Is “PMS-SHANK3 unrelated” truly unrelated to SHANK3? Maybe not.

David relaxing in the car during a drive through the countryside

Originally posted 10 April 2024

In 2022 a group of scientists associated with the Phelan McDermid Syndrome Foundation (PMSF) published a consensus paper that addressed a controversy around what constitutes Phelan McDermid syndrome (PMS). It was an important step toward defining the disorder, providing guidance to geneticists, and working towards an ICD code for diagnosis and medical reimbursement. Although the consensus opinion was not universal, the clarification was welcome. These experts split PMS into two mutually exclusive classes: “PMS-SHANK3 related” and “PMS-SHANK3 unrelated”. It is a simple, clear dichotomy. But genetics are rarely simple, as we shall see.

The thinking at the time was from the perspective of genetic testing. If the test result includes an abnormality of the SHANK3 “coding region”, then it gets the designation PMS-SHANK3 related. All other test results would be PMS-SHANK3 unrelated.

The people who hammered out this definition (distinction) are all experts. They were fully aware of all the possible ways genes can contribute to a disorder. There are dissenters, also experts, who feel that if SHANK3 is not involved, then the name PMS should not be applied. The consensus paper explains that people with interstitial deletions (PMS-SHANK3 unrelated) do not appear to have a syndrome different from PMS. There is also no transition from PMS to some other syndrome as deletion sizes get larger, whether or not SHANK3 is involved. There is no clear evidence that PMS-SHANK3 unrelated is some other type of disorder. The key concern for dissenters is that genes other than SHANK3 do not contribute to the disorder in the same way that SHANK3 causes PMS.

However, what if we can show that other genes on chromosome 22 contribute to PMS through their impact on SHANK3, or their impact on the molecules that interact with SHANK3? If the genes of 22q13.3 (the site of interstitial deletions) have such direct impact on SHANK3, then perhaps the term “PMS-SHANK3 unrelated” is misleading. If the biology of PMS-SHANK3 unrelated is highly related to SHANK3, then a distinction may not be warranted. The latest evidence suggests there are at least six genes that impact SHANK3 (and partner molecules), and these genes contribute to PMS when deleted. I would call these genes SHANK3 related.

The six genes and the details of how they interact with SHANK3 are discussed in a recent paper. The paper is open source (anyone can read it), but very technical. Full disclosure: I helped write the paper, so this blog post is undeniably biased. People who have read my previous blog posts should know that I have long been a proponent of looking closely at the many genes of PMS. The paper is a review of work done by scientists primarily between 2017 and 2024. Science is a continuous process and during this period enough information came to light to explain the tight relationships between six genes (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, TCF20) and SHANK3. The first two genes are physically close to SHANK3 on chromosome 22, and thus are deleted in most deletions that include SHANK3. The remaining four genes are fairly evenly spaced across the last 4 Mb (megabases) of the PMS region of chromosome 22.

I have written blog posts about all of these genes at one time or another. I identified PLXNB2 and PHF21B in Why PMS is worse for people with larger deletions, and PMS Gene PHF21B is critical for normal brain development. I wrote about TCF20, a gene that has long been associated with intellectual disability (TCF20 may explain why some big deletions are worse than others). I have flagged the potential importance of BRD1 in several blogs (e.g., Regression and psychiatric dysfunction in PMS). CELSR1 was highlighted in CELSR1: Do some people with PMS have more fragile brains? SULT4A1 has also been on the radar for some time: New science: SULT4A1, oxidative stress and mitochondria disorder. My message has always been that genes important to PMS will emerge once there was sufficient evidence to critically explain why larger deletions have greater impact. SHANK3 has always been the most important gene and it has been the most intensely studied, but from the beginning of PMS research, it was never the only important gene. By “important” I mean important to families.

All seven genes (including SHANK3) impact brain development and all are involved with the process of inflammation. In this case inflammation includes “cellular stress”, “mitochondrial function”, and “recovery from injury”. These are all related processes, and all known to exacerbate PMS. So, impact on early development and response to stress and injury are features common to all of the genes.

Three of the genes (BRD1, PHF21B and TCF20) regulate what other genes do in the brain. For example, all three regulate the activity at synapses, the part of neurons that SHANK3 regulates. In addition, two more genes (PLXNB2 and SULT4A1) are directly involved in synaptic function. In fact, SULT4A1 not only regulates the same glutamate receptor as SHANK3, but it also regulates breakdown of SHANK3 at the synapse.

At this point it should be clear why PMS-SHANK3 unrelated may not really be unrelated to SHANK3. The six genes listed above join SHANK3 in shaping the development of the brain, the response of the brain to insults, and the operation of the synapses – the most important role of SHANK3 in the brain. It should also be clear why people with interstitial deletions typically have symptoms consistent with other cases of PMS. Likewise, it should also be clear why people with larger and larger deletions tend to have more severe PMS (see: Why PMS is worse for people with larger deletions).

