Which PMS genes are most associated with Autism?

Figure 3
Genes disrupted in autism and schizophrenia.  Modified from Gandel et al. 2018 Science.  doi:10.1126/science.aad6469.

The previous blog looked at the relationship between SHANK3 and autism risk (Does SHANK3 cause autism?). Today’s blog looks at another new study.  This study is an analysis of which genes are dysregulated (“out of whack”) in major psychiatric disorders, including autism and schizophrenia (Gandel et al. 2018 Science. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap).  In the previous blog we learned that people generally have slightly different versions (variants) of each gene.  An unlucky person may have hundreds to thousands of gene variants that, added up, conspire to create a high risk of autism.  Thus, there are a lot of different combinations of genes that can lead to autism.

What the new study shows is, regardless how a person gets autism or schizophrenia, the same networks of genes become dysregulated.  Let’s first discuss what gene regulation means.  DNA is like a well-stocked bakery.  A good cook can prepare many different kinds of breads or desserts by choosing how much of each ingredient to use, and when.  Just about every cell in the body has the same DNA.  What makes one part of the body different from another is how much, and when, each gene is used. DNA cooking is called gene regulation.  In autism and schizophrenia, the proportions of ingredients have gone awry.

The green diagram at the top of this blog maps the results of the new study.  The researchers found certain critical “modules” (functional groups) of genes that are dysregulated in the brains of individuals with these two disorders.  Once, again, these genes are dysregulated regardless of how one acquires autism or schizophrenia.   The map identifies the 20 most dysregulated genes in each module (140 total) and how they interact in the brain.

What does this diagram tell us?  It says some things we already knew.  Autism (and schizophrenia) cause problems in neurons, the brain cells responsible for sensation, thinking and action.  Less obvious, autism seems to be related to two other cell types, astrocytes and microglia.  Astrocytes nourish neurons.  Microglia, which also come in contact with neurons, are known to regulate the formation and removal of synapses.  There are other important cell types, as well.

What is the news for PMS?  We learn that two PMS genes are core genes of the dysregulated neuron networks. I have circled these genes in RED.  There are about 20,000 genes in the human genome.  The paper identifies the top 140 dysregulated genes. Obviously, they are quite important for psychiatric disorders.  The two PMS genes are MAPK8IP2 and SULT4A1.  Not surprisingly, MAPK8IP2 and SULT4A1 have already been identified as two of the 18 most important genes of PMS (see Which PMS genes are most important?).

Which individuals with PMS are missing these genes?  Nearly all (over 95%) of people with PMS are missing MAPK8IP2.  About 30% of people with PMS are missing both MAPK8IP2 and SULT4A1.  If your child has a typical (terminal) deletion, you can look up which important PMS genes are missing in this blog:  Which PMS genes are most important?

At this point, it seems pretty likely that deletions of 22q13.3 do more than raise the risk of autism.  Deletions can directly impact MAPK8IP2 and SULT4A1, two core genes dysregulated in autism, schizophrenia and other neuropsychiatric disorders.  Perhaps the good news is that people who study autism and schizophrenia have a new impetus to study MAPK8IP2 and SULT4A1.  It is up to PMS parents to lobby, cajole and otherwise let everyone know that studying these genes is very important to us.

 

arm22q13

Previous blogs

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?
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 modelsScience 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

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Does SHANK3 cause Autism?

David 10 March 2018
David shows you don’t need to have autism to promote autism awareness.

Phelan McDermid syndrome (22q13 deletion syndrome or PMS) is often equated with autism spectrum disorder (ASD).  The exact definition of PMS is somewhat murky.  There are disagreements among families, scientists and clinicians.  The controversies have been around for at least 6 years and remain a sticking point for parents trying to get diagnoses and services for their child.  Equally messy, it seems, is the relationship between PMS and ASD.  Some studies find up to 70% of their PMS patient population has ASD; others find as low as 30%.  Many parents admit they have received a somewhat arbitrary ASD diagnosis from clinicians to help their child receive services. One scientific study that looked closely at the symptoms of PMS patients argued the behaviors are not really ASD.  Another study showed the ASD diagnosis is unreliable in children with both intellectual disabilities and movement problems.  Two studies suggested the number of cases with ASD depends on the sizes of the chromosomal deletion in the population.  No wonder there is so much confusion regarding the incidence of ASD among PMS patients.

