepsies reviewed in 2016–and yes, there is already a KCNQ2 page maintained by some of the experts in the field that are part of your community.
In your New Year’s Eve 2015 post you wrote: “In many ways, KCNQ2 is one of our model genetic diseases, with a tightly connected group of researchers, clinicians, and patient organization. We hope that we can spin this energy into novel approaches for precision medicine soon.” Can you tell our readers what you mean by precision medicine and how the KCNQ2 community might be able to contribute to, or benefit from, it?
I knew that you would pick up on this! I must say that I am really impressed by the KCNQ2 community, which connects families, clinicians, and researchers. The vision of precision medicine is to use our knowledge of the genetic causes to find custom treatments, which may either be known medications that we did not think of yet or new compounds that were designed for specific disorders.
JPF booth at AES in Philadelphia. KCNQ2 families sent in #WeAreKCNQ2 videos to demonstrate their spirit and unity to the research community. Pictured: in video, baby Parker and family; Liz Pribaz, Jim Thompson, Dr. John Millichap. View the #WeAreKCNQ2 video on our YouTube channel.
We feel that this approach may be promising as we are facing two fundamental problems in many severe epilepsies. First, seizures in these epilepsies are often difficult to treat and secondly, other than controlling seizures, our treatment strategies often have little impact on the developmental outcome. Precision medicine or personalized medicine aims to identify the cause of the epilepsy first. For patients with KCNQ2 encephalopathy, this is often a mutation that renders the potassium channel non-functional. The idea of precision medicine is to find model systems that replicate this defect and then systematically search for compounds that may correct it. A closely-knit community as the KCNQ2 community will be required to make sure that future treatment options can quickly be translated to clinical trials. Many people underestimate the efforts of finding patients with rare diseases for trials, and I feel that having the community organized is a prerequisite for this.
A closely-knit community as the KCNQ2 community will be required to make sure that future treatment options can quickly be translated to clinical trials.–IH
For parents of children suffering seizures and other effects of a genetic mutation, no science can ever move fast enough to find a cure or better treatment. What does that timeline for precision medicine advances look like?
Unfortunately, it is difficult to provide timelines for this. In many aspects, we are still not at the stage yet where generating model systems and testing of a wide range of possible candidate drugs is a predictable pipeline. Having said this, there is considerable effort dedicated towards finding therapies for patients with ion channel diseases.
There is one additional aspect to treatment of genetic epilepsies that I would like to mention at this point. You mentioned the word “cure.” While both families and clinicians often expect the scientific community to come up with game-changing interventions that significantly alter the course of the disease, a different strategy is to systematically focus on exploiting small gains in the field.
Take the pediatric leukemia field as an example. Even though many individual chemotherapy and radiation therapies have increased survival, it was only the thoughtful combination of therapies and systematic adaptation of protocols based on prior experience that has led to the significant increase in cure rates that we see today. Translating this to genetic epilepsies, I feel that we already can learn a lot from existing experience, but access to that data, how best to aggregate it while protecting patient privacy, and the possibility to mine this information are major issues.
Until recently, public discussion of scientific ideas was the purview of peer reviewed articles and books. The internet, and especially blogs like Beyond the Ion Channel, have created new space for sharing ideas and debate. As a scientist-blogger, what do you see as the benefits and risks of these new public platforms?
Basically, these public platforms serve as the communication backbone of communities that are not represented in the traditional publishing format. The main benefit of these platforms is that they provide a “running commentary” on what is happening in the area; they help put novel and existing information into context. I have always felt that we are piecing together the puzzle of an ongoing mystery, the genetic architecture of a disease. And we are trying not only to look at whether the pieces fit, but also to present the bigger picture on what they contribute. Another big advantage of these platforms is the fact that they are updated regularly in small increments as they follow the rhythm of social media. This is different to the traditional format where only the final product is presented. Through these platforms, we are able to follow the thought process and generation of ideas, which gives us the possibility to interact and contribute. Finally, I have also felt the effects of blogging personally. It is a way for me to clear my mind and experiment with novel ideas. It’s the thing that keeps me up at 3AM.
With regards to risks, especially for online platforms that develop a certain authority in a healthcare-related area such as the rare disease space, you have to be very careful that the information on treatment and prognosis that you provide is solid and agreed upon by the community. We are currently in the process of adding a “Personalized Medicine” subsection for our gene reviews and have the discussion in the community on what constitutes reliable information that can be displayed in this section. This is particularly difficult given the publication lag in this field–there is much knowledge and experience in the community that is unpublished and representing this adequately remains a challenge.
How did you first become interested in the study of genetic epilepsies?
During my medical doctoral thesis in Heidelberg, Germany, I worked on neuronal gap junctions or “electrical synapses,” direct cell-to-cell connections between neurons. This type of communication between nerve cells had been forgotten for a long time, but was rediscovered in the early 2000s, and we characterized the proteins that were involved. At one point, we speculated that mice deficient in one of the critical proteins called Connexin 36 may have a reduced threshold for seizures, as this protein was thought to enhance the connection between so-called inhibitory cells (neurons that are typically involved in reducing the activity of other neurons).
We could not validate this hypothesis and actually found the opposite. We also tried to assess whether variants in this gene may predispose to epilepsy, but there was nothing to be found. Independent of my disappointment, this started my interest in genes that predispose to epilepsy and also left me with a fundamental skepticism of falling in love with any particular hypothesis too much. On our blog, I am often referring to the power of team science and hypothesis-free approaches in genetics, which is somewhat a reference to my earlier disappointments.
Independent of my disappointment, this started my interest in genes that predispose to epilepsy and also left me with a fundamental skepticism of falling in love with any particular hypothesis too much.–IH
My other “key moment” happened during a trip to Australia when I interviewed for positions in various fields, some of which did not include epilepsy at all. As I mentioned in a post last year, I was sitting in a rock pool at Red Johanna Beach in Victoria, Australia, reading Nigel Tan’s “The truth is out there,” a 2004 review on the state of association studies in epilepsy. The writing style and big picture view of his review made me realize that epilepsy genetics is something that I might actually be interested in. I typically publish a post “Red Johanna Day” every year, which I consider my birthday in epilepsy genetics.
These two stories were my early beginnings. In retrospect, I think it is interesting how my strong clinical interest in genetic epilepsies was born out of a primarily scientific interest. The clinical part was something that I learned and became fully invested in while getting involved in patient care. To me, being a clinician and a scientist is an interesting combination that allows me have both the care of the individual patient and the larger picture in mind.
Have you registered your child or patient in the KCNQ2 patient registry? Access RIKEE here to help the KCNQ2 community.
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 theQ2 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.
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.