The very close association between SHANK3 and at least six other PMS genes has a number of ramifications. First, while the distinction between SHANK3-related and -unrelated is sensible from the point of view of genetic testing, it may not be a good way to think about PMS as a disorder. Second, treatments that target SHANK3 will likely miss other relevant genes that tightly influence SHANK3, and thus may not produce very satisfying results in patients with chromosomal deletions. One way to think of the problem is that SHANK3 treatment in people with deletions essentially expands the number of PMS patients with interstitial deletions. It may be difficult to distinguish between a treatment that is not effective for SHANK3, and a treatment that is not effective because of other genes. Finally, when we are searching for an effective treatment for SHANK3 haploinsufficiency, maybe we should also look at treatments for one or more of the other genes. We may be missing out on developing additional valuable treatments.

arm22q13

SHANK3 Haploinsufficiency and Gene Therapy

Image of a bridge borrowed from Wikipedia page on rivets

Originally posted 20 September 2022
Updated 21 September 2022

Haploinsufficiency is a genetics term that gets used frequently. The definition of haploinsufficiency is rather simple but understanding when to use the word can be complicated. Often, describing something as haploinsufficient is an incomplete description. Sometimes, it is misleading or even wrong.

Unpacking the word

Humans and other mammals (e.g., cats, dogs) are diploid animals. That is, we have two copies of the major 22 chromosomes (autosomes). That means, we have two copies of nearly every gene in our DNA. Why two copies? We evolved that way. Apparently, having two copies worked out well given that most animals are diploid. Haploid means one set of chromosomes, not two. It also implies one copy of a gene rather than the normal two copies.

Insufficiency means “not enough”. Thus, the word haploinsufficiency suggests having only one copy of a gene is not sufficient for normal body (or brain) function.

Molecular biology

Haploinsufficiency is a word from the field of molecular biology. Molecular biology includes the study of how a gene is used to make proteins. Typically, a gene is the recipe for making proteins. The cell decides when and how much of a protein is needed. Given two copies of a gene, the cell can summons production from both copies to meet its needs. Haploinsufficiency (or haploinsufficient) means that having only one copy of a gene restricts the production of its protein to the point of causing a major problem.

Understanding problems associated with protein production

I like analogies, so please consider this story about a bridge that uses rivets. A construction company needs 1,500 rivets to build a bridge. (Rivets are like permanent screws used to hold metal part together. See the bridge photograph, above.) There are two suppliers of rivets, each able to supply up to 1,000 rivets. The contractor orders 1,000 rivets from each company to make sure she will have extras in case some extras are needed. Let us review some of the things that might go wrong with the orders.

• One company is unable to deliver any rivets.
• Neither company is able to deliver rivets.
• One company can deliver some rivets, but not the full 1,000.

Other, more pernicious (damaging), things can go wrong.

• Some or all the rivets from one company look like rivets but are too weak or otherwise unable to hold metal parts together.
• Some or all of the rivets will damage the equipment that handles the rivets (e.g., wrong size or shape) or will damage the bridge (e.g., premature rusting).

This scenario is designed to mimic some aspects of protein production by two genes. With genes, similar things can go wrong.

• Two genes can produce enough protein, but one gene cannot. This would be haploinsufficiency (one copy of the gene is not enough).
• One gene can produce enough protein on its own. This is called haplosufficiency (one copy of the gene is sufficient). Haplosufficiency implies that you need to have at least once good copy of the gene, otherwise there is a problem

Like rivets, the product of a gene may be defective.

• A gene can produce a product that looks like the needed protein, but not act like the protein. The defective protein may get used by the cell even when there is sufficient good protein around. I will call this “defective protein“, which is not really a technical term.
• A gene can produce a protein that interferes with the machinery that assembles, transports, or maintains normal cell function. This is called “gain-of-function“. While gain-of-function sounds like a good thing, in this case the “function” is damaging.

What is and is not haploinsufficiency

Now we know that haploinsufficiency is the simple case of not having enough protein after one gene is lost. However, when a gene is abnormal, the resulting protein from that gene might be missing, defective, or have a gain-of-function. In other words, when a person has an unusual and disruptive version of a gene (called a pathogenic variant), that person may suffer from multiple things that can go wrong.

SHANK3 and haploinsufficiency

People who have intellectual disability, autism, or other aspects of the syndrome due to a deletion of the q13.3 region of chromosome 22 have Phelan-McDermid syndrome (PMS). Most of those people have PMS-SHANK3 related, meaning that the SHANK3 gene has been disrupted. In most cases of PMS the SHANK3 gene is missing altogether along with many other genes. In these people PMS results from the combination of genes deleted. Some of these genes, including SHANK3, are haploinsufficient. That is, a problem is created because having only one copy of the gene leads to not producing sufficient protein for normal function. In rare cases, the 22q13.3 deletion precisely deletes the SHANK3 gene without impacting any other haploinsufficient genes. These rare cases have pure SHANK3 haploinsufficiency.