There is a misconception among many parents that a case of PMS that involves the SHANK3 gene must lead to ASD, since “SHANK3 is an autism gene”.  For the record, there are no “autism genes”, only autism-associated genes.   The SFARI organization tracks genes that are associated with ASD in their SFARI Gene database.  There are currently 990 autism-associated genes.  SHANK3 is one of the 990 autism associated genes.  What does that mean?

There are two types of autism-associated genes.  Let me explain them by example.  Let’s say you have a large boat filled with lots of people on choppy seas.  The waves in the water can make the boat rock back and forth, but they pose no risk to capsizing the boat.  A single person walking from one side of the boat to the other side has no visible impact on the boat in the water.  Yet, send too many people to one side of the boat, then even a modest wave might capsize the boat and send everyone into the water.

Most genes of the human genome come in slightly different flavors. Each flavor is a “variant”.  The SFARI database tracks those variants that can contribute to autism. Like the people on the boat, each variant contributes only a tiny bit on its own.  But, if you have too many variants on the autism side of the boat, you have a major risk of developing ASD.  To be clear, everyone has these variants in their genome.  Only some people have enough to be at risk for autism.

What about PMS?  PMS occurs primarily by a deletion on chromosome 22.  That deletion often includes SHANK3, MAPK8IP2, BRD1, CELSR1, and SULT4A1, each associated with neurodevelopmental disorders.  SHANK3 deletion is the most common simply because it sits near the end of the chromosome. MAPK8IP2 is almost as common because it is adjacent to SHANK3. In 90% of PMS cases they get knocked off the chromosome together.  Most, if not all, of these genes cause intellectual disability when a copy is missing (haploinsufficiency). When the deletion or disruption does not exist in the parents, but does exist in the person with the disorder, it is called a “deleterious de novo” event.  In this context, deleterious means damaging and de novo means new, since the parents are not missing the gene.   The deleterious de novo event might be a chromosome deletion (22q13 deletion) or a gene mutation.

I began by explaining there are two types of autism-associated genes.  There are common variants that, together, can add up to a huge risk of ASD, like too many passengers on one side of the boat.  The other type of gene, those that arise from a deleterious de novo event, are like the large ocean waves.  In and of itself, a large wave is not going to capsize the ship (cause ASD).  But, the combined risk of too many common variants on one side of the ship, plus a deleterious de novo event, can send a child tumbling into ASD.  This is why most people with ASD do not have a syndrome like PMS.  They have many common autism-associated variants that have combined with developmental and environmental factors to produce autism.  The combined impact of common variants and de novo events also explains why many children with PMS have autism or ASD-like behaviors.  Perhaps they don’t have a huge overload of common variants, but they have enough when combined with the loss of PMS genes.  It is also why many children with PMS are quite social, with no evidence of autism.

 

arm22q13

Previous blogs

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?
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 modelsScience 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

We need to study interstitial deletions to cure PMS

David Jan 2018
David has a terminal deletion, but he will benefit from studies of interstitial deletions.

Two very recent studies of Phelan McDermid syndrome (PMS) drew exactly the same conclusion: We need to recruit and study more PMS patients with interstitial deletions if we are going to understand the syndrome (see references 1 and 2, below).  This blog explains why that is a critical need.  In some ways, this blog is an update to an earlier blog (Why don’t we have better drugs for 22q13 deletion syndrome?).

