Looking for opportunities

David 11 March 2017 small
Six years to learn walking, 9 years before eating by mouth. This picture seems so ordinary, but his parents see more than meets the eye.

Success is very much about seizing opportunities. With all of David’s early issues, we could not address everything at once, but we always looked for opportunities.  For example, when he started climbing in the refrigerator we encouraged him (under watchful eyes). See the picture here: Gene deletion versus mutation.

Science is about hard work, but it is also about seizing opportunities.  The discovery of penicillin is a classic example.  Alexander Fleming made his discovery in a moldy petri dish.  The open dish was contaminated by a mold that killed bacteria in the dish.  The mold in the dish was accidental, but Fleming’s observation was not.  He was a scientist looking for ways to kill bacteria. A few years after the initial discovery, penicillin saved its first life: a child.  We need to keep our eyes open for opportunities and we need to make opportunities happen.  So how can we do that?

This past week a group of 22q13 deletion syndrome parents took on a challenge.  I asked them to identify other children who are most like their own.  The goal was to find ways to “cluster” the characteristics of children with 22q13 deletion syndrome, as described in my most recent blog: Splitting, Lumping and Clustering. It was a lot of fun and, just as I suspected, there are groups of kids that are very similar to each other. The information on the Facebook group could be compiled and studied.  I would recommend someone do that. The exercise could be expanded.  There is a lot to learn.  Parents have insights into their children that medical researchers cannot. Categorizing how groups of children are alike and different could speed up research.

This blog is about other, untapped opportunities to look at categories of 22q13 deletion syndrome children. There are special cases we should not overlook.

Matched deletions

I hear people say that no two deletions are exactly alike. Not true.  There are cases where the deletions are exactly the same. Here is the list: 1) twins (yes, there are twins in our community), 2) unbalanced translocations (my son’s deletion and my niece’s deletion are exactly the same, as are several other children and adults in our extended family), and 3) germ line deletions. I do not know any 22q13 deletion syndrome families with multiple children from germline deletions.  I would be interested in hearing of any cases.

I have heard some doctors and scientists say “no two deletions are alike” even though they should know better.  We need to exploit these cases to find out what matched deletions have in common and how they differ from each other. Those observations will hint at which aspects are genetic and which are probably not.

Interstitial math

There are a lot of 22q13 deletion syndrome children with terminal deletions. There are fewer people with interstitial deletions.  What if we take each person with an interstitial deletion and matched them up with someone who’s deletion starts at the same spot on the chromosome?   In such a case both people would be missing the same interstitial genes. What can we learn? It is a kind of A minus B experiment. It might tell us a lot about what the genes in common are doing.

Pure SHANK3 deletions

One popular theory about 22q13 deletion syndrome is that SHANK3 mutations act simply by reducing the amount of SHANK3 protein.  If a SHANK3 gene is missing altogether, there is no controversy.  However, there is an alternative theory that mutations of SHANK3 cause the formation of damaging proteins.  The difference is important.  In the first case, studying SHANK3 mutations are likely to help anyone with a SHANK3 loss (most people with 22q13 deletion syndrome).  In the second case, a cure for SHANK3 mutation is not likely to help most people with 22q13 deletion syndrome.  Right now the differences are being studied in mice and rats.  As valuable as such research might be, it does not resolve the question in people.

We need a study that specifically compares these two groups, people with SHANK3 mutations and people with complete (or nearly complete) SHANK3 deletions that are small enough to leave other, nearby genes, alone.  Once again, we as parents can look at our children, and start listing their characteristics and share the similarities and differences.

Where next?

I believe parents can be major contributors just by our ability to see similarities and differences in our children.  The scientists and clinicians studying our children have all kinds of ideas, but frankly they can use a little guidance.  Drug studies are mixing kids with the tiniest mutations and kids with big deletions.  Tools to measure vocalizations are being tested on kids that make very few sounds, and their parents already know what those sounds mean and how often their kids make them.  We can appreciate that our kids are difficult to understand, but the whole research/investigation process can be improved.   The PMSF International Registry has been a big step in the right direction, but listening to the parents explore like-children this week on Facebook, it is clear families are ready to do more.

arm22q13

 

Previous blogs

Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
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
Science Leadership
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.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction


Splitting, Lumping and Clustering

David circa 2009
David happily watching his videos in the summer of 2009

If we want to find treatments for Phelan McDermid syndrome (PMS), first we need to figure out what is PMS.  That was spelled out in my blog: Why don’t we have better drugs for 22q13 deletion syndrome? My next blog addressed how to organize all the different genetic deletions and mutations so that we can define PMS (Defining Phelan McDermid syndrome).  Today’s blog addresses ways we can define different types of PMS.  If we don’t define different types, we are wasting our time experimenting with treatments.  For instance, some PMS kids talk fluently, some talk in short sentences, some can only say single words and many, like David, do not talk at all.  These and many other difference warrant different groups of kids when we test treatments.

Just as there is huge variation in abilities and behavioral characteristics, our kids have very diverse genetics.  Recent studies of rodents  show that not all with Shank3 mutations are alike.  In fact, drugs may work very differently on different Shank3 mutations. Anyone who has kept up with my blogs knows that deletions of different genes are likely to have very different effects on our children.  These difference are very important.

Useful drug testing is stuck right now until we develop a way to categorize people with PMS based on both phenotypic characteristics (symptoms and manifestations) and genotypes (deletions versus mutations and which genes are affected).

I have heard scientists who study Shank3 mice talk about “splitting” and “lumping”.  Splitting is breaking groups into subgroups.  Lumping is putting everyone/everything together into a single group.  Lumping has not worked and the growing consensus is that lumping will never work in our population. Splitting based on just one characteristic (e.g., deletion size) probably won’t work, either.  We need a more refined approach.  What we need is “clustering”.  Clustering is what mathematicians and scientists do when categorizing requires using many different characteristics at once.

Here is an example.  Let’s say you want to buy a car.  You might look at various cars and think about both price and gas milage.  You could make a graph something like this:

Car Clustering2Similar types of cars have similar prices versus gas milage tradeoffs.  Race cars are more expensive, but get poor gas milage. Clustering is when you identify meaningful subgroups on a graph because the individual points are close together.  Each group is a cluster.  Even if not every car fits neatly into a cluster, you still have an organizational scheme that can be very helpful.

PMS needs meaningful groups.  Clustering can get complicated when there are more and more features that divide up the population.  However, computer programs can take care of the complexities.  What we need first is to identify which characteristics are important for grouping.  As a practical matter, researchers go back and forth. They consider characteristics, run a program that automatically clusters the data based on those characteristics, and then look to see if the clusters make sense.  That is what we need to do.

When we took David to the PMS Foundation Family Conferences in 2008 and 2010, we met a handful of kids that were remarkably like David (see photo of David, above).  What was it about those kids?  As I recall, they walked the same way, loved watching music videos, asked for help the same way, were nonverbal and all have relatively larger deletions.  Are those meaningful characteristics?  Will they help us divide PMS into different groups for meaningful drug studies? We need to find out.

arm22q13

 

Previous blogs

Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
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
Science Leadership
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.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

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

david-19-feb-2017-cropped2

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 will 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 impact it has on 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 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.  Autism is thought to be a polygenic disorder (like schizophrenia). Thus, we expect that many individuals from autism databases will also have mutations of multiple autism-related genes, not just SHANK3.  Finding a large enough group of people with one (or two) SHANK3 mutations to study drugs will probably 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 flaw.  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 unlikely that a big enough group of people with 22q13 deletion syndrome can be found with deletions that don’t involve other critical 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?).

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.

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.  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.  The question becomes, who will take us there?

arm22q13

 

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
Science Leadership
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.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

What do parents want to know?

david-dressed-up
David dressed up in his birthday best

One nice thing about writing a blog is getting feedback.  While I embrace and benefit from all kinds of feedback, I admit being partial to positive feedback.  I get some nice comments from friend on my Facebook page.  I love the encouraging comments that get posted here.  There is another kind of feedback that is neither positive nor negative, but very informative.  It is the kind of feedback that we should all pay attention to.  Visitors vote with their mouse (or touchscreen).  Every time someone clicks on a blog link, WordPress adds one to a blog page counter.   Now that it is 2017, let’s see what the numbers recorded in 2016 tell us.

stats-2016
Frequency of access for all English Language pages of this blog in 2016

The most requested page is at the bottom of the graph: How do I know which genes are missing?  That is the number one question on parents’ minds.  It makes sense.  If your car breaks down, you want to know what caused it, even if you don’t know much about cars.  At the very least, you have some idea of what needs fixing.