There is another group of PMS patients with pure SHANK3 haploinsufficiency. These individuals have a SHANK3 variant that does not cause the production of any disruptive proteins. There are no proteins produced that have gain-of-function and no defective proteins that might compete with the normal protein for incorporation into the cell. Unfortunately, available molecular testing cannot provide sufficient information to be sure which patients with SHANK3 variants fall into this category. For most patients we do not know what combination of haploinsufficiency, defective protein, or gain-of-function protein a person has.

The messy reality of SHANK3 variants

There is strong evidence that SHANK3 variants include all three types of problems. For example, in general, people with PMS from SHANK3 variants are higher functioning than people with moderate or large deletions of 22q13.3. Yet, among this group with SHANK3 vaiants are some low functioning individuals, suggesting these patients have a substantial contribution from a defective protein or gain-of-function protein. Experiments in rodents where the Shank3 gene is mutated to imitate human cases of SHANK3 variants show that different mutations can have distinctly different impacts on brain development, synapse formation and behavior. This rodent work is further evidence for contributions from defective or gain-of-function proteins.

What does this mean for gene therapy?

Current work on gene therapy for PMS is focused on “gene replacement therapy”. The goal is to supplement the amount of Shank3 protein in the brain to compensate for haploinsufficiency by introducing an additional copy of a gene similar to SHANK3. This is an exciting and cutting-edge approach to seeking an effective treatment for PMS. It is currently in the animal experiment (“pre-clinical”) phase. If this approach leads to drug testing, we need to understand its limitation. While most of PMS involves SHANK3 haploinsufficiency, rarely is that the only problem. People with deletions of 22q13.3 can have many (up to 18) impacted haploinsufficient genes, and many people with SHANK3 pathogenic variants are likely to have contributions from defective or gain-of-function proteins. There is at least one known gain-of-function mutation tested in mice that effectively wipes out any attempt by the cell to produce SHANK3. So, even if the gene therapy helps some people, there are likely those people who would need an alternative therapy to benefit.

The current work on gene replacement therapy may or may not produce a product safe enough to try on human beings. Even if things go well, it may be 10 to 15 or more years before a product becomes available to families with PMS. Even if this happens, we are still faced with the messy reality of PMS: on one hand, people with chromosomal deletions that include SHANK3 are almost always missing other important genes, and, on the other hand, people with SHANK3 variants may be suffering from more than haploinsufficiency. I would like to offer three take-home messages:

• While SHANK3 haploinsufficiency is an important aspect of Phelan-McDermid syndrome (SHANK3-related), we honestly do not know if it is 30%, 50% or 75% to blame in any given individual.
• Because PMS is not just haploinsufficiency of SHANK3, any success with this first-generation gene replacement therapy (if there is any success) will be mixed at best. The first patient might do really well or have no response at all.
• Likewise, we should not be too discouraged if early clinical trials are unimpressive. There are many possible reasons for a weak effect early in testing. There is a long road ahead.

arm22q13

New science: SULT4A1, oxidative stress and mitochondria disorder

A visit with David during the COVID-19 epidemic

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

 

 

 

PMS, IQ and why interstitial deletions matter

David is nonverbal and music is very important to him

Originally posted 24 November 2018
Updated 27 November 2021
Available in Portuguese  https://pmsbrasil.org.br/pms-qi-e-por-que-as-delecoes-intersticiais-sao-importantes/

Phelan McDermid syndrome (PMS) is an intellectual disability developmental disorder. The most common reported form is a “terminal deletion” of the q end of chromosome 22. A terminal deletion occurs when a continuous segment of the chromosome is broken off at the end. Terminal deletions lead to intellectual disability (ID), language problems and coordination problems. Most people with PMS have additional problems (sleep disorder, feeding disorder, seizures, etc.), and these problems can often be severe. Many, perhaps most, have autism spectrum characteristics. I would argue that the hallmark trait of PMS is intellectual disability, because that manifestation of the disorder is the only one that occurs in 100% of people with a terminal deletion. By consensus, cases of unusual variants of the gene SHANK3 are also called PMS. These pathological variants of SHANK3 can have many of the same manifestations as seen with terminal deletions, although not all.

There are two related conditions that have lead to disagreement regarding what is and is not PMS. First, are deletions of 22q13.3 that do not disrupt SHANK3 (often called “interstitial deletions”) still called PMS? Second, does a person with a SHANK3 disruption, but without the hallmark manifestation (ID), have PMS?  Out of consistency, I would argue that a 22q13.3 deletions that causes ID should be called PMS, and SHANK3 variants that do not cause ID should not be called PMS. To go one step further, given two people with the same SHANK3 variant, one person might have ID (and therefor, PMS) and another person might not have ID. This unusual combination of circumstances has been observed. Likewise, two people with the same 22q13.3 interstitial deletion might or might not have PMS. This sort of definition is common with neurodevelopmental genetic syndromes. The genetics (called “genotype”) must cause a matching set of manifestations (called “phenotype”), to meet criteria for a named disorder. Some disorders have subtypes, but PMS has no official subtypes yet.