PMS can be broken down into a few obvious classes.  The original disorder, 22q13.3 deletion syndrome, has terminal deletions and interstitial deletions.  Later, SHANK3 variants (often called “mutations”) were added.  As I have discussed before (Gene deletion versus mutation: sometimes missing a gene is better), mutations are a mixed bag. Some mutations produce symptoms like 22q13.3 deletion syndrome, but other mutations produce other disorders (like ASD or Aspergers), or no disorder at all.

The overwhelming majority of 22q13.3 deletion syndrome / PMS cases are terminal deletions.  The smallest terminal deletions include the genes SHANK3, ARSA and RABL2B.  Of these, SHANK3 was identified as the most important gene for small deletions.  SHANK3 is not the only important gene (see Which PMS genes are most important?).  Early on, researchers were aware that interstitial deletions have the features of PMS (Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development).  Like other deletion syndromes (e.g., 16p11.2 deletion syndrome ), no one gene deletion explains all the cases of PMS.

PMS research started out with SHANK3, but somehow it got stuck there.  Being stuck has led to some serious deficiencies in our understanding of PMS.  First, very little is being done for the future of children with interstitial deletions.  Their SHANK3 gene is intact, so SHANK3 research does them no good.  Second, drug studies that use PMS patients to study SHANK3 are likely to fail without accounting for the important genes in each PMS patient.  This was discussed in the recent paper on PMS genes (reference 2). PMS patients have such a mix of deleted genes that the benefits of a drug for SHANK3 loss might not be detectable.  Third, certain serious problems seen in PMS are unlikely a result of SHANK3.  These issues, like poor thermoregulation (body temperature control), lymphedema, cerebellar malformation, mitochondrial problems, and certain developmental problems, impact a large proportion of children with PMS.  Every year children and adults with PMS die. We need to know which genes are associated with lethality. These issues will remain serious problems for people with PMS as long as SHANK3 remains the narrow focus of PMS research.  Even our understanding of SHANK3, itself, is incomplete without a much better understanding of the other important genes of PMS.  

The best way to understand the many genes of PMS is to study people with interstitial deletions.  They are the only PMS patients where we can safely say that SHANK3 deletion does not play a role. My last two blogs show that we actually know a lot about PMS genes that are most likely to cause problems.  However, we need to know much more about how each of these genes affect people.  That requires people with different size interstitial deletions.

There was one research study of people with interstitial deletions published in 2014 (Disciglio et al.).  It covered 12 patients.  Since that paper, there has been only one additional (single) case study  of an interstitial deletion.  By comparison, PubMed shows 164 papers with SHANK3 in the title.  Most PMS families are probably not aware that the current major studies of PMS specifically exclude interstitial patientsNatural History of Phelan McDermid Syndrome and the Electrophysiological Biomarkers of Phelan-McDermid Syndrome.  Some of the sites in these multisite studies have not excluded participants with interstitial deletions, recognizing the scientific importance of these cases.  Scientifically, excluding interstitial deletion patients makes no sense.  We should be seeking them out, recruiting them.  As a parent, excluding interstitial deletions seems unfair to both those families, and to the rest of us.  We need to get unstuck. We need the best science possible to help our children.

 

arm22q13

References

  1. A framework to identify contributing genes in patients with Phelan-McDermid syndrome. NPJ Genom Med 2017
  2. Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome. Eur J Hum Gen 2018

 

Previous blogs

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?
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 modelsScience 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 we know about PMS genes?

16 Dec 2017 1 - small
Our children trust us to do the best for them

Recap

In the previous blog we learned which Phelan McDermid syndrome (PMS) genes are most important. SHANK3 has often been touted as the gene that causes PMS, but SHANK3 rarely operates on its own and in some people has nothing to do with PMS (those with interstitial deletions). We learned that large studies of human populations identify 18 PMS genes that are impacted by “natural selection”. Loss of these genes are highly likely to cause problems, the problems that add up to PMS. The genes are:

SHANK3, MAPK8IP2, PLXNB2, TRABD, PIM3, ZBED4, BRD1, TBC1D22A, GRAMD4,
CELSR1, SMC1B, PHF21B, PRR5, SULT4A1, SCUBE1, TCF20, SREBF2, and XRCC6.

