Monday, January 18, 2016

Seeking Answers

My name is Jennifer Lange.  I am a wife, a nurse, and the mother of 2 children Asher (4 years old) and Lorelei (8 years old).  My husband, Robert, and I are desperately seeking answers for our son's disorder, a neurodegenerative vacuolar storage disorder that has only been identified in dogs with changes to Atg4d as the identified cause.  http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005169


Asher was born at 41 weeks gestation weighing 7 lbs 11oz. He sat up,  crawled, climbed,  walked and talked within appropriate times. He was strong but always a little clumsy. At his 2 year well check up,  the pediatrician noted he was a little floppy for his development.  She suggested getting him in the pool and try and strengthen up his core muscles. So we put him in swimming lessons,  let him "swim" in our big tub and things looked good.


Then late August 2014, Asher was 3 years old and 2 months, we were out for a walk and stopped at a park.  He got out of the stroller and was very euphoric and extremely uncoordinated.  It lasted for a few minutes and then passed however the ataxia was still present. He was no longer able to walk up the stairs in a reciprocal manner, no longer able to pedal his tricycle, was having "staring" spells and was falling several times a day.


We took him to see a neurologist who ordered an EEG, a battery of blood work,  and an mri. His was relatively normal with only short epochs of posterior delta slowing while awake. Initial blood work was fine however his mri showed moderate cerebellar atrophy. The neurologist ordered more blood work and an EMG. Blood work was normal except his carnatine level was mildly low. EMG was also normal.  And we were referred to a biochemical geneticist for further testing,  as he was thinking this may be a mitochondrial disorder.
In the meantime,  Asher was started on keppra as he was suffering absence seizures and lost consciousness on two occasions. He also started physical therapy (PT) and occupational therapy (OT) to help with some of his strength and coordination.


In November 2014, we saw the geneticist.  They wanted to do whole exome sequencing, not just mitochondrial testing. They explained this was the latest and most exhaustive genetic testing available at this time. Of course we had to wait for the insurance company to sign off and then wait for another appointment in order to draw the blood.  Dec 17 2014, all the of us had our blood drawn and now all there was to do was wait and wait.


At this point, we had fallen into a routine.  Therapy 1-2 times a week, watch for seizures,  increase Keppra,  work,  more blood tests,  an absolutely useless second opinion from neurology, and watch the severity of his symptoms wax and wane.
Finally at the end of June our tests results were back however the clinic told us they needed to do more research and they wanted us to make an appointment to come in and get the results.  An "urgent" appointment was made for 3 weeks out.


At the appointment they informed us his test results were negative for both definitive mutations and variants in genes possibly associated with reported phenotype. However, his results for candidate genes revealed 2 variants of unknown clinical significance on ATG4D, c.266G>A(p.S89N) was paternally inherited and c.839a>G(p.Y280C) was maternally inherited.   This mutation was only recently identified in a particular breed of dogs as the cause of a neurodegenerative vacuolar storage disease, in which my son exhibits the almost exact same symptoms, and they are 97% positive this is cause of his disorder.  The genetics consoler further explained the mutations on ATG4D that my husband and myself possess, are known but are very rare.  She even stated, "The chances of either of you having children with someone else who has a mutation on this gene are so low, you have a better chance of winning the lottery. We have gone from what we thought was a rare disorder to an extremely rare disorder. Asher is human number 1."


The geneticist then gave us a layman's term description of what is occurring in Asher's body.  He compared the body to a house needing all different working parts to make it work.  Autophagy genes are needed to pick up the trash from around your house to trash can. In Asher's case, his vacuum is broken and they don't know how to fix it.  So his cells are building up with toxins and outdated material without an effective way to clean up and are not able to maintain neuronal homeostasis, which makes this a progressive disease. We then agreed to publish these results in hopes of getting more answers.


Currently Asher's symptoms wax and wane in severity.  His hand grip is further weakened, he has become more lethargic, and has somewhat of an activity intolerance along with all of his other symptoms. We continue on with PT, OT, and various doctor appointments and specialties.  He attends pre school and we continue to try balance raising an otherwise typical 4 year old boy and his difficulties.
We are searching for answers, any information or any "share" of this blog is much appreciated.  All it takes is for the right person to read this.

14 comments:

  1. I cannot even fathom what you are going through and i hope you get the answers you need. I read about the seizures and thought how the Ketogenic Diet has helped kids with Epilepsy. ..so maybe you want to try that while looking for answers.

    Also, interesting scientist that you may read up on and may even ask questions directly to: Stephanie Senneff. Doctors that have good info about diet: Steve Phinney and Jeff Volek.

    I hope your son finds quality in health and life.

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    1. My son went from having grand mal(2-4 monthly), and drop seizures (20-80+ day), and started the ketogenic diet, after little success with keppra & depakote. He has not had a seizure since this diet was fully in his system (6 weeks after starting). Warmth to you mama, you're not alone.