Three more questions are virtually tied for 2nd place. Have you ever met a child like mine? and How to fix SHANK3 are discussions of SHANK3 and its relationship to the other genes of 22q13 deletion syndrome.  Together, with the most requested blog page, over one-third (35%) of mouse clicks on this blog are from people who want to understand how all the genes of 22q13 deletion syndrome operate together to produce the disorder.  The other blog page that is tied for 2nd place addresses the same topic from the opposite direction: How can the same deletion have such different consequences?

Taken together, nearly half (46%) of the information people want from this blog is to understand what genes are missing and why those genes matter.

Most visitors in 2016 already knew about 22q13 deletion syndrome.  Only about 4% of all clicks went to 22q13 deletion syndrome – an introduction. Fewer clicks went to learning about the author. (I can live with that!)  But, I think there are a other links that deserve attention.  Here is a suggestion for the new year:

Gene deletion versus mutation: sometimes missing a gene is better.
SHANK3 is not the only gene of 22q13 that can have serious consequences when mutated (modified, but not lost altogether).  Much is said about SHANK3 mutations, but 98% of people with 22q13 deletion syndrome are missing SHANK3 altogether. Understanding the difference may be crucial to finding cures.

I have dedicated the past few months to formal writing about 22q13 genes aimed at the scientific community.  That work has taken me away from this blog, but, hopefully, taken us all closer to effective treatments for our children.   That work is done for the moment and I hope to get back to this blog on a more regular basis.

arm22q13

 

Previous blogs

Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
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.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Is 22q13 deletion syndrome a mitochondrial disorder?

david-on-hike
David enjoying a walk in the park

Science is really interesting if you don’t let the details overwhelm you.  Scientists master huge piles of details, but they always step back to see the big picture. They are truly fascinated with science.  That fascination motivates their quest.  In this blog I will point out some really interesting facts so  you can share that fascination.

This blog is about organelles of the cell called mitochondria. If you look at cell with a high power microscope you will see something that appears to be another tiny organism living inside the cell.

Interesting fact #1: Mitochondria may have originally been single cell organisms that invaded larger cells.  Now, mitochondria are simply part of our cells.

Interesting fact #2: Mitochondria are the battery chargers of the cell. They turn sugars and oxygen into ATP.  ATP molecules are the rechargeable batteries used by the cell for nearly everything – from muscle contraction to digestion, growth and thinking.  Imagine what might happen if all your battery chargers were on the fritz. That would be a cell phone (mitochondrial) disorder with dramatic consequences.

Interesting fact #3: A paper published in January of this year shows that most people with 22q13 deletion syndrome have mitochondrial dysfunction (http://www.ncbi.nlm.nih.gov/pubmed/26822410).  Mitochondrial dysfunction affects more kids than any other problems except for intellectual and physical disabilities.

Interesting fact #4: Mitochondria are unique organelles because they operate using two separate sets of genes.  One set of genes is on the regular (nuclear) DNA.  The other genes are actually inside the mitochondria.  These genes, mitochondrial and nuclear, operate together.

Interesting fact #5: mitochondrial genes come only from the mother, whereas nuclear DNA is an even mix of both parents. The term “mitochondrial gene” is confusing.  Sometimes it means a gene from the mitochondrial DNA.  Other times it means a nuclear gene that is needed to help the mitochondria work properly.  In 22q13 deletion syndrome, a group of genes on chromosome 22 (nuclear DNA) are lost.  Many of these genes are important to normal mitochondrial function.  These are the mitochondrial genes I will discuss now.

The following genes impact mitochondria.  I have written on several of these genes previously.  This list includes the minimum size of a terminal deletion that would damage or delete the gene.  The list is borrowed from my earlier blog (How do I know which genes are missing?).

