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.

 

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Looking for opportunities

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

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

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

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

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

Matched deletions

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

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

Interstitial math

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

Pure SHANK3 deletions

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

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

Where next?

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

arm22q13

 

Previous blogs

Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction


Splitting, Lumping and Clustering

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

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

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

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

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

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

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

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

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

arm22q13

 

Previous blogs

Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Defining Phelan McDermid syndrome

david-and-dad-4-march-2017-small
It is all a matter of how you look at the problem.

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, 4.5 years later.  In my opinion, the discussion is overdue.

definition-of-22q13

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:

relationship-between-shank3-and-pms

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 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.

 

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
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

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

david-19-feb-2017-cropped2

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

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

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

SHANK3 mutations are complicated

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

Too few patients have the same SHANK3 mutation

To date, no one has been able to find enough people with the same SHANK3 mutation to do a drug study.  You can find SHANK3 mutations in large autism databases, but these are not like a registry where you can call the patient up and ask them to participate.  There is no doubt that medical researchers would pull together a SHANK3 drug study population, if they could.  Autism is thought to be a polygenic disorder (like schizophrenia). Thus, we expect that many individuals from autism databases will also have mutations of multiple autism-related genes, not just SHANK3.  Finding a large enough group of people with one (or two) SHANK3 mutations to study drugs will probably never happen.

Individuals with 22q13 deletions are too diverse

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

Solutions

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

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

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

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

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

arm22q13

 

Previous blogs

What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

What do parents want to know?

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

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

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

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

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

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

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

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

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

arm22q13

 

Previous blogs

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

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Is 22q13 deletion syndrome a mitochondrial disorder?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

arm22q13

Previous blogs

Educating children with 22q13 deletion syndrome
How to fix SHANK3

Have you ever met a child like mine?

How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction