Why don’t we have better drugs for 22q13 deletion syndrome?

Originally posted 27 February 2017
Updated 10 April 2024

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This blog was originally posted in 2017. Read later blog posts to see the advances in medicine since that time. The information here is still quite valuable in understanding why treatments for 22q13 deletion syndrome (Phelan McDermid syndrome, PMS) are so difficult to develop.

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David does not talk, although I am certain he would like to. He has poor hand control. He can just barely manage a spoon or glass of water with great effort. Although he walks a lot, he is always at risk of falling. There are so many things that are difficult for David. It would be nice if we had a medication to make his life easier.

After years of drug testing on children with 22q13 deletion syndrome we are probably no closer to a treatment now than when it started. This problem is not unique to 22q13 deletion syndrome; it is true for many, if not most neuropsychiatric disorders (see: Hope for autism treatment dims as more drug trials fail).  Recently, Rachel Zamzow wrote a very readable review about why autism clinical trials have failed (Why don’t we have better drugs for autism?).  Her review is in Spectrum, the on-line magazine affiliated with the Simons Foundation Autism Research Initiative (SFARI). Rachel identifies three problems that plague clinical trials: 1) bad design, 2) wrong measures and 3) too broad a range of participants. While problems 1 and 2 are important, problem 3 is a major stumbling block for 22q13 deletion syndrome that I would like to address.

Clinical trials for 22q13 deletion syndrome are intended to treat defects or loss of SHANK3 (Kolevzon et al., 2014). The problem with finding a treatment for SHANK3 is just as Rachel – and many others – have described. If the subjects you are testing are too diverse, you will never see a clear impact of the drug you are testing. The subjects recruited for these studies have either SHANK3 mutations or have 22q13 deletion syndrome with terminal deletions of different sizes. This group is more diverse than many, perhaps all, of the other autism-related clinical studies that have failed. Going on past experience in the field, this clinical group may not provide useable results. Here are the reasons why.

SHANK3 mutations are complicated

Early on, there was hopeful enthusiasm about hunting for a cure for people with 22q13 deletion syndrome. At that time, SHANK3 mutations were lumped together with chromosomal deletions.  Importantly, SHANK3 mutations were thought of as simply a loss of SHANK3 function. As it turns out, SHANK3 mutations are tremendously complicated. Different SHANK3 mutations can have very different effects on the gene, on the proteins it produces, on the neural development of the brain, and on the net effect in both people and experimental animals. The most recent and most thorough review of Shank proteins (Monteiro and Feng, 2017) says it clearly: “Indeed, the idea that isoform-specific disruptions [different mutations] will result in different phenotypic consequences (and even result in different disorders) has recently gained momentum.”  I can say with some pride that the momentum includes my June 2016 blog How to fix SHANK3, which makes that very same point.  You probably cannot lump together people with different SHANK3 mutations and expect to get a single clear result.

Too few patients have the same SHANK3 mutation

To date, no one has been able to find enough people with the same SHANK3 mutation to do a drug study. You can find SHANK3 mutations in large autism databases, but these are not like a registry where you can call the patient up and ask them to participate. There is no doubt that medical researchers would pull together a SHANK3 drug study population, if they could. Finding a large enough group of people with one (or two) SHANK3 mutations to study drugs may never happen.

Individuals with 22q13 deletions are too diverse

Another approach might be to use 22q13 deletion syndrome patients with terminal deletions that remove SHANK3 altogether.  Every one of these patients would have exactly the same SHANK3 loss.  Further, there is a registry for 22q13 deletion syndrome patients that might help with recruitment (PMSIR).  While this seems appealing, it has its own limitations. Just as the SHANK3 mutation population is likely to have other autism and intellectual disability genes complicating the picture, chromosome 22 is full of genes that likely contribute to autism, intellectual disability, hypotonia and other phenotypic traits associated with SHANK3. Anyone who has read my other blogs has seen numerous examples of those genes (see Mouse models and How do we know which genes are important?).  Because of the densely packed genes near SHANK3 (see Understanding deletion size), it is difficult to develop a big enough group of people with SHANK3 deletions that don’t involve other important genes on 22q13.

Solutions

In her article, Rachel Zamzow discusses the N-of-1 Trials approach. We parents do this all the time. We experiment with different medicines on our one child. N-of-1 design simply has the clinical researcher follow the child during the test. I’m not a big fan of N-of-1. I prefer a mixed experimental approach where research animal testing is done in tandem with human testing (see Have you ever met a child like mine?). But, I leave decisions like these up to the experts.

In their detailed review of Shank proteins and autism, Monteiro and Feng recommended that “..careful genotype-phenotype patient stratification is required before individual testing of specific pharmacological agents.”  That is, don’t test drugs until you understand the impact of the genes that have been lost. If you have been reading my blogs, that should sound very familiar.

Two things must change before we can expect drug testing to bring meaningful results. First, we need to organize Phelan McDermid syndrome, SHANK3 mutation syndrome(s), and chromosome 22q13 deletion syndrome into a meaningful “genotype-phenotype patient stratification”. That is, we need to define different types and subtypes of the syndrome that was once called 22q13 deletion syndrome.  I proposed running an interactive session with parents and researchers in 2012, and for the session I put together a Power Point presentation called: “Defining PMS across Genotypes Phenotypes and Molecular Pathology.”  I was asked not to present my ideas.  Perhaps I will be given a chance, someday. Since then, some progress has been made at subtypes (see this blog post).

Second,  we must spend the time to characterize the genes that are near SHANK3 on chromosome 22 and understand (in experimental animals) how they might contribute to 22q13 deletion syndrome.  We need to study people with interstitial deletions, so we can isolate the effects of these genes. Efforts to explore the contributions of 22q13 genes has been lacking, yet they are a major impediment to the search for effective drug treatments.

22q13 deletion syndrome has left David completely dependent upon others for his day-to-day living. Both David and I have come to accept that fact. What we cannot do for David is know where it hurts when he is sick or injured. If I had one wish for a new medicine, that medication would let David point to where it hurts. That medicine, or any useful medication, is not going to happen until someone takes the needed steps to remove the impediments that interfere with productive drug testing. It is clear where we need to go. It will take time to get there.

arm22q13

Some previous blogs

What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse models
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Understanding deletion size
22q13 deletion syndrome – an introduction