The big question is, what do we know about these genes? That is, how might they be contributing to PMS? This blog is based on a paper that not only identified these genes, but also pulled together what is currently known about each. Although the paper describes each gene’s function in detail (for well-characterized genes), it also classifies genes into groups. Those groups are quite informative and help us understand why PMS has certain characteristics.

Genes that impact brain development

It is now very clear why PMS can occur with or without SHANK3. Of the 18 PMS genes that are likely to have a high impact on PMS, at least 7 impact brain development: SHANK3, MAPK8IP2, PLXNB2, BRD1, CELSR1, SULT4A1, TCF20.

MAPK8IP2 sits almost adjacent to SHANK3 and we have known for years that loss of MAPK8IP2 in mice interferes with brain function. PLXNB2 regulates the growth of neurons, especially early in development. PMS is a neurodevelopmental disorder, so nothing could be more important than regulating neuron growth.

CELSR1 is also crucial for neurodevelopment. Neurons are exquisitely organized into nuclei in the deep structures of the brain and into very precise layering in the cortex. For example, pyramidal neurons of the cortex are located only in certain layers of the cortex, with the dendrites reaching upwards and the axon pointing down, often winding its way towards the white matter. CELSR1 is important for orchestrating the orientation of individual neurons.

BRD1 regulates hundreds of other genes during development. It is highly associated with schizophrenia, as well as PMS.

Genes associated with sleep

There are three genes that have close association with sleep or sleep disturbance. SHANK3 impacts sleep in some individuals with PMS, but PIM3 and PRR5 have been identified in studies that explore which genes regulate circadian rhythms (so called, “clock” genes).

Gene associated with lymphedema

CELSR1, the gene important for proper orientation of cells during neurodevelopment, is also associated with inherited lymphedema. Presumably CELSR1 influences cell orientation and the structure in the lymph system during development.

Genes that have unknown function

We must recognize that just because a gene has never been closely studied, that does not mean it is unimportant. In fact, one genomic study has provided a convincing argument that genes of unknown function are as important as the well-characterized genes. PMS has 7 genes likely to be important, yet not well-studied: TRABD, ZBED4, SMC1B, PHF21B, SCUBE1, SREBF2, and XRCC6. The first two genes, TRABD and ZBED4, are of very special concern. One copy of each gene is missing in over 95% of individuals with terminal deletions. It is imperative we find out what these genes are doing and why their loss might be highly impactful in PMS.

Concusion

This new study of PMS genes has breathed new life into PMS research. It has provided a short list of culprits. It explains why interstitial deletions cause PMS and it identifies where our research efforts need to be focused. Most importantly, we have new targets for therapeutics. New targets mean new hope.

Unfortunately, a lot of time has gone by without any serious effort to encourage research into the full array of PMS genes. We have not taken any advantage of 17 opportunities to make PMS children better. As a parent of a child with PMS, I strongly feel there should be greater respect for parents’ hopes. These hopes deserves every effort to search for treatment options.

arm22q13

Previous blogs

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?
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 modelsScience 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

Which PMS genes are most important?

David sitting up Dec 2017 - small
David hanging out on a Saturday morning

What makes a gene important?

Ask anyone who has read about 22q13.3 deletion syndrome (Phelan McDermid Syndrome) which genes are most important and they will start with SHANK3, even though some people who have 22q13.3 deletion syndrome are not missing SHANK3. SHANK3 is most important for two reasons. First, mutations or deletions of SHANK3 can (although not always) have a strong negative impact on individuals. Second, a large percentage of the PMS population are missing SHANK3. Thus, SHANK3 meets the criteria of 1) potentially large impact on an individual and 2) a large percentage of the population is missing SHANK3. This blog is a closer look at all the genes that meet these criteria.