Mitochondria related gene Deletion size (Kbase)
CHKB 235.47
CPT1B 240.05
TYMP 288.47
SCO2 292.86
SELO 600.85
GRAMD4 4,180.53
TRMU 4,484.77
ATXN10 4,973.16
KIAA0930 5,577.70
SAMM50 6,821.94
TSPO 7,655.23
MCAT 7,675.07
BIK 7,688.76
ATP5L2 8,177.87
NDUFA6 8,727.69
SMDT1 8,735.12
ACO2 9,289.48

This list has 17 genes.  About half the children with terminal deletions are missing 5.3 Mbases (5,300 Kbases) or more (see Understanding deletion size).  That means half or more of our children are missing at least 8 mitochondrial genes.  Have you met a child with a really large deletion?  They generally have multiple major health issues.  It is not clear which mitochondrial genes contribute the most to their problems, but even children with smaller deletions are outside the normal range of mitochondrial enzyme functioning.

Some of these genes likely have little or no impact.  I have written about ATXN10 (Gene deletion versus mutation: sometimes missing a gene is better.). Some people inherit a mutated copy of ATXN10 that has an extra sequence.  It is an unused sequence that gets stripped off when the protein is produced.  The protein is normal.  However, the excess stuff that gets stripped off interferes with another enzyme in the body.  The interference ends up poisoning the mitochondria and killing the cells (http://www.ncbi.nlm.nih.gov/pubmed/20548952).  Fortunately, this is not a gene we need to worry about.  Our children are missing ATXN10.  They don’t have the mutated gene seen in certain families. Likewise, based on what is know about the BIK gene, it is also unlikely to contribute to our children’s mitochondrial problems.

So, which mitochondrial genes are causing so many problems?  One gene is specific for muscle function (e.g., CPT1B). We should not be surprised if that mitochondrial gene contributes to hypotonia (see 22q13 Deletion Syndrome: hypotonia). However, most mitochondrial genes are essential for normal function in every part of the body.

The degree of damage mitochondrial genes can cause can be seen with SCO2.  Loss or damage to both copies is often fatal early in life (http://omim.org/entry/604377?search=sco2&highlight=sco2).  Perhaps more importantly, loss of just one copy of that same gene reduces essential enzyme activity and leads to behavioral defects in mice  (http://www.ncbi.nlm.nih.gov/pubmed/22900024).  Thus, SCO2 could be a major contributor brain dysfunction in many children.

We know that more than half of our kids are outside the normal range of mitochondrial function.  Many scientist believe that mitochondrial genes contribute to neurodevelopmental disorders (http://www.ncbi.nlm.nih.gov/pubmed/26442764), and that those disorders (e.g., 22q13 deletion syndrome) are associated with mitochondrial dysfunction (for example, http://www.ncbi.nlm.nih.gov/pubmed/26439018).   What is needed now is a more complete study that includes all of our children.  How? When the scientific paper came out in January describing mitochondrial dysfunction in our children, I was certain the researchers would be invited to the 2016 conference.  The head of that study was eager to come, present his results and gather more cheek swabs. What happened?

arm22q13

Previous blogs

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
Science Leadership
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.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

 

How to fix SHANK3

david-eating-cerial-bars
David snacking on some cereal bar bits
Aubree and Mickey rev 2
Human – Mouse Partnership

Anyone who has read most or all of my blog pages knows that my goal is to help parents, scientists and other members of the 22q13 deletion syndrome community understand how the genetic landscape of chromosome 22 must shape our thinking if we are going to realistically pursue treatments. If you have not read the earlier blogs, much of this one may seem foreign.  This blog is based heavily on prior ones.  Because of the overlap, I will omit scientific references and simply recommend reviewing prior posts for supporting evidence.


There has been a recent flurry of mouse model papers on the Shank3 gene. The number of model mice has passed one dozen.  People who work on Shank3 mice love to describe their rodents’ behaviors as mouse analogs to human behaviors.  When an unusual mouse behavior is “rescued” with a chemical compound, the implicit (sometimes explicit) suggestion is that mouse research is on a path to curing autism, “Phelan-McDermid syndrome” (PMS) and maybe even schizophrenia.  Some researchers like to define PMS as a disturbance of SHANK3, which guarantees that any SHANK3 fix will fix PMS, whether or not the child is any better.  I am not going to argue with this rosy, perhaps fanciful, view of current rodent research.  It helps patients’ families feel hopeful and keeps funding and publications flowing. These are good things that a more conservative interpretation of the data might never accomplish.

