It has been known for some time that many people with Phelan McDermid syndrome (PMS) have mitochondrial issues. I discussed this in an earlier post (see Is 22q13 deletion syndrome a mitochondrial disorder?). At the time of that posting there were 17 PMS genes known to impact mitochondria. There is evidence that the PMS gene RABL2B generates a protein to transport mitochondria into synapses. That would be 18 genes. Now, new evidence has emerged that the SULT4A1 gene, a highly important PMS gene (see Which PMS genes are most important?) is critical for protecting the brain from oxidative stress by regulating mitochondria function.
After 20 years the role of SULT4A1 is finally coming to light. SULT enzymes have been known as important enzymes for a while, but SULT4A1 has always been a mystery. The other SULT enzymes have an active region used to regulate critical proteins in the cell, some involved with mitochondria function and the key neurotransmitter, dopamine. But, the SULT4A1 protein lacks the same active enzyme site. The other mystery has been that the SULT4A1 gene is highly specific for brain and brain development. Cathrine Ziats’ scientific paper last year found SULT4A1 to be one of the top 4 PMS genes expressed in the human brain during development (see her paper: Functional genomics analysis of Phelan-McDermid syndrome).
The new evidence paints a picture placing SULT4A1 as a critical regulator of brain metabolism. The thing to understand about the brain is that it sucks up 30% of the total body’s energy supply! This puts a huge load on the mitochondria of the brain. SULT4A1 regulates two other SULT proteins, SULT1A1 and SULT1A3. These enzymes are found on the outside membrane of mitochondria, connected together in pairs. By regulating these enzymes, SULT4A1 is able to crank up the output of the brain’s mitochondria. This reduces the reactive oxygen species, reduces oxidative stress and prevents neuronal damage. (See the two articles on PubMed: Hossain et al 2019 and Idris et al 2020). As SULT4A1 regulates these two other enzymes it can also regulate the effects of dopamine. Dopamine is a key neurotransmitter involved in learning and decision making. Too much dopamine, especially during development, can damage a cell. Too little dopamine is associated with motor and psychiatric disorders, like Parkinson’s disease and major depressive disorder.
Nearly a third of our PMS kids are missing the SULT4A1 gene (deletions larger than 7 Mb). Finding a way to fix the SULT4A1 gene would be a game-changer for these children. Like the other essential brain genes of PMS (e.g., SHANK3), the precise regulation of SULT4A1 is critical to normal development and healthy brain function. There are people with interstitial deletions of 22q13 that impact SULT4A1 without affecting SHANK3, and these people have severe developmental problems indistinguishable from others with PMS. (That some scientists are still arguing over whether or not to keep them in the family of PMS is a travesty, in my opinion as a father. See PMS, IQ and why interstitial deletions matter.)
We need more research on SULT4A1. We need treatments sooner rather than later.
arm22q13
arm22q13 
Hi Andrew, I‘m a father of a 5 years old PMS child from Germany, I saw your articles about PMS which give us really much enlightenment.
Recently I read there’re two companies who are testing their medicine. One is named AMO-01, which is even in its phase II test, another one is from the company NNZ, it’s medicine named NNZ-2591 will be tested for its phase II in 2021.
The test with Schank3 knockout mouse was allegedly a success, and it was said the medicine could restore normal learning functions, do you have some information about them and how much beneficial they will be for the PMS children according to your forecasts? I do really hope it would true that the children could make significant progress, like speaking and running, with this kind of medical care.
And thank you for taking your time to read this message in advance!
BR
Eric
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There have been several drugs tested on people with 22q13.3 deletion syndrome. These are all drugs that were developed for some other target population. IGF-1 has been used for growth deficiency. Oxytocin has been used for child birth. Because they have been used in the past, there is no requirement for Phase I (safety) testing. All repurposed drugs start in Phase II.
AMO-01 is a repurposed drug. It has undergone multiple name changes that makes it a difficult drug to track its history. You need access to a special pharmaceutical database. I did that tracking once. If I recall correctly, the drug was originally tested on people with brain cancer. It was unsuccessful. It is a drug looking for an application.
I know less about NNZ-2591.
I am a skeptic regarding repurposed drugs. I don’t trust the one-shot mouse or rat experiments that show an effect. There are a dozen reported “rescues” of SHANK3 mice with everything from histone deacetylase inhibitors to allosteric modulators. Many drugs being tested are aimed at down-stream targets.
Drug companies are funding the clinical studies. Universities and institutes benefit from the funding and parents are signing their children up for testing. My worry is that a very weak positive result will lead to a lot of money wasted on a treatment that helps very little. The big winner, of course, would be the drug company. We shall see.
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Well written and I’m still shock how anyone can separate a group. If you fracture your arm, it’s a fracture. If you fracture your back and your paralyzed it’s a fracture. I would think academics would just embrace the ideas of new research and see where it leads instead of labeling it.
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