The rest of this discussion does not depend whether you call interstitial deletions PMS, treat interstitial deletions as a future subtype of PMS, or just avoid giving them a name. Understanding interstitial deletions is crucial to understanding PMS, because PMS can include the deletion of up to 108 different genes. Some of these genes are very important. If we want to end the suffering of PMS, we need to know which genes are important and in what way. Interstitial deletions can help teach us. Let me explain how, starting with old radios.

When I was a child I took apart radios to understand how they worked. This was a dangerous undertaking for a young boy. Radios were high voltage affairs in the old days. If the power mains didn’t kill you, burned fingers from hot vacuum tubes or a hot soldering iron left painful reminders of what not to touch. My logic in those days was to remove parts until the radio stopped working. The obviously necessary part was then soldered back into place and the hunt for more nonessential parts continued. When done, I still had a working radio, plus a collection of spare parts. “Working” did not always mean “working perfectly”.

Fifty years later, teams of scientists have used this same logic to grade the importance of each gene in the human genome. One such measure is the pLI score. Think of all people who are healthy enough to have children. Analyze every gene in every one of these people. Make a note of which genes in these healthy people are missing or incomplete in some way. These are the nonessential parts. A gene that is almost never missing or incomplete gets a pLI score of 1. It must be important. A gene that is often missing or incomplete gets a pLI score of zero. You can sound technical by calling the score a measure of reproductive fitness, but the theory is no more complicated than a 10-year-old with a soldering iron. Essential parts are almost never missing from people or radios. The pLI score is the measure of gene importance.

In 2018, a team of scientists studied all deletions greater than 50 Kb in groups of people with ID (Huguet et al 2018). Basically, they asked the question, “Can ID be explained by looking at the deletion size or (similarly) counting the number of genes deleted?” They came up with a formula: add up the pLI scores of all the deleted genes, multiple by about 2.6, then add the impact of known ID genes. That gives you the number of IQ points lost due to the deletion. (Technical note: I have averaged performance IQ and verbal IQ together).

Everyone has heard of IQ to measure intellectual ability. The IQ measure was designed so the median score on an IQ test is 100 across a large population. The work of Huguet et al, including subsequent work shows that you can predict the IQ loss caused by a deletion. A deletion removing genes with a cumulative pLI of 10 will reduce a persons IQ score by about 26 IQ points. The expected IQ of a person with such a deletion would be 100-26=74. This is not a good way to predict a child’s future IQ, since we don’t know if the child’s IQ would have been 75 or 125 without a deletion. But, if the prediction is a loss of 26 IQ points and the person has mild ID, it is likely that the genetic result essentially explains that person’s intellectual disability. There is an on-line tool to help do the calculation.

The next part is a little complicated, but PMS deletions are complicated. I hope everyone can understand at least the main points.

When we apply this IQ calculation to PMS, lots of strange things about PMS start to make sense. I will use a graph to explain. The graph below shows the number of IQ points that are lost when each part of chromosome 22 is deleted. It is a prediction based on some reasonable assumptions (which will not be discussed here). Read the graph from upper left to bottom right. The graph tracks how much the IQ falls as deletion sizes get larger and larger. I have an explanation below for each numbered circle on the graph.

Circle 1: Loss of SHANK3 at the very end of the chromosome (top left corner) has a major impact on intellectual function (IQ). See how the curve drops from 0 to -30 IQ points next to circle 1? I have assumed a SHANK3 deletion costs 30 IQ points, which is a big drop even for an identified intellectual disability gene.

Circle 2: Deletion of the next 1 Mb of the chromosome has a cost of another 20 IQ points. Already, we see that deletion of SHANK3 is not necessary to reduce ID. We also see that even relatively small 22q13.3 deletions (e.g. 1 Mb) can have a large impact over-and-above the loss SHANK3.

Circle 3: See how flat the curve is at circle 3? Additional deletion of the chromosome between 1.1 Mb and 4.1 Mb has virtually no impact. For those people who say that deletion size does not matter, that is why there are so many examples. The curve is flat and, indeed, in that region increased deletion size does not influence IQ.

Circle 4: IQ takes nearly a steady drop with deletion size in region 4. Nearly, because there are two “hot spots” with individual genes that appear to have a substantial impact. The proposed genes are CELSR1 and SULT4A1. I have written about these genes multiple times, see Which PMS genes are most associated with Autism?, What do we know about PMS genes? and CELSR1: Do some people with PMS have more fragile brains? Deletions in this region can cause serious intellectual disability. It is a clear example of how an interstitial deletion can cause ID, the primary manifestation of PMS.

Circle 5: An important intellectual disability gene shows up about 8.4 Mb from the end of the chromosome. This causes another steep drop in the curve comparable to (perhaps larger than) SHANK3. See my earlier blog about this gene (TCF20).

Circle 6: I have created a hypothetical example of a 2 Mb interstitial deletion. A 2 Mb deletion is about half the size of an average 22q13.3 deletion. This deletion causes a drop in IQ (27 IQ points) that is roughly equivalent to a SHANK3 deletion. Thus, from an intellectual disability perspective, interstitial deletions can easily be equivalent to other, more common cases of PMS.