From a practical standpoint, however, we still need a strategy for fixing SHANK3 problems in humans.  We need a plan that has more to do with the human disorder than the rodent one, and more to do with  therapeutic benefit than a detectable statistical change. The plan needs to be based on what we know more than what we speculate.  The plan needs to be about the patients, not the scientists, funding agencies or feel-good charity organizations.

The first thing we don’t know is whether human SHANK3 mutation causes the same problems as SHANK3 deletion.  Numerous rodent studies speculate that the influence of Shank3 mutation is a “dosage effect”.  That is, the effect is simply due to how much SHANK3 protein is lost.  Yet, total removal of all SHANK3 protein from a mouse has less effect than many Shank3 gene mutations.  Among the many different Shank3 mutations studied in mice, the behavioral, molecular, electrophysiological and drug effects differ widely. This “diversity of phenotypes” is the hallmark of a mutation syndrome, not simply a dosage effect.  In other words, in rodents there is a Shank3 mutation syndrome that is different from Shank3 deletion.

What about humans?  Is SHANK3 mutation different from SHANK3 deletion?  Well, no one knows, because only one patient has ever been described in the published literature as having a complete SHANK3 deletion without also damaging or removing other well-established brain genes, and the published information on that patient is limited.  It should not be necessary to emphasize this, but it make no sense to talk about exquisitely, selectively removing exactly one gene in a mouse and comparing that to humans missing 20, 30 or 100 genes. Any study based on a mouse model that accidently knocked out 2 or 3 nearby genes would never get published.  It is disingenuous to insist on precision mouse gene editing and then make comparisons to patient populations that are nearly devoid of matching examples. It is inconvenient that we don’t have clean human examples, but we parents of 22q13 deletion syndrome children deal with a lot of inconveniences that we cannot wish away.  In that regard, we are not very sympathetic to wishful scientists.

So, let’s be clear on what we don’t know.  We don’t know if selective SHANK3 deletions are different from SHANK3 mutations in humans.  However, we do know that humans with different SHANK3 mutations can have very different presentations, including autism spectrum disorder (ASD), intellectual disability (ID), combined ASD with ID, and combined schizophrenia with ID. So, we know that the diversity of phenotypes associated with mouse Shank3 mutations parallels the diversity of human phenotypes.  This parallel gives us some, albeit weak, evidence that the effects of human SHANK3 mutations are not a simple a dosage effect.  We are still limited by the paucity of human cases to assess the real impact of a pure SHANK3 deletion.

Wishful thinking aside, let’s go with what the (limited) evidence says: human SHANK3 mutations (including deletions that disrupt the gene) probably have effects other than reducing the availability of SHANK3 protein.  Because mutation syndromes are not uncommon on chromosome 22 and elsewhere, there is ample precedence for understanding how mutations can disrupt normal function. The mouse (and human) Shank3 gene has 7 intragenic promoter regions and  an estimated 20 to 100 natural isoforms (variants of the protein produced). The SHANK3 protein is very similar to SHANK1 and SHANK2, with many molecular binding partners in common.  That is, the three shank proteins  all interact with essentially the same molecules in the neurons of the brain. Taking a reasonable speculative leap, mutation of SHANK3 gene can produce some or many SHANK3 fragments that wreck havoc with the assembly of the synapse. As an analogy, think about placing a bunch of defective nuts and bolts into the manufacturing process for a car or airplane. The production line is better off substituting different hardware (e.g., using SHANK1 or SHANK2) than installing parts with defective hardware (broken bits of SHANK3).   The somewhat unexpected conclusion is that we might be able to treat disorders of SHANK3 mutation by shutting down the SHANK3 genes partially, or altogether. This approach can be tested in mice.

If we are considering SHANK3 deletion as a treatment for SHANK3 mutation, then we better be prepared to treat SHANK3 deletion.  I believe recent results from the first Shank3 complete knockout mouse provides a path for understanding and treating human SHANK3 deletion.  The most abiding and measureable effect of complete Shank3 deletion in the mouse is failure to engage and benefit from an operant conditioning task (lever pressing for a reward).  This effect appears to be associated with abnormal ventral striatal function, which is consistent with many previous studies of the ventral striatum.  Failure to explore and learn would be indicative of ID in humans, so it is of great interest to understand the exact relationship between the learning deficits in humans with pure SHANK3 deletions and mice with pure (complete) Shank3 deletions.  Such an undertaking would require a very modern and somewhat novel strategy in the world of pre-clinical neuropsychiatric research.