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  2. What a beautiful boy you have! We have an Asher too. ;-) Well, the good thing is they found the spelling error. Now, what to do with it? We haven't found my daughter's spelling error yet. She has all the symptoms of OTC Deficiency, but she doesn't have any of the common variants. We treat the symptoms and not worry quite so much about where the error is happening. For now, anyway. Have they checked his ammonia levels? There are scavenger drugs that can be given to clean up the blood and remove some of the toxins. My daughter is currently in the intensive care unit having that done. She is on Ammunol. I don't know enough to know if there are other similar types of scavenger drugs. Please feel free to find me on Facebook ( Leah Spring) or via my blog www.gardenofeagan.blogspot.com

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    1. I forgot to mention, my daughter was treated for a wide variety of medical "schtuff" for 19 years prior to diagnosis, including simple partial seizures. She wasn't having seizures, she was suffering neurological damage from the ammonia and glutamine levels in her brain. Once we were able to start treating her, she is a whole new person.

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    2. Blogging was suggested to me by one of the physicians I work with as a way to get some answers. One of his friends has a child with a rare genetic disorder and within 2 months of blogging, they were able to obtain some answers. Quite frankly, the thought of doing this was very overwhelming and I did come in contact with his friend but I still was so unsure. Its so overwhelming to be t
      so transparent on such a large scale. I spent the next 2 months praying about it and then 2 weeks ago I got my answer. I was in a multiple clinic waiting room and next to me was Genome Magazine. I was intrigued and opened it up. The first article I saw was titled, "Are you Out There...what to do when you are the first patient." The article recommended blogging since genetic and research labs don't readily share information. Our doctor is publishing the results but that takes forever to go through. Once published it will show up in other genetic labs.
      Right now, we are doing symptom management and looking for more answers. He has so many different doctors, including Physical Med and Rehab, and we have thought of also looking into some alternative therapies maybe diet related or whatever.
      I wish you best of luck in your endeavors and any tips you can give me on this whole blogging thing is much appreciated.

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  3. My heart goes out to you.
    Perhaps you already know about this, but in case you don't, maybe it can help your family.
    http://www.matchmakerexchange.org
    http://www.ncbi.nlm.nih.gov/pubmed/26255989

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    1. Thank you so much! I appreciate you taking time out of your day to read this and think of how you could help! Yesterday wad the first time I had heard of this and haven't had a chance to do yet but we will!

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    2. Hi Jennifer!

      Susan McClure here. I'm the publisher of Genome, that magazine you found in the waiting room! I've shared your blog on my social media pages as I am connected to many researchers, pharma execs and patient advocates. I hope that sharing your blog with a broader audience will help you with your search!

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    3. Thank you so much Susan! Your magazine is so helpful! A guide when no one is telling you what to do!

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  4. Hi Jennifer,
    I wish you all the best for your son and my heart goes out to you and your family.
    You may want to attend this event and speak to people who are experts in rare diseases: https://rarediseases.info.nih.gov/news-and-events/pages/28/rare-disease-day

    The NIH also has a program and office for rare diseases- you may want to contact them for advice. Genetic Alliance is another resource: http://www.geneticalliance.org/

    Good luck

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  5. Hi Jennifer

    Me again- I was just doing some reading, so from what I can gather: ATG4 is a serine protease that converts LC3 I into LC3 II. Your son seems to have a somewhat defective ATG4 (serine protease enzyme) so that LC3 I does not get converted into LC3 II which results in the non-generation of the cytosolic autophagic vacuole, or in plain language the machinery that cleans up the trash in the cells is defective. Your options for treatment would be :

    • Bone marrow transplantation to slow disease progression
    • Infusion of recombinant enzyme (gene therapy).
    • Umbilical cord blood stem cell transplantation to restore the defective enzyme (serine protease ATG4)

    There is an assay that can measure the level of activity of ATG4- AU4S can measure ATG4 activity in living cells (culture) so you could use this to test the activity of the ATG4 enzyme to determine how severe the condition is.

    You can find the paper on PubMed, I would suggest contacting the authors for their opinion.
    Autophagy. 2015;11(2):403­15. doi: 10.1080/15548627.2015.1009773.
    AU4S: a novel synthetic peptide to measure the activity of ATG4 in living
    cells.
    Ni Z1, Gong Y, Dai X, Ding W, Wang B, Gong H, Qin L, Cheng P, Li S, Lian J, He F.

    Please do get in touch with Genetic Alliance- they are a patient advocacy group and can help you with getting support and contacting the NIH. Sharon Terry the CEO is a personal friend and collaborator of mine. I work on the rare disease PXE, I am a PhD not an MD so the clinical side is not really my area of expertise. If you need to reach me my email is: MoitraK@trinitydc.edu
    I am an Assistant Professor of Molecular Biology at Trinity Washington University in DC.

    Good luck!
    All the best
    Dr. Moitra

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  6. You might want to talk to your doctors about possibly trying an antioxidant called n acetylcysteine (nac). Antioxidants help remove toxins from the body, And this one has shown some promise in research in helping clean them up and those with ataxia and some neurodegenerative condition. Not a cure but may be of some help in delaying progression? My son takes it, who is also undiagnosed, and it is available over-the-counter as pills or pharmaNAC if your doctor is able to okay it with his list of meds. You can read about it in pubmed.

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  8. Thank you for sharing what is going on with your son and your family. I am sure it is scary at first, but I also think that by sharing your story, you may be lead to the answers you are looking for. That is my hope and prayer for you and your family.

    Leonardo @ US Health Works

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