This method of studying IQ impact of chromosome deletions was not created specifically for PMS, but it seems to apply very nicely. To accurately apply this method, we need to accurately measure the IQ cost of a complete SHANK3 deletion without including the effects of other genes. Calibrating the IQ cost of deletions, including SHANK3 loss, can be done by carefully studying cases of interstitial deletions. Current data from the longitudinal PMS studies may be sufficient if more effort is put into the analysis of interstitial deletions. Finally, the method can be used to identify who might need further testing. If the estimated IQ loss does not agree with the deletion size, the person could have other genetic issues worth exploring: a mismatch could be used to justify more detailed testing (e.g., whole exome sequencing).

The research in IQ loss associated with chromosome deletion shows that, for most people with 22q13.3 deletion syndrome, fixing SHANK3 is likely to be beneficial, but not a cure. SHANK3 accounts for less than half the intellectual disability for an average size deletion (4.5 Mb) and less than 25% of a large deletion. Finally, we need to take interstitial deletions more seriously. From a scientific perspective they are hugely informative. From a PMS perspective, they are part of the same disorder.

Interstitial deletions matter because 1) they can be used to help calibrate IQ loss as a function of deletion size, 2) they can help identify which genes cause some of the manifestations of PMS not caused by SHANK3, and 3) effective treatments of PMS will depend upon how well we can treat all the important genes of 22q13.3.

arm22q13

Some previous blogs

MAPK8IP2 (IB2) may explain the major problems with walking and hand use
TCF20 may explain why some big deletions are worse than others
Current trends in SHANK3 research
Which PMS genes are most associated with Autism?
Does SHANK3 cause Autism?
We need to study interstitial deletions to cure PMS
What do we know about PMS genes?
Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
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?
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 translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
22q13 deletion syndrome – an introduction

Are children with Phelan McDermid syndrome insensitive to pain?

It is not always easy to read David’s expression.

 

The two largest studies of children with 22q13 deletion syndrome (PMS) report that a high tolerance for pain is a very common.  One study reports that 88% of individuals are insensitive to pain based upon medical record review (1) and the other report indicates 77% of individuals are insensitive based on parent reports (2).  Do you believe that?  I have always felt that David tolerates far more pain than most people, but I also had my doubts about how can we really know.  After reading the scientific literature, my doubts are only deeper.  This blog is a quick survey of the literature and what it tells us.  Numbers in parentheses “( )” refer to the scientific studies listed at the end of this blog.

Recently, a group of scientists investigated the pain sensitivity of mice with no Shank3 (complete knockout of both genes) (3). These mice did not have reduced sensitivity to sharp pain. They did have an unusual response to certain types of long-lasting pain. Normally, the skin is more sensitize after certain long lasting pain and mice lacking Shank3 don’t develop as much sensitivity. Like the brain pathways, the spinal cord seems to have deficits, but does this translate to low pain sensitivity in children?

As I reviewed the research literature for pain in children with intellectual disability (ID) and autism spectrum disorder (ASD), a red flag went up immediately.  There is strong evidence that medical practitioners and parents treat most people with ID as if they feel less pain.  This is  not just a problem with PMS.  Children with ID receive less pain medicine after surgery than other children, even though there is no evidence that the side-effects of the medicines are worse for children with ID (4). Parents report that non-communicating children experience painful episodes frequently, yet the parents rarely give these children pain medications (5).  That is not to say parents know less than medical practitioners.  Certain pain scales (which I will discuss in a moment) used in clinical settings are more accurate when parent input is included in the measurement (6). But, parents and medical practitioners seem to think nonverbal children are less pain sensitive. Are they, or do we misunderstand their reactions to pain?

Sensitivity to pain can be objectively studied in several different ways. Luginbuhl et al assessed which methods might provide the most reliable measure of pain (7).  They tested each method with different doses of an analgesic, alfentanil. The idea is, increasing doses of pain medicine should give increasing pain thresholds.  Pain measurements that show less pain with more drug are good ones. Measurements that do not show a consistent reduction of pain with higher doses of drug are poor measures.

The testing was done on normal volunteers: the painful stimulus is gradually increased until the subject either presses a button to stop the stimulator or pulls away from the painful stimulus. The controlled sources of pain were: electrical pain on the toe, pressure pain on the finger, heat pain on the forearm, ice-water pain by immersing the hand, and ischemic pain (tourniquet). In the end, the most reliable tests were electrical pain, pressure pain and ice water. These tests are good measures of pain, right?