The precise nature of the mouse learning deficit is not yet understood.  Learning is a complex process and many aspects are very subtle.  Even the reported rescue of learning in the Shank3 knockout mouse creates more questions than answers.  These questions go to the heart of how SHANK3 loss might contribute to intellectual disability in humans.  How can the details of learning deficits caused by SHANK3 deletion be dissected out?  Given the rarity of pure SHANK3 deletion, I propose that a single subject (or two) be invited as true participants in a scientific study of their learning abilities, and that the latest computational approaches (often used in animal research) be applied in a series of iterative testing to model and measure the learning deficits.

Current, state-of-the-art scientific learning studies are computationally based.  Learning tasks are designed to incorporate variables that can be directly tied to equations describing an underlying theoretical framework of the learning process.  Animal researchers are adept at designing learning tasks in ways that do not require verbal instruction.  They  are equally practiced at inferring the results without the need for verbal reports. Still, with the participation of a fluent verbal subject, researchers can work with the subject to help design tasks (games) that are interesting and engaging.  Rewards for mice are often in the form of sweetened concentrated milk droplets.  For healthy adults, money is commonly used as an incentive.  The SHANK3 deletion participant may prefer to see dancing fairies or a music video clip.

As these learning tasks  begin to characterize the nature of the deficit seen in the subject/participant, they are then re-designed for testing in animal models. Current rodent models can be used, but there is no reason the same tasks cannot be explored in nonhuman primates for fMRI and electrophysiological investigation. The technology of gene editing, common in mice, has reached farm animals and at least two species of nonhuman primates.   As these methods become more mainstream, complete SHANK3 deletion could be a practical research option, especially in old world monkeys, species that shares important common features with human cortical evolution.

The goal of this scientist/participant research partnership is to develop a sensitive cross-species measure of learning ability that parametrizes the impact of SHANK3 dosage.  Such a measure provides two invaluable assets to the development of treatments. First, animal models can be validated (or not) based on exquisite computational approaches that may be able to distinguish species differences from the influence of SHANK3 dosage.  Second, interventions, either learning-based or pharmaceutical, can be tested using measures sufficiently sensitive to reflect the identified nature of the deficit. What can this human research/animal research partnership hope to produce?  The first successes may be refinements to educational methodologies.  The learning models could point the way to improvements in teaching strategies.  Later, dare we hope, may be pharmaceutical interventions.

Wouldn’t it be splendid if parents could continue to hope, scientists could continue to get published, feel-good organizations could continue to raise money, and in the meanwhile, our kids could get better, too?

 

arm22q13

Previous blogs

Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
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.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

 

22q13 deletion syndrome and science leadership

My previous blog (How can the same deletion have such different consequences?) ended with a discussion of science leadership.  I asked the question, “Why have we not benefited?”  That is, why have 22q13 deletion syndrome children like my son, David, seen little or no benefit after decades of research?  I have heard many reasons: limited number of patients, limited financial resources, limited knowledge, etc.  I frequently hear even less convincing phrases like, the research is “very promising” and “scientists are doing their best”.

However, these are not reasons for lack of results. These are reasons that emphasize the need for qualified, family-centric science leadership.  In the previous blog I identified another chromosome deletion syndrome (18q deletion syndrome) with all the same difficulties, yet their story is much different (See the scientific articles Making chromosome abnormalities treatable conditions and Consequences of chromosome 18q deletions).  Research on 18q deletion syndrome has been enormously successful in plotting a scientific course towards treatments.  Since writing that blog I discovered why.  Rather, who: Jannine Cody.  Dr. Cody got her PhD to develop treatments for her daughter with 18q deletion syndrome.  The success of 18q comes from the science leadership of Dr. Cody.  Dr. Cody is a qualified scientist without any other conflict of interest.  She is committed not only to every family, but also to the impact of each and every gene on the long arm of chromosome 18.  I encourage you to watch the YouTube and hear her story.  Science leadership makes all the difference in the world.

 

arm22q13