11.27.16 A Silver Bullet

We left our appointment with Neurogenetics on Monday with a multitude of emotions. One of them was hope.

Dr Dobyns described to us that knowing the underlying cause of Aimee's symptoms could allow us to find a "silver bullet" solution. We now know that her brain cells are not communicating well due to the signal being damaged by malfunctions in the potassium channel. Dr Dobyns is guessing that Aimee's malfunction is causing the channel to remain nearly closed. It is blocking signals. He is making this guess based off of the fact that Aimee's seizures are much less of an issue for her and her developmental delay and central nervous system issues are a much bigger issue.

Back in 2013, this potential for a targeted approach was described by an article from the American Academy of Neurology:

Until now, the focus of treatment of patients with epilepsy in general has always been on treating the symptoms, i.e., seizures. Nevertheless, now that increasing numbers of genetic causes of EE (epileptic encephalopathy) are being discovered, we should start targeting the underlying cause rather than the symptom. In the last few years, gene therapies for neurologic diseases are being intensively studied in neuromuscular disorders and Huntington disease... In the field of epilepsy, we are still lagging behind in targeted gene therapy development, and it is time to make the mental shift when we think about developing novel epilepsy therapies. Indeed, specifically inhibiting transcription or translation of the mutated KCNQ2 allele would lead to a loss-of-function situation, mimicking a KCNQ2 deletion, which in turn is known to lead to the milder BFNS phenotype. Such a strategy therefore has the potential to turn a severe EE into a benign neonatal epilepsy syndrome.

(From the Neurogenetics Group (S.W., R.H., A.S., P.D.J.), Department of Molecular Genetics, VIB, Antwerp; Laboratory of Neurogenetics (S.W., R.H., A.S., P.D.J.), Institute of Born-Bunge, University of Antwerp, Belgium; Epilepsy Centre Kempenhaege (S.W.), Oosterhout, the Netherlands; Department of Paediatrics (V.I.), University Hospital Centre Zagreb, Croatia; Division of Pediatric Neurology and Metabolism (R.V.C.), Department of Pediatrics, University Hospital Ghent, Belgium; Danish Epilepsy Centre (H.H., R.S.M.), Dianalund; Institute for Regional Health Research (H.H.), University of Southern Denmark, Odense; Department of Child Neurology (S.G.), Juliane Marie Center, Rigshospital, Copenhagen, Denmark; Pediatric Neurology (A.-S.S., B.C.), Department of Neurology (A.-S.S., B.C., P.D.J), Antwerp University Hospital, Antwerp University, Antwerp, Belgium; Epilepsy Research Centre (S.B.H., S.M., I.S.), Department of Medicine, University of Melbourne, Austin Health, Australia; Great Ormond Street Hospital (C.E.), London; Institute of Genetic Medicine (R.H.), Newcastle University, UK; Child Neurology and Neurorehabilitation Unit (G.C., M.A.), Department of Pediatrics, Central Hospital of Bolzano; Neurology Unit and laboratories (T.P., R.G., C.M.), A. Meyer Children's Hospital, Florence; Child Neuropsychiatry Unit (L.G.), Spedali Civili, Brescia, Italy; Padiatrie I (K.R., E.H.), Division of Pediatric Neurology, University Hospital Innsbruck, Austria; University Hospital Essen (B.A.), University Duisburg-Essen; Department of Paediatric Neurology and Developmental Medicine (A.B.), University Children's Hospital Tubingen, Eberhart Karla University Tubingen; Center for Child Neurology (I.B.), San Krankenhaus Gerresheim, Dusseldorf; Department of Neuropediatrics (S.S.), Hospital for Children and Adolescents, University of Leipzig, Germany; Department of Neurology (B.S., A.P.), Boston Children's Hospital, Harvard School of Medicine; Department of Biology (B.S.), Brandeis University, Waltham, MA; University Children's Hospital (J.R.L), Division of Human Genetics, Inselspital Bern, Switzerland; Departments of Radiology (S.M.) and Pediatrics (S.M., I.S.), University of Melbourne, Royal Children's Hospital, Melbourne; Florey Institute (I.S.), Melbourne, Australia ; and Pediatric Neurology and Muscular Diseases Unit (P.S.), Department of Neurosciences, University of Genoa, G. Gaslini Institute, Genova, Italy:  Extending the KCNQ2 encephalopathy spectrum, American Academy of Neurology, 2013 Nov 5; 1703)

There are two major types of KCNQ2. The first is known as BNFE, which is Benign Familial Neonatal Epilepsy. It has zero detrimental long term effects and seizures end early on in life. The second is labeled as NEE or Neonatal Epileptic Encephalopathy. It has varied effects, though all include at least some form of intellectual disability. In the above reference, it is discussed that there is a possibility of creating a therapy to turn the severe form (which is what Aimee has) into the benign form.

Since the above article, a designer drug has been refined, which is "an activator of neuronal expressed KCNQ channels."  This medication is now in its 2nd generation and it has shown hopeful results, including increase in cognitive function. This precision medicine is known as Potiga (Ezogabine/Retigabine). Unfortunately, it is being pulled from the market this coming summer due to the low number of sales. We are joining an effort with other KCNQ2 families to petition the maker GlaxoSmithKline to keep this option available for the increasing number of patients diagnosed. That being said, more recent articles do reference newer, improved drugs that are in early developmental stages. It is an amazing feeling knowing that, although there is no cure, there is hope for normalizing function.