Wrong. These tests rely on how quickly the subject reacts to the pain. We can easily misjudge the pain threshold of people with ID because they have slower reaction times. This problem was studied in a group of individuals with Downs syndrome and others with mild ID.  Defrin et al measured pain using two different approaches (8).  One relied on the speed of reacting (Method of limits), and the other did not rely on speed (Method of levels).  Most subjects in this study were verbal, but to make sure, the subjects also pointed to a happy face or sad face to indicate painful or not painful. The results of this study were clear.  The pain threshold of people with ID is very easy to misjudge because of their slower ability to respond.  Even more surprising from this study is that people with ID are more sensitive to pain than control subjects. So, not only were people with ID labeled as being less sensitive to pain, but they were actually more sensitive.

These studies were done with people who had some ability to report pain, but what about people who cannot report pain? The standard practice is to observe the person who is experiencing pain and make a judgement. Is this approach valid?

Symons lead a group wanting to see if trained observers can judge when a nonverbal person is having a sensory experience, and if the observers can identify pain when the experience is painful (9). They tried a simple experiment. Subjects were seated comfortably in a chair. A camera captured 15 seconds of video divided into 3 periods: before, during, and after a stimulus. The stimulus was either a pinprick, warm object, cold object, pressure, or light touch. We assume that at least the pinprick was painful, but we do not know for sure. The camera also recorded 15 second periods with no stimulus at all. The trained observers had to judge whether or not the person was reacting to a stimulus. Reactions were based on the Facial Action Coding System (FACS) and also based on a method by Defrin and colleagues that evaluates head posture (10). The experts were good at deciding which video clips occurred when a stimulus was given. They also found that the 5 second period of stimulus to the skin could be distinguished from the periods just before and just after the stimulus. There was, however, no ability to distinguish pin prick from the other stimuli. So, trained observers can see changes, but it is not clear from this study how well facial expression helps separate painful from non-painful experiences.

A very interesting outcome of this study was the discovery that individuals with self-injurious behavior (SIB) showed greater sensitivity to sensory input than other individuals with ID (9). This is the opposite of what most people expected, and the results have been replicated (11). This is a serious matter and we will return to it later.

Probably the best experimental way to establish a measure of pain in nonverbal subjects with ID is to make measurements when a known pain is present. Two types of known pain have been tested, post-surgical (12), which produces sustained pain, and during a flu shot (10) or blood draw (13), which produces momentary pain. These and similar studies have led to several different measures of pain for clinical settings (14). For example, the Non-Communicating Children’s Pain Checklist (NCCPC-R) and the adult version, the Non-Communicating Adult Pain Checklist (NCAPC) look at reactions to pain: vocalizations, behaviors, facial expressions, body language, flinching/protective actions and physiological reactions (red face, irregular breathing) (15, 16).  They seem to be quite good measures of pain in nonverbal individuals.

The NCCPC has been criticized because it takes 10 minutes to administer, which is too long for clinical settings (14).  The Pediatric Pain Profile (PPP) scale is somewhat faster to administer, but it is still demanding in some settings.  It also requires detailed information from parents/caregivers.  Input from parents/caregivers can be very valuable for improving the accuracy of a pain scale (17).  Unfortunately, even with caregiver input, health practitioners (and likely many others) rely too much on facial expressions when judging pain reaction (13).  Thus, the pain measurement tools are validated (and valuable!), but not simple to use.

In summary, there are objective measures of pain for nonverbal individuals, and young children with ASD or ID, although these measures require careful application to be reliable.  Even verbal individuals with ASD or ID are typically misjudged and often undermedicated.  Painful events are a frequent part of the lives of individuals with PMS.  The belief that children with PMS are less sensitive to pain than other children has not been examined experimentally and, if the story is similar studies of ASD and ID, that belief may be wrong.  If we allow pain to linger, increased pain is not only associated with self-injurious behaviors, but also aggression and stereotypy (11).  We must be very careful about how quickly we judge the potentially painful experiences of our children, and we must let the science help guide our thinking. The alternative may be to subject our children to a lifetime of unnecessary suffering.

 

arm22q13

 

Previous blogs

Looking for Opportunities

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

 

