David relaxing in the car during a drive through the countryside
Originally posted 10 April 2024
In 2022 a group of scientists associated with the Phelan McDermid Syndrome Foundation (PMSF) published a consensus paper that addressed a controversy around what constitutes Phelan McDermid syndrome (PMS). It was an important step toward defining the disorder, providing guidance to geneticists, and working towards an ICD code for diagnosis and medical reimbursement. Although the consensus opinion was not universal, the clarification was welcome. These experts split PMS into two mutually exclusive classes: “PMS-SHANK3 related” and “PMS-SHANK3 unrelated”. It is a simple, clear dichotomy. But genetics are rarely simple, as we shall see.
The thinking at the time was from the perspective of genetic testing. If the test result includes an abnormality of the SHANK3 “coding region”, then it gets the designation PMS-SHANK3 related. All other test results would be PMS-SHANK3 unrelated.
The people who hammered out this definition (distinction) are all experts. They were fully aware of all the possible ways genes can contribute to a disorder. There are dissenters, also experts, who feel that if SHANK3 is not involved, then the name PMS should not be applied. The consensus paper explains that people with interstitial deletions (PMS-SHANK3 unrelated) do not appear to have a syndrome different from PMS. There is also no transition from PMS to some other syndrome as deletion sizes get larger, whether or not SHANK3 is involved. There is no clear evidence that PMS-SHANK3 unrelated is some other type of disorder. The key concern for dissenters is that genes other than SHANK3 do not contribute to the disorder in the same way that SHANK3 causes PMS.
However, what if we can show that other genes on chromosome 22 contribute to PMS through their impact on SHANK3, or their impact on the molecules that interact with SHANK3? If the genes of 22q13.3 (the site of interstitial deletions) have such direct impact on SHANK3, then perhaps the term “PMS-SHANK3 unrelated” is misleading. If the biology of PMS-SHANK3 unrelated is highly related to SHANK3, then a distinction may not be warranted. The latest evidence suggests there are at least six genes that impact SHANK3 (and partner molecules), and these genes contribute to PMS when deleted. I would call these genes SHANK3 related.
The six genes and the details of how they interact with SHANK3 are discussed in a recent paper. The paper is open source (anyone can read it), but very technical. Full disclosure: I helped write the paper, so this blog post is undeniably biased. People who have read my previous blog posts should know that I have long been a proponent of looking closely at the many genes of PMS. The paper is a review of work done by scientists primarily between 2017 and 2024. Science is a continuous process and during this period enough information came to light to explain the tight relationships between six genes (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, TCF20) and SHANK3. The first two genes are physically close to SHANK3 on chromosome 22, and thus are deleted in most deletions that include SHANK3. The remaining four genes are fairly evenly spaced across the last 4 Mb (megabases) of the PMS region of chromosome 22.
All seven genes (including SHANK3) impact brain development and all are involved with the process of inflammation. In this case inflammation includes “cellular stress”, “mitochondrial function”, and “recovery from injury”. These are all related processes, and all known to exacerbate PMS. So, impact on early development and response to stress and injury are features common to all of the genes.
Three of the genes (BRD1, PHF21B and TCF20) regulate what other genes do in the brain. For example, all three regulate the activity at synapses, the part of neurons that SHANK3 regulates. In addition, two more genes (PLXNB2 and SULT4A1) are directly involved in synaptic function. In fact, SULT4A1 not only regulates the same glutamate receptor as SHANK3, but it also regulates breakdown of SHANK3 at the synapse.
At this point it should be clear why PMS-SHANK3 unrelated may not really be unrelated to SHANK3. The six genes listed above join SHANK3 in shaping the development of the brain, the response of the brain to insults, and the operation of the synapses – the most important role of SHANK3 in the brain. It should also be clear why people with interstitial deletions typically have symptoms consistent with other cases of PMS. Likewise, it should also be clear why people with larger and larger deletions tend to have more severe PMS (see: Why PMS is worse for people with larger deletions).
