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What She Tried

Everyone responds to the same treatments differently even within a variant especially in Mosaic variant, but this is how things went for Elizabeth.   We tried the followings:

See "What We Can Start Now for Symptoms"

Finding out that your child has a rare disease is devastating, but we need to stay focused on what we can do now and what's ahead of us.

Although SKS presents a variety of tough symptoms to cure, there are things we can do now and in the future.  Here is a big picture I see.

Rapamycin/Everolimus (In USA)

Benefits, Limits and Tricky Dosing

While I wait for a better mTOR inhibitors, she's tried Sirolimus and Everolimus since 2019.  They were not approved for SKS treatement, but in the US, doctors could prescribed them as individual experimental trial, and some insurances cover them.  **Citation are coming later.

  • They have been used safely for many years

  • At a right dose, Rapamycin and Everolimus improved many of Elizabeth's issues. They prevents excessive hanger (probably by reducing proliferation and glucosis?),  improve  attention span and muscle coordination, prevents club feet, helps with digestion (probably because of normalized lipase level?) and intestine mobility. She's also become less sensitive to sound and sleeps better.

  • They may improve seizures.  In different doses, they help some SKS, and stop working for some others.  



  • May not be immediately available to try in other countries,

  • There have been a limited random trials on SKS.  Depending on the does, some have no apparent side effects while others have some side effects that are specific to SKS and not common in general population,  (Hyperstimulation and insomnia in Elizabeth, Sleep disorder in others)  For Elizabeth, the dose good for her body seems too high for her brain.

  • They inhibit only partial functions of mTORC.  They can possibly inhibit mTORC2, but it's difficult to balance inhibition levels of  mTORC1 and mTORC2 at the same time.

  • MTOR should not be inhibited too much or too little, but we have no biomarkers to estimate how much they are in brain. A blood test doesn't seem to reflect the level in brain (IMO), and we need to depend on caretaker's observation.  We need to find a way to measure our goal in numbers.  (For Elizabeth's overstimulation, counting how many times my eyeglasses get kicked and fly away is one data.)   

  • mTOR is complex and interconnected to multiple signaling pathways.   Besides the famous PI3K/AKT feedback loops, there are many other things that throws everything off balance when mTOR is inhibited by a medicine too much in one way.

How I Dose

After a few years of trial and errors, now my goal is how to get the best dose for Elizabeth's brain and behavior.  (This does is not enough for the dose recommended for TSC's epilepcy management.)     

It seems the medications just like Curcumin stays in brain much longer than what I see in blood test. It's not a conventional way, and I don't know why it works the way it does, but hope this example makes some sense to you.

Let's say we are driving a car with no brakes, and our goal is to keep driving at the speed just below the speed limit, so we drive fast but don't get caught by the police.  Let's say the speed limit is 50km/hr.

At 47km/hr, just bellow the speed limit, she's the happiest.  She's not hungry and cranky, and thus she sleeps better at night. She's happy, vocal, focused to make a new developmental progress. Her club feet are fixed, her muscle coordinates well, and her bowel movement is better. 

And let's assume daily dose is how much we step down on the accelerator. 

If I'm not pushing the accelerator enough, the car slows down and all her symptoms come back. The first obvious sign is her excessive hunger.  Even at the same blood glucose level, low or high, her brain seems to start craving for food more than usual.*

The higher the daily dose, the faster I reach to the speed limit, where she's the happiest. Also, the faster we go, more benefits to her bodies, but after passing the speed limit, neurological side effects starts....strange.

When passing the speed limit, I need to release the accelerator so the speed comes down bellow the limit, then when it comes to about 47km/hr again, I need to step down on the accelator a little less than before to say at the speed.  l call the new lower dose  a "maintenance dose".  Finding the maintenance dose takes time, but once I find it, I can keep it steady and press the cruise control button. 

When I pass the speed limit, if I release the accelerator soon, the speed comes back to 50km/hr soon.   But remember that this car doesn't have a break?  If I wait longer to release the accelerator, the car might reach to 100 km/hr, and it will take much longer to come back bellow 50km/hr again.    At 1.5mg/day Sirolimus, when I waited an extra day to stop the dose, it took an extra week for Elizabeth being overstimulated and not sleeping much.  Ideally, I want to start releasing accelerator around 40km/hr, so I won't pass the speed limit too much. 

At 55km/hr, (5km/hr above the speed limit), she starts inappropriate laughs for no reasons especially near bed time, and she sleeps 1 hr late if she doesn't take  0.5mg of Melatonin.  

At 60km/hr, she starts mood swings, stars at ceiling, screams, kicks, and falls asleep 2-3 hrs late.**  Melatonin needs to be 1mg.

At 70km/hr. she screams like a Tarzan, laughs like a Halloween toy, and kicks and knocks down everything around her for several hour at night.  2mg of Melatonin doesn't help much.

So, what this Speed Limit mean exactly?

Here are my hypothethis,

1. Concentration in brain reaches to the point where bad feed back loops of other signaling pathways start(AKT, and many others).

2.  The partial inhibition of mTORC substrates throws some signaling pathways off balance. (EB10? 4EBPs)

3. Inhibition of mTORC2 becomes to much.

I hope new generation mTOR inhibitors can address her side effect issues.

*Her glucose in head (CSF glucose)was normal when measured when she was a baby. 

(And it was my only chance to see what a high dose Sirollimus can do.)


** When she was overstimulated and creaming at this level, EGG didn't show any seizure activities or anything different from other times.  

Stem Cell Therapy

2.  Stem Cell Therapy

In 2018, Elizabeth tired Stem Cell therapy at Duke University and her brother's stem cells from his cord blood we've stored was a good match and it was given to her through IV in her arm.  At that time, Duke's Stem Cell clinical trial for Hydrocephalus was over and the treatment through an extended access plan was allowed only because she didn't have any diagnosis, yet.  She was also small enough to get sufficient stem cells from the cord blood.  The result?  I don't know if it worked for Elizabeth in a short term or a long term.  A week after the treatment, she started to reach for objects for the first time.  Maybe it worked, or probably it was a coincidence.

There are some private clinics offering stem cell therapies for a high price, but a doctor told me that Duke would be the safest place to try.  The problem is that a responsive clinic like Duke usually would not allow such experimental treatments to those with genetic conditions. 

New approach of stem cell is to inject stem cells closer to brain, (lumber puncture or ventricles, for example), when she received the stem cells in her arm, they wouldn't have reached to her brain. Brain cells are not replaced as often as in other body parts, and even if the stem cells reach to brain and become new healthy brain cells, the brain cells that were already affected probably will not change.  Other things in stem cell therapy injection might have helped temporarily, but probably her stem cell therapy in arm was not a permanent solution for her.  

Image by Fulvio Ciccolo


Supplements and Therapies

Although there aren't any official proven treatment options available, there are well-known activators and inhibitors of mTORC1, mTORC2, and relating signaling pathways.  I've tried some vitamins and supplements within the range safe to normal population.  


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