References

1. Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, et al. Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism. 2013;4(1):18.
2. Sarasua SM, Boccuto L, Sharp JL, Dwivedi A, Chen CF, Rollins JD, et al. Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome. Human genetics. 2014;133(7):847-59.
3. Han K, Holder JL, Jr., Schaaf CP, Lu H, Chen H, Kang H, et al. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature. 2013;503(7474):72-7.
4. Malviya S, Voepel-Lewis T, Tait AR, Merkel S, Lauer A, Munro H, et al. Pain management in children with and without cognitive impairment following spine fusion surgery. Paediatr Anaesth. 2001;11(4):453-8.
5. Stallard P, Williams L, Lenton S, Velleman R. Pain in cognitively impaired, non-communicating children. Arch Dis Child. 2001;85(6):460-2.
6. Hunt A, Goldman A, Seers K, Crichton N, Mastroyannopoulou K, Moffat V, et al. Clinical validation of the paediatric pain profile. Developmental medicine and child neurology. 2004;46(1):9-18.
7. Luginbuhl M, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Zbinden AM. Comparison of five experimental pain tests to measure analgesic effects of alfentanil. Anesthesiology. 2001;95(1):22-9.
8. Defrin R, Pick CG, Peretz C, Carmeli E. A quantitative somatosensory testing of pain threshold in individuals with mental retardation. Pain. 2004;108(1-2):58-66.
9. Symons FJ, Harper V, Shinde SK, Clary J, Bodfish JW. Evaluating a sham-controlled sensory-testing protocol for nonverbal adults with neurodevelopmental disorders: self-injury and gender effects. J Pain. 2010;11(8):773-81.
10. Defrin R, Lotan M, Pick CG. The evaluation of acute pain in individuals with cognitive impairment: a differential effect of the level of impairment. Pain. 2006;124(3):312-20.
11. Courtemanche AB, Black WR, Reese RM. The Relationship Between Pain, Self-Injury, and Other Problem Behaviors in Young Children With Autism and Other Developmental Disabilities. Am J Intellect Dev Disabil. 2016;121(3):194-203.
12. Breau LM, Finley GA, McGrath PJ, Camfield CS. Validation of the Non-communicating Children’s Pain Checklist-Postoperative Version. Anesthesiology. 2002;96(3):528-35.
13. Messmer RL, Nader R, Craig KD. Brief report: judging pain intensity in children with autism undergoing venepuncture: the influence of facial activity. J Autism Dev Disord. 2008;38(7):1391-4.
14. Crosta QR, Ward TM, Walker AJ, Peters LM. A review of pain measures for hospitalized children with cognitive impairment. J Spec Pediatr Nurs. 2014;19(2):109-18.
15. Lotan M, Ljunggren EA, Johnsen TB, Defrin R, Pick CG, Strand LI. A modified version of the non-communicating children pain checklist-revised, adapted to adults with intellectual and developmental disabilities: sensitivity to pain and internal consistency. J Pain. 2009;10(4):398-407.
16. Lotan M, Moe-Nilssen R, Ljunggren AE, Strand LI. Measurement properties of the Non-Communicating Adult Pain Checklist (NCAPC): a pain scale for adults with Intellectual and Developmental Disabilities, scored in a clinical setting. Res Dev Disabil. 2010;31(2):367-75.
17. Malviya S, Voepel-Lewis T, Burke C, Merkel S, Tait AR. The revised FLACC observational pain tool: improved reliability and validity for pain assessment in children with cognitive impairment. Paediatr Anaesth. 2006;16(3):258-65.

 

Splitting, Lumping and Clustering

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:

Similar 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

Defining Phelan McDermid syndrome

It is all a matter of how you look at the problem.

Originally posted 4 March 2017
Updated 10 April 2024

It is very hard to talk about and explore, much less cure, a syndrome if you don’t define it first. While 22q13 deletion syndrome seems like it should be straightforward — a deletion of 22q13 — life is rarely that simple. In 2012 I was offered a chance to bring people together to address the question of how to define Phelan McDermid syndrome (PMS). I took the role and opportunity seriously. I decided to make a slide presentation that would set the stage for parents, scientists and clinicians to discuss a definition for the syndrome. As it turned out, the offer was rescinded. Without any modification, I present the final slide from my talk (see figure).  There has been a more recent effort to establish a simple classification (see this blog). However, there remains poor agreement in the field and the catagories, thus far, contribute more to diagnostic criteria than a structure to understand the disorder.

The color coding is important. Things in green are PMS. Things in rust red are not PMS. Dashed lines are just to make it easier to see. The scheme covers nearly every circumstance, including pathology of regulatory sites. The only unaddressed issue is what might be considered phenotypic. It seems to me now that any intellectual disability that is not syndromic in some other way (e.g., metachromatic leukodystrophy caused by the deficiency of arylsulfatase A, OMIM #250100), should be considered the core phenotypic trait of PMS. Regardless, the slide represents the only detailed framework I have ever seen for a definition of PMS.

There is a great interest in SHANK3 and its relationship with 22q13 deletion syndrome. Using the scheme, above, and other information that we know about SHANK3 and 22q13 chromosomal deletions, I recently put together this chart:

In this case, the dashed line indicates that autism spectrum disorder may accompany intellectual disability and still be part of PMS. The chart shows that many SHANK3 mutations are not PMS. They are either nothing (have no phenotype) or some other neuropsychiatric disorder. When 22q13 deletions include SHANK3 (even just a part of SHANK3), they can be PMS. In fact, they are rarely not PMS. Some SHANK3 mutations (pathogenic variants) lead to the phenotypic traits of PMS. Mutations of SHANK3 that confer a different primary phenotype (e.g., schizophrenia or autism spectrum) should not be lumped into the PMS category.