The very close association between SHANK3 and at least six other PMS genes has a number of ramifications. First, while the distinction between SHANK3-related and -unrelated is sensible from the point of view of genetic testing, it may not be a good way to think about PMS as a disorder. Second, treatments that target SHANK3 will likely miss other relevant genes that tightly influence SHANK3, and thus may not produce very satisfying results in patients with chromosomal deletions. One way to think of the problem is that SHANK3 treatment in people with deletions essentially expands the number of PMS patients with interstitial deletions. It may be difficult to distinguish between a treatment that is not effective for SHANK3, and a treatment that is not effective because of other genes. Finally, when we are searching for an effective treatment for SHANK3 haploinsufficiency, maybe we should also look at treatments for one or more of the other genes. We may be missing out on developing additional valuable treatments.
David enjoys walking, but his balance and coordination are not good. He has taken many falls in his lifetime. Sometimes he hits his head. He has had numerous stitches over his eye, on his forehead and has injured his nose more than once. I have always worried that these falls might have a cumulative effect on his brain.
In 2019, just before COVID-19 started to spread, a group of researchers in Shandong, China asked the question: what does the gene CELSR1 do? CELSR1 is on my list of high importance genes of PMS (see Which PMS genes are most important?) One copy of CELSR1 is missing in about half of all people with Phelan-McDermid syndrome who have a terminal deletion of chromosome 22. Only a few months ago I wrote about the relationship between CELSR1 and lymphedema (see Have we found the gene that causes Lymphedema?), based on research done elsewhere in China. As I describe in that blog, research on CELSR1 has become truly international.
It has been known for years that the CELSR1 gene is especially active (producing the celsr1 protein) following a brain injury. The celsr1 protein is associated with the creation of new neurons and enhancing the blood flow in the brain. Until now, it was not clear if the increase in celsr1 protein following injury protects the brain. Now we know a lot more. I will describe the research (see the scientific paper here).
The researchers used a very modern technique. They used a “short hairpin RNA” (shRNA) to reduce protein production by the CELSR1 gene in rodents. This method cut the level of the celsr1 protein production by 50%. Humans missing one copy of the CELSR1 gene should also have about a 50% loss in protein production. In other words, this is an animal model of PMS!
Using a standardized procedure to invoke a brain bleed in rats, the researchers looked to see if rats lacking half of the normal celsr1 sustained more brain damage than expected. Both the amount of brain damage and the ability to walk were significantly affected by the reduced celsr1. The researchers then refined their methods to analyze exactly how celsr1 was protecting the brain. Celsr1 is an amazing protein. It protects injured neurons from dying, it speeds up the production of new neurons and it promotes the formation of new blood vessels to provide oxygen to the injured region. The researchers were also able to pinpoint what part of the brain jumps into action when the celsr1 is needed.
For years, scientists have been looking for natural substances that might protect the brain after a bleed. These “neuroprotective” substances have been studied and they include familiar chemicals, like IGF-1. Thus far, none of the known chemicals or their derivatives have provided useful treatments for brain injury, intellectual disability or autism. The question becomes, is celsr1 nature’s way of protecting the brain? Perhaps we should be focused on restoring the normal level in people missing the CELSR1 gene?
We know that, in general, people with PMS who have larger than average deletions (average size is about 4.5 Mb) have more deficits/problems than people with smaller deletions. This has been shown repeatedly. What we do not know is whether people with deletions greater that 4.5 Mb accumulate brain damage over time. The brain bleeds (strokes) in the rat study are severe enough that a few of the animals die from the bleed. But, are smaller events — perhaps events that David experienced — causing serious long term problems because of the missing CELSR1? If these problems accumulate, perhaps the deletion size will be more important in older people with PMS.
This new information about CELSR1 reminds us that with each important gene comes an opportunity to help people with PMS. Some of the important genes remain poorly characterized. As we are seeing with CELSR1, the more we study these less-well-known genes, the more opportunities we have to develop new treatments.