In a recent study, a group of researchers looked at genes that are highly likely to contribute to PMS and are missing in most people with PMS (Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome [full disclosure: this blog was written by an author on the paper]). That is, genes that appear to meet the same two criteria as SHANK3 for importance. What makes this study important is that it does not differentiate between genes that have been carefully studied and genes that have never been studied. We parents are not interested in gene popularity contests, we are interested in learning what is making our children sick.

I read that SHANK3 was the only important gene

Up until now, nearly all PMS research has been focused on one well-known gene, SHANK3. But, for the overwhelming majority of PMS sufferers, some 97% (see Understanding deletion size and How do I know which genes are missing), PMS is a polygenetic disorder. That is, many genes are involved. Is it possible, as a few SHANK3 scientists have suggested, that only the SHANK3 matters? Considering that people can have all the problems of PMS even with intact SHANK3 (called “interstitial deletions”), it does not seem possible that SHANK3 is the only gene that matters. (For the minority of parents whose child only has a SHANK3 variant or loss, SHANK3 is the only important PMS gene, but that strikes me as a rather selfish viewpoint.)

How can we find out which genes are most important?

There are 108 PMS genes and only 44 have been well studied. If there was no way to identify the important genes, we would be in serious trouble. Fortunately, the recent study of PMS genes was possible because of a recently compiled database of over 60,000 genomes of normal individuals (Exome Aggregation Consortium). Normal in this case means no developmental or neurological disorder. Why normal individuals? Because, this huge database lets you predict which genes can cause trouble.

Here is the trick to finding a likely gene troublemaker. Pick a gene. Look at 120,000 copies of that gene. (Each human has 2 copies, so 60,000 people = 120,000 copies of the gene.) Like anything else, some will be a little different than the others. In fact, you can estimate how many variants you would expect to occur by chance in a population of 60,000 normal people. So, for a given size gene, maybe you would expect 40 different variants of that gene in the population. What if you find only 5 variants? Something’s fishy if you find only 5. The best explanation is — here is the trick — that the other 35 possible variants of that gene cause serious problems. For one reason or another, those 35 variants removed the owners of that gene from the population of “normal individuals”. Those missing 35 variants are pathological. They cause a loss-of-function. The gene is called loss-of-function (LoF) intolerant, and those genes that are very LoF intolerant are the ones most likely to cause major health problems.

Wow! Which genes are most important?

So, which PMS genes are very LoF intolerant? That is an easy question to answer. You can go to the EaAC web site and look up any gene. Look for the row with LoF and get the “pLI” value. A value between 0.9 and 1.0 is a bad news gene. SHANK3 is 1.0 — no surprise there, but what about other genes? Let me save you some time. Below is a list of PMS genes that have a pLI value above 0.9.

Genes in this list are in the order of their position on the chromosome. The ones at the top of the list are more frequently lost in the population. If your child has a terminal deletion, look at all the genes with a Kb value smaller than your child’s deletion size. Those are the genes that most likely contribute to his/her disorder.

   Gene       Minimum deletion size (Kb) 
   SHANK3          85 
   MAPK8IP2       207 
   PLXNB2         540 
   TRABD          619 
   PIM3           854 
   ZBED4          928 
   BRD1           995 
   TBC1D22A     3,643 
   GRAMD4       4,181 
   CELSR1       4,281 
   SMC1B        5,405 
   PHF21B       5,809 
   PRR5         6,081 
   SULT4A1      6,956 
   SCUBE1       7,475 
   TCF20        8,603 
   SREBF2       8,911 
   XRCC6        9,154 

The first thing to notice is that what started out as 108 genes is now reduced to 18 genes. There are a few other genes with pLI below 0.9, but not far below 0.9. These may also be important. Regardless, the number of PMS genes has gone from intractable to something much more manageable. If your child has an average size deletion (around 4,500 kb), then there are 10 relevant genes. Note that some, although relatively few, children are missing only SHANK3.

In my next blog I will discuss what these genes do and how they might impact your child.

arm22q13

Previous blogs

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?
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 modelsScience 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

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.

 

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