12.1.16 Doctor's Prognosis

It is icky to talk about end of life ahead of time, but, practically, we have to discuss it. Here is what we heard from the neurogenetics doctor. 

The first questions addressed in this issue were financial. Do we need to worry about who will take care of our child when we pass away? Do we need to be concerned about caring for our child as she grows and we age? He was strongly of the opinion that we do not need to plan for either event. This brought a sickening blend of relief and repulsion inside of me. It is terrifying to think of leaving Aimee's care to anyone else. Yet... he gave her no chance. 

As far as life expectancy in numbers, this doctor gave her a 50% chance of living to 14, 25% of living to 21, and down quickly from that point. His opinion is that the body wears down exponentially fast under these conditions. 

Lastly, the doctor encouraged us again to discuss (and continutally rediscuss) our wishes as far as care and resuscitation in case of life threatening illness. He recommended attempting to make this decision from Aimee's perspective, not from a parent point of view. We would try to take into account her comfort, her quality of life, her ability to live the life she enjoys. We don't want to miserably prolong life beyond its natural ending basically. 

In all of this, we come back to Aimee. Aimee is happy, healthy, and having fun. She is delighted that Christmas lights are up and music is playing. She is here and she is enjoying living! There is future to discuss, hypotheticals to consider, and then there is this smile to catch. 

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.

11.24.16 De Novo KCNQ2

Yesterday I got a confirmation phone call from the genetics lab that there were zero KCNQ2 genes in either Ed's or my blood.     They are confident that this is a sporadic mutation, which means that although it is in the gene, it is not inherited. 

However, they cannot give us a 0% chance of having another child with the same genetic mutation. There is a slight possibility of germline mosaicism, though this risk is approximately 1%. The medical recommendation is amnio testing on any future pregnancy, which they estimate to be near 100% accurate for gene mutation. This doctor would recommend termination and said that he would not see why another course would be chosen. 

Obviously, Ed and I had already made a decision to continue having children without waiting for a diagnosis. We knew it would potentially be a risk. This is not a simple decision to make, but we see Aimee as valuable and worth raising. We would be very grieved if there was a reoccurance, but we would not consider missing out on bringing a precious person into our family whether disabled or fully able. To be clear, I can understand the great pain that would cause a family to choose termination. I can understand, though it breaks me, because I also know how much we would have missed without Aimee. 

That being said, one of my primary questions after we received Aimee's diagnosis was for Caleb and Elliot. Could they possibily be carriers? Blessedly, no. There is 0% chance that they would pass this mutation to their own children. If they had received a single mutated cell, it would have been in all their cells, meaning that they would have been in the boat with Aimee. They have no chance of passing KCNQ2 on to their children. 

11.23.16 KCNQ2 Variant

It is really amazing that researchers are even able to identify KCNQ2 and its variants. The genetic counselor described the process to us as using Google Maps. As if we were looking at the whole earth and needing to find our house on that map. Researchers remove the DNA strand from a cell, unravel it, look at each portion, zoom in, and search for spelling errors. In Aimee's case, the error is a replacement in one location of one amino acid for another. The chromosome is 20q13.33 (this is the KCNQ2 gene). Her variant is coded at location c.602 G>A and the swap is Arginine to Histidine (Protein name Arg201His). This is called a missense mutation. All of this from swapping in the wrong amino acid in one little tiny spot. Dr Dobyns shook his head as he said that this particular swap out was particularly incompatible.

There are numerous other possible errors that happen in the gene, each causing a different variant. From what I can tell so far, there are least 150 different variants currently registered. Because there are so many and because this gene is newly discovered, there is not sufficient data to determine how each variant influences outcome.

I am in the process of filling out paperwork to have Aimee participate in the RIKEE Project (Rational Intervention for KCNQ2/3 Epileptic Encephalopathy). There is hope that with more data effective therapies will be developed based on underlying causes.

11.22.16 Aimee and KCNQ2

Yesterday's big appointment with the Neurogenetics Reseach Doctor was full of details and answers. There is so much to share that I will spend the next several days posting different bits of information. 

The basics are as follows:

-Aimee tested positive both in the research genetics lab and clinical dna diagnostics lab for KCNQ2 gene.