There are other ways to define a disorder, but the worse thing we can do is not define it at all. Developing any classification system is tricky. It is always political. The politics impacts both the science and the families. Even after 12 years, the politics have not been resolved. Perhaps the answer is to have multiple definitions, and identify the definition being used when writing or speaking about the disorder. The definition of this disorder remains in disarray.

arm22q13

Previous blogs

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
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

How to fix SHANK3

David snacking on some cereal bar bits

Human – Mouse Partnership

Originally posted 16 June 2016
Updated 19 August 2022

Anyone who has read the majority of my blog pages knows that my goal is to help parents, scientists and other members of the Phelan-McDermid syndrome (PMS) community understand how the genetic landscape of chromosome 22 must shape our thinking if we are going to realistically pursue treatments. At least one company has proposed to tackle the challenging task of a genetic intervention. While very exciting, we also must be humble about the difficulty of making it work. This blog looks at the limitations of this approach.

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 most scientific references and simply recommend reviewing prior posts for supporting evidence.

---

There are a remarkable number of optimistic-sounding mouse model papers on the SHANK3 gene. The number of model mice has passed one dozen. People who work on SHANK3 mice often 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, PMS, or maybe even schizophrenia. Some researchers like to define PMS as a disturbance of SHANK3, which guarantees that any SHANK3 fix will fix PMS. This is not consistent with research that looks at the complete genetic landscape of PMS. Rodent research papers are often rather optimistic. Perhaps writing papers this way promotes optimism in the patient community. Optimistic papers help to keep financial donors excited. These are probably good things, but we need to recognize the limitations of the research.

From a practical standpoint, we need a strategy for fixing SHANK3 problems in humans that accurately reflect the science. 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 charity organizations.

One critical clinical concern is the relationship between SHANK3 deletions and SHANK3 sequence variants (sometimes referred to as SHANK3 mutations). Nearly all rodent studies are studies of SHANK3 mutations. The reason for so many rodent models is largely because different laboratories study different mutations. This is not such a bad idea because many of these mutations are designed to duplicate human SHANK3 gene variants. The mouse studies are virtually always described as studies of SHANK3 deletion. However, they are rarely complete removal of the SHANK3 gene (or removal of both SHANK3 genes). Among the many different SHANK3 mutations studied in mice, the behavioral, molecular, electrophysiological and drug effects differ widely. Importantly, a study that looked at total removal of SHANK3 protein from a mouse found less impact on the mouse behavior than many of the other SHANK3 mutation studies. The important message here: in rodents some mutations have a greater impact than complete SHANK3 deletion.

What about humans? Are SHANK3 variants different from SHANK3 deletion? That is, do people with SHANK3 variants have the same problem as people with 22q13 terminal deletions (complete deletion of SHANK3). In 2022 there was a paper that hints at the answer. After carefully looking at patients with small terminal deletions (under 0.25 Mb) and comparing them to patients with SHANK3 variants, they observed:

Although individuals with small deletions and SHANK3 variants showed similar findings in most of the categorical variables (Table 5), a remarkable difference was observed in “the ability to make sentences” between the two groups, with 30/65 (46.2%, Supplementary Table S3) of individuals with deletions below 0.25 Mb able to make sentences compared with 5/18 (27.7%, Table 1a) among those with SHANK3 variants.
Nevado et al 2022 Variability in Phelan-McDermid syndrome in a cohort of 210 individuals, Frontiers in Genetics

Significantly more people with complete deletions of SHANK3 were able to speak in sentences compared to people with SHANK3 variants. This and previous studies have shown that different human SHANK3 variants can produce very different impacts. Clearly, some of these variants interfere with the normal operation of SHANK3 in ways that are worse than just reducing the amount of available protein.

This effect is not difficult to explain. Some SHANK3 variants can produce improper SHANK3 proteins 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 may be better off omitting some hardware (or producing fewer products) than installing defective parts. The somewhat surprising conclusion is that we might want to to treat some SHANK3 variants by shutting down a defective SHANK3 gene.

If we are considering SHANK3 deletion as a treatment for SHANK3 mutation, then we better be prepared to treat SHANK3 deletion. Results from the first Shank3 complete knockout mouse provides a hint at how to treating human SHANK3 deletion. The most abiding and measurable 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 intellectual disability 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? I do not believe it can be done in mice, but it is difficult to find humans missing the entire SHANK3 gene, but little else (pure SHANK3 deletion). Given the rarity of pure SHANK3 deletion, I propose that scientists could do an in depth study of one or two human volunteers with very small deletions. This research could be modeled after behavioral research methods from studies of nonhuman primates. These are studies where behavior from just one or two animals is studied in great detail.

The studies with the PMS volunteers would combine behavioral testing and advanced computational modeling. The results of each new test leads to a modification of the model, and the results of each new model identifies new things to test. These state-of-the-art computationally-based scientific learning studies 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. Why not let the subject have fun?

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 could be used with simple tasks, but more demanding tasks may require nonhuman primates. These studies could include fMRI and electrophysiological investigations. 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, could 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 for our kids with PMS. Later, dare we hope, new pharmaceutical treatments could emerge.

We all hope that initial human trials of gene replacement therapy will provide a critical new treatment for our kids with PMS. Those trials may take many years to materialize. In the meantime, we need to better understand what we can expect from gene replacement, and the exact nature of learning deficits that arise from loss of SHANK3.

arm22q13

Previous blogs

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