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 Stem Cell Therapy, Rapamycin (Sirolimus), Everolimus(Afinidor), and natural mTOR inhibitors. 

Rapamycin/Everolimus (In USA)

Benefits, Limits and Tricky Dosing

While I wait for a better mTOR inhibitors, she's tried Sirolimus and Everollimus 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, they improved many of her issues. (Prevents excessive hanger(probably by normalizing glycosis IMO), Improves  attention span, better muscle coordination, prevents club feet, helps with digestion (probably because of normalized lipase level IMO) and intestine mobility. She's also less sensitive to sound and sleeps better.

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

Benefits

Limits

  • 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.

  • 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 Dosed

After a few years of trial and errors, now my goal is how to get the best dose for Elizabeth's brain and behavior.     

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, but hope my 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 right speed, just at the speed limit of 50km/hr for example,.    

Just slightly 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 sympto ms come back. The first obvious sign is her excessive hunger.  Even at the same blood glucose level, her brain starts overly craving for food.

The higher the daily dose, the faster I reach to the speed limit, where she's the happiest
 

After that, I need to release the accelerator a little to stay just bellow 50km/hr,  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 several more seconds to release the accelerator, the  car might reach to 100 km/hr, and it takes much longer to slow down to 50km/hr  again. .   At 1.5mg/day Sirolimus, when I waited an extra day to stop the dose, it meant 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.

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

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