-This is inherited in an autosomal dominant or heterozygous manner, though Aimee appears to have a de novo variant.

-This micro change alters the function of the potassium channel in brain cells, though how severely, and in which way, depend on which variant. 

-There are possible treatment indications and drug trials specifically targeting the potassium channel.

-KCNQ2 is quickly becoming a bigger deal. It is currently considered the major epilespy gene and is just beginning to be understood. Most of the studies and literature are from the past 2 years. Some from early 2016 list only 100 known individuals. There are over 400 and counting in more recent papers. There is a VERY broad prognosis spectrum and as many questions as answers at this time. 

The nitty gritty is still to come. I will pass on all the information about genetic factors, Aimee's particular variant, drugs, future planning, ect as I digest and as I read through the most recent studies and trials. 

Meanwhile, here is a picture of us nervously waiting for the doctor on Monday. 

11.18.16 Yesterday's Appointments

Aimee had a full day of appointments yesterday. We started out with a renal ultrasound, which is to monitor kidneys and bladder. Next, we met with her respiratory pulmonologist. He was pretty concerned about the continuing ulcer on her nose. We also discussed the plan for this sick season, getting stocked up on supplies, and determining what specific numbers mean we need to get doctors involved. It really gives me peace of mind to have these criteria agreed on between us ahead of time. From this clinic, Aimee was sent to the lab for a blood draw to check electrolytes and carbon dioxide levels. We then met with the Urologist to review the ultrasound findings, which were perfect. We increased the urinary cath size and finally ran over to the pharmacy for meds. 

Monday is the long awaited appointment with the genetic neurologist to learn all about KCNQ2.

11.17.16 Another Language

Waiting in the radiology department for an ultrasound. A little girl has come to sit across from us with her dad. She is moaning and making sounds like Aimee does. Aimee is so excited. She is talking back to the girl and kicking her feet whenever the other girl makes a sound. 

This little connection makes my heart happy. 

11.14.16 Home

Aimee finished her study and we made it home. Though last night was a really rough night, even by Aimee standards. 

The EEG gave really good information and the preliminary review showed the best results she has ever had. We will know more in a week or so about the actual findings. 

11.12.16 EEG

Today is a much improved day. It has been a frustrating stay, because typically when you are admitted the job of making decisions and caring for the child goes from the hands of 1-2 parents to a committee of 10+. This stay was planned and she is perfectly healthy. Simple, daily tasks must be approved. It took hours to get her on bipap, because I had to consult with the neurologist, the wound care specialist, and the respiratory therapist first. I had to get special approval from the dietician and the formulary nutrition room to pour the prescribed formula liquid hope that I brought into the feeding bags without diluting it. They insisted that it would not go through the pump, which is the same pump I use at home and that if any water was added I would not be allowed to mix it. It would have to be done in the nutrition room. 

Now that we have established what is allowed and had bandaging for her nose wound approved, ect it is much more calm. The staff here are generally very helpful and friendly. Once they understand that I actually know how to take care of her, they start to give some freedom. I know they are just operating under the rules that are there to protect them and the kids. 

Wore herself sobbing through all the gluing of electrodes. Hoping to find little seizure activity after her most recent med increase. 

11.11.16 EEG

Aimee recovered finally from her cold and made it back to school on Monday and Wednesday. We are now settled in at Children's for an extended EEG to check on seizure activity. We'll be here for a few days. 

We have only done one of these extended EEGs one other time. Similar to the Sleep Study, we have to bring all our own things, including diapers, machines, meds, food, ect. It is pretty challenging and a good reminder of why we have decided to no longer travel with Aimee. 

11.2.16 Mending

Aimee is recoverying from this first cold of the season that started with that day of seizures at school a few weeks ago. We are working to slowly move her back to her normal feedings and routines. She is working with us to get her airway cleaned out and to rid herself of some eye infections. The one little challenge we are having in particular is an open wound on the bridge of her nose, which was created by extra bipap use. It is really difficult to get rid of skin breakdown on her face, because she still needs to use the bipap, still needs the cough assist, and because she keeps reopening it with her waving arms/hands on her own face. We are making an (unauthorized) attempt to put her on oxygen only for a couple of nights to allow the wound to heal. Praying her brain remembers to keep breathing and that her wound is finally able to heal.