Originally posted 4 July 2021. Updated 28 May 2023.
David loves to walk. He has a strange cycle of activity and there are periods where he just cannot sit still. So, he walks and walks to burn off the need to have activity. Getting him to walk was a major undertaking. It took 6 years of hard work with the physical therapist and his family at home until walking emerged. His gait is clunky. He walks as if he has weights in his shoes. But, he walks and walks when he needs to. Walking is so important for David in so many ways.
David might not be able to walk if he had serious lymphedema. David has peers with 22q13.3 deletion syndrome (Phelan-McDermid syndrome, PMS) who suffer from lymphedema. Lymphedema is seen much more often in cases of large terminal deletions. Undoubtedly, there is a gene somewhere in the list of PMS genes that causes lymphedema (see How do I know which genes are missing?). A group of medical researchers in China who study lymphatic surgery and pediatrics teamed up to treat a 20-year-old woman with lymphedema due to PMS. After careful examination of the woman, her genetics and the pathological mechanisms that can lead to lymphedema, the research group has come up with a very plausible explanation. Subsequent work has verified the gene involved.
The key to this investigation is that the young woman suffers not only from lymphedema, but also from protein-losing enteropathy (PLE). PLE is a condition where the body has an insufficient amount of protein. PLE is related to lymphedema when problems with the lymph vessels supplying the lining of the intestine cause poor absorption of nutrients. When improperly formed intestinal lymph vessels or blockage of lymph flow from the intestines (called lymphangiectasia) occurs, you can have insufficient protein absorption. In 2013 it was shown that loss of the gene celsr1 in mice leads to improperly patterned lymph vessels and lymph valves. In 2016 it was shown that an error in the CELSR1 gene in several generations of a family caused inherited lymphedema in their legs (Gonzalez-Garay et al 2016). Through this understanding, Xia and colleagues have provided a strong case for human CELSR1 as the causal gene for lymphedema in PMS (Xia et al 2021 Lymphedema complicated by protein-losing enteropathy with a 22q13.3 deletion and the potential role of CELSR1).
The researchers were not able to specifically demonstrate GI lymph flow was disrupted in their clinical case, partly because the young woman was not a candidate for lymphography and there was no clinical justification for sampling with endoscopy. Still, the lymphedema was quite clear in this patient and likely the cause of PLE. More importantly, the patterning gene CELSR1 can explain both lymphedema and PLE.
So far as seen the in literature, PLE seems to be very uncommon in PMS. Maybe it showed up in this case because of a diet less protein-rich than in many Western countries. Would we have discovered this sooner if we had more low-income or otherwise disadvantaged people in our community? Diversity and inclusion is not just an ethical concern. It is at the heart of scientific understanding.
A new study was published in May 2023 confirming CELSR1 as the central gene for lymphedema (https://pubmed.ncbi.nlm.nih.gov/37232218/). In this study, the authors reviewed 404 cases from the PMS Foundation Data Hub and showed that the likelihood of lymphedema is greatest when CELSR1 is missing.
Perhaps it is time to look more closely at protein absorption in people with PMS. Are there subclinical cases of malabsorption? Since CELSR1 is the central gene for lymphedema, people with PMS terminal deletions of sizes greater than 4.3 Mb are at risk for lymphedema and (perhaps) PLE. In both cases, the penetrance is incomplete: the deletion of one copy of CELSR1 makes someone more prone to these problems. We should not dismiss the importance of this work even if the problems are not expressed in every case.
I see an additional take home message from this research. It is clear that helping people with PMS requires understanding and considering all the genes lost when a deletion occurs. This requires input from many different medical and research fields. As parents of children with PMS, it is our job to encourage and reward novel and valuable contributions. In science, one way to acknowledge the contribution of a fellow scientist is to cite his/her work. This blog serves as a thank-you to Song Xia, Wenbin Shen and colleagues. This blog is not the first time I have acknowledged the work of Gonzalez-Garay et al in the Sevick-Muraca laboratory. The mouse work on the Celsr1 protein was done in the Makinen laboratory in the UK and the mouse model was developed by Fadel Tissir in Belgium. Fadel Tissir has studied Celsr1 over many years. All of these people deserve recognition for their contributions. I have personally emailed Dr. Tissir to thank him for his contributions to PMS. Letters of encouragement are a powerful and largely untapped tool we parents have to accelerate the discovery of new treatments for our children. I think we miss an opportunity each time a relevant paper gets published without thank-you notes from our community.
Originally posted 30 December 2019
Updated 4 March 2022
Regression is one of the scariest words among the Phelan McDermid syndrome (PMS) community. It is not clear how common regression is in PMS. Recent and ongoing studies are addressing the problem. Regardless, regression does occur, can be unpredictable, and it can sometimes be devastating. After years of hard work helping your child navigate a world that is well beyond his or her comprehension, you then lose some or all of the gains to an invisible and unforgiving demon. In the PMS world, you either loath regression or fear its occurrence.
Three papers recently looked at regression in PMS, each taking a somewhat different approach. Reierson et al 2017 used scores from the Autism Diagnostic Interview-Revised (ADI-R) based on 50 patients seen in their clinical study. Verhoeven et al 2019 studied 24 adult PMS patients with psychiatric presentations and followed them over years. Kolevzon et al 2019 did a detailed literature review of PMS and SHANK3 mutations (denovo deleterious variants). This blog will be mostly a technical overview of the Kolevzon paper, with some additional notes from the Verhoeven study, both aimed at patients over 12 years of age and who present with psychiatric issues or sudden loss of function.
All of the authors have struggled to define “regression” and identify trends in occurrence and treatment methods. I am told there are important differences between “regression” and psychiatric decompensation. I’m not a psychiatrist so I won’t untangle the technical differences. But from what I read, either type of event can be a setback. Psychiatric decompensation seems to bring with it the likelihood of recovery and can repeat (episodes).
If you don’t want to read my full post, here some of the take-home messages.
1) There is yet no clear measure of how often regression or psychological decompensation occurs with PMS.
2) Relying on previous papers is difficult because not all descriptions in the literature provide sufficient detail about each patient.
3) Diagnosis of psychiatric illness is more difficult in people with low intellectual function and absent of functional language.
4) People with SHANK3 variants (“mutations”) and tiny chromosome deletions are a small minority of identified PMS cases. In general, they are more functional than others with PMS (higher intellectual function, better language and better motor skills). This minority are the patients who most often present with psychiatric problems. The great majority of patients with deletions greater than one or two Mb (more common PMS patients), show psychiatric problems far less often, at least given the limited research done so far.
5) When looking at the psychopathology overlap between SHANK3 variants and typical PMS patients, the common feature seems to be bipolar disorder.
6) In spite of the difficulties studying psychiatric problems in PMS, following best practices of psychiatric care used in the general population can be helpful for people with PMS.
7) Over-medication and certain medication choices can harm, rather than help.
8) Proper personal and social care of the adult with PMS is important for the successful management of regression and psychiatric problems.
9) These early studies provide a first, and perhaps hopeful picture, but much more work needs to be done to understand the natural history of PMS and the risks we face as parents.
Kolevzon and his co-authors specifically excluded individuals with interstitial deletions (called PMS-SHANK3 unrelated, explained here). That is, they chose to only study the category of PMS called PMS-SHANK3 related. The Kolevzon paper could have included interstitial deletions to look more closely at the causes of PMS regression. It is an unfortunate omission that I have warned against in the past (see: PMS, IQ and why interstitial deletions matter and We need to study interstitial deletions to cure PMS).
Most of the important information from the Kolevzon paper is in their Table 1, which is the result of an in-depth search for papers on PMS patients. Table 1 provides an excellent resource to the PMS research community despite ignoring interstitial deletions. I spent a few hours hunting down the original articles listed on the table and studying them. PMS science benefits greatly from this work. The table itself has a flaw that readers should be aware of. The reference numbers of the table are messed up. The following reference numbers are wrong (4-6, 8-12, 15-19, 22-25, 30, 32, 35-42). The author names and dates are correct, so there is no problem if you simply ignore the reference number and do a text search for the author name.
As noted above, it is difficult to define regression and the authors did not clearly describe the difference between regression and psychological decompensation. Presumably, experts in the field recognize the distinction. Regardless, the Kolevzon study required some rule set to execute a literature review. These authors chose: “Sudden change in the psychopathological presentation”. They focused on patients older than 12 years. The literature search looked for: 1) psychiatric decompensation, 2) loss of skill, 3) sudden behavioral change.
They found 56 cases, including 15 cases of ring chromosome, referred to as r(22). While it is laudable to dig deep into older medical literature and pull out r(22) cases, most of these predate the time when deletion size was easy to measure. There is another problem with evaluating r(22). Just as interstitial deletions can cause PMS without disrupting SHANK3, r(22) can cause developmental delays without disrupting SHANK3. In fact r(22) can cause developmental delays without disrupting any gene (see: Guilherme et al 2014). Also, as the Kolevzon paper points out, r(22) can lead to Neurofibromatosis 2 (NF2) disorder, which can be degenerative. The authors are careful to identify which results are dominated by r(22) cases. I think only the most recent cases (cases 19, 35 and 51) are helpful to the study. The earlier cases date from 1985 to 2007. One other case, 32, does not seem to provide much information.
By removing cases of PMS deletions that lack deletion size information, we can explore the impact of deletion size. What we discover is that psychopathology is almost exclusively diagnosed in patients with small deletions. The plot below uses the Kolevzon data from Table 1. It shows the frequency of diagnosis (number of cases) as a function of deletion size. SHANK3 variants are not included.
Psychiatric problems show up mostly with small deletions, which are uncommon.
To understand these results, remember that 95% of people identified with PMS have deletions greater than 1 Mb (see: Understanding deletion size). The cases found by Kolevzon are heavily weighted towards small and very small deletion. That is, most cases of psychopathology in the literature come from deletions that represent about only 5% of the PMS population.
If we merge the data from SHANK3 variants with the smallest deletions (size 0 to .9 Mb), the first bar more than doubles in size. We can conclude that psychopathology shows up almost exclusively when chromosome 22 is disrupted near the terminal end. That is, it shows up in the atypical cases where damage is limited to primarily SHANK3 disruption. Is this generally true for PMS or just for the sample of papers found during the literature search? We don’t know. For the moment, it is the best data available.
The authors suggest that because people with SHANK3 variants and tiny deletions are higher functioning, psychopathological changes might be easier to observe. Indeed, in their sample the cases of SHANK3 mutation and small deletions had both significantly higher intellectual function and motor skills. I suggest another possibility. It may be that loss of genes in the 2 – 4 Mb region of the chromosome help stabilize brain function. The most likely candidates in this region of the chromosome are BRD1, TBC1D22A, GRAMD4, CELSR1. I have discussed some of these genes in detail, in my other blogs (see 22q13: a hotbed for autism and intellectual disability genes?, and CELSR1: Do some people with PMS have more fragile brains?) Whether these genes seriously impact brain function, stabilize the brain, or both, there is no doubt that these genes greatly influence the outcomes of patients with PMS. The importance of these genes have come up in other studies, as well. These genes likely also contribute to the impact of PMS from interstitial deletions (see: Which PMS genes are most important?).
These initial results are concerning to families dealing with very small deletions or SHANK3 variants (limited primarily to SHANK3 disruptions). On the other hand, most of the Kolevzon study has less relevance to 95% of families. Still, there are 8 of the 56 patients that represent typical size deletions: P20, P21, P23, P24, P28, P33, P47 and P50. It is valuable to look specifically at these typical cases of PMS to see what might be more generally relevant to PMS families. For example, none of these 8 patients were diagnosed with psychosis and only one had tremor. Thus, psychosis and tremor might not be very relevant to most families. On the other hand, only typical PMS patients lost the ability to walk. Catatonia was seen in only one typical PMS patient (P50).
One feature in common between typical PMS patients and the uncommon cases of SHANK3 disruption is the incidence of bipolar disorder. Half of the typical PMS patients were diagnosed with bipolar disorder, as were many of the patients with SHANK3 disruption. This observation suggests a common mechanism, likely the SHANK3 gene. Do PMS patients with interstitial deletions have bipolar disorder? That would be an extremely valuable question to explore. Reviewing cases of interstitial deletions may support or refute the specific role of SHANK3 in bipolar disorder.
Verhoeven et al observed a similar overlap between typical PMS and cases of SHANK3 disruption. They state: “Based on actual psychiatric classification, in 18 patients, a diagnosis of atypical bipolar disorder was established of which symptoms typically started from late adolescence onward. In most patients, treatment with mood stabilizing agents in combination with individually designed contextual measures, and if indicated with the addition of an atypical antipsychotic, resulted in gradual stabilization of mood and behaviour.” Note the phrase “with individually designed contextual measures”. Proper social treatment of the person with PMS appears to be important for “recovery” (not a technical term).
Kolevzon et al discuss which treatments were more or less effective for both the SHANK3 disruptions and typical PMS patients. The overlap with Verhoeven is very encouraging. Together, the agreement between recent studies on regression and psychopathology provide improved guidance for the medical caregivers who may encounter bipolar disorder in PMS patients. The work of Kolevzon is especially valuable for cases of SHANK3 disruption (variants and very small chromosomal deletions). The number of cases where the PMS adult was stabilized was encouraging in both studies, which provides hope for families facing adult psychopathology.
It will take more studies to make strong statements about regression and psychological decompensation in Phelan McDermid syndrome. These early studies hint at the type of problems that do occur in PMS, the types of remediation that have been beneficial and the differences that appear to be associated with deletion size.
My son, David started life with some rather major problems. He was 6 years-old before he could walk and 9 years-old before he could eat by mouth. He never developed speech. His developmental trajectory has been slowly upward. At age 34, he has not had a regression or anything that could be called psychological decompensation. (His mom is qualified to recognize decompensation.) His deletion size is unknown, but I would wager it is not a small deletion. Does his stability come from missing certain genes?
When we moved David to a new group home two years ago, his mom and I were vigilant about managing the changes and constantly gauging his comfort. We were, frankly, scared that he would decompensate or regress. The transition was successful and David feels at home. But, what will be the next challenge and how will David respond? We don’t know.
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:
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.
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. The axon often winds its way towards the white matter. CELSR1 is important for orchestrating the orientation of neurons to assure proper organization.
BRD1 regulates hundreds of other genes during development. It is highly associated with schizophrenia, as well as PMS. PMS individuals with terminal deletions greater than 1 Mb are missing BRD1 and the loss of BRD1 impacts the entire genome (see https://pubmed.ncbi.nlm.nih.gov/33407854/).
SULT4A1 was recently shown to impact the mitochondria in the brain (see New science: SULT4A1, oxidative stress and mitochondria disorder). Mitochondria convert food into energy for cells. Dysfunction of mitochondria explains why deletions that disrupt SULT4A1 can have a severe impact on neurodevelopment and adult brain function.
TCF20 is a very important gene for brain function. It can cause intellectual disability and other problems on its own. It probably explains why very large deletions in PMS can be more devastating than smaller deletions (see TCF20 may explain why some big deletions are worse than others).
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 (see this paper) and PRR5 (see this paper) 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 makes a convincing argument that genes of unknown function are just 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 how loss impacts PMS.
Conclusion
This study of PMS genes was a critical step forward in understanding PMS. It 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, it provides new targets for therapeutics. Unfortunately, a lot of time has gone by without any serious effort to encourage research into the full array of PMS genes. The genes listed above warrant much more study. As a parent of a child with PMS, I strongly feel we should make an effort to encourage the scientists who study these genes. It is hard to understand why so many important genes of PMS are being ignored by the PMS community.
Originally posted 17 July 2016
Updated 10 April 2024
If you ask me what is wrong with David, I don’t think I can answer the question without making a laundry list of problems, deficits and other issues. He has 22q13 deletion syndrome (Phelan McDermid syndrome, PMS) – that is what’s wrong. Some of his problems almost killed him. Someday, that risk may return. In the meanwhile, his biggest problem is learning new knowledge and skills. Can we make learning more efficient for our children? To investigate this question, we need to understand more about how individual and groups of genes can affect the brain.
I have written blog posts on specific issues in the context of individual genes. Individual genes can impact many parts of the body. A single gene may have multiple functions, an effect called “pleiotropy“. We are often concerned with the primary impact of a gene more so than the secondary issues. We can learn from examples of genes from other disorders. For example, for people with cystic fibrosis, CTFR is an important gene. Its impact on the lungs is very damaging, but it also impacts other parts of the body.
Many 22q13 deletion syndrome genes are pleiotropic. We must look carefully at all the potential effects of a gene. Why? Because, many genes can be lost with PMS. Subtle effects can add up. When I read the scientific papers on a gene, I spend a lot of time comparing the subtle effects of this gene with all the other genes of 22q13. I look for cases where multiple genes have subtle effects on the same organ.
Pleiotropic effects come in two flavors. Either the gene has one function, but in different parts of the body, or the gene can do more than one function. CTFR is the most common cystic fibrosis gene. CTFR is involved in making secretions (fluids used in the body). CTFR mutations are most important in the lungs, but the gene also causes faulty secretions in the digestive tract, and elsewhere.
CELSR1 is a PMS gene. Over 40% of people with 22q13 deletions are missing this gene. Like CTFR, one function affects many different parts of the body. If one copy of Celsr1 is mutated in a mouse, the most serious result is a neural tube closure defect (e.g., spina bifida or other spinal cord problems). Mouse studies of Celsr1 show that it participates in helping cells organize into physical patterns so that cells can operate as a group. Celsr1 was shown to be involved in early development by organizing certain cells into functioning tissues (Feng et al, 2012). However, the central role of CELSR1 in adult brain function was identified later (Schafer et al, 2015).
During development, Celsr1 mutations can interfere with the organization of many different cells (Boutin et al, 2014). For example, ventricles are nourishing fluid lakes inside the brain. Cilia, cells with tiny hairs, line the ventricles of the brain and stir the cerebrospinal fluid (CSF) along its path through the ventricles. Stagnation of the CSF fluid is dangerous. Disordered cilia from Celsr1 mutations cause inefficient motion. In humans, stagnant CSF may have accumulating impact over years.
Very different cells with cilia are used in the ear to hear sounds. CELSR1 mutations disrupt the orientation of “outer hair cells,” responsible for hearing at low sound levels. Cilia are responsible for other body functions, as well, like keeping the airways clear and digesting food. Given its impact on different organs, CELSR1 is pleiotropic.
When someone asks me what is wrong with David, one of the first things I say is he struggles to learn. David is aware and interested in his environment, but he knows trying to learn anything new is difficult. A previous blog post discussed SHANK3 and its impact on learning that involves the ventral striatum in the brain. Mutations in CELSR1 disrupt a different kind of learning, learning that is unique to the hippocampus of the brain. (Note that SHANK3 is also important for the hippocampus.) In rodents, only two areas of the brain are able to grow new neurons. One of these areas feeds the new neurons into the dentate gyrus of the hippocampus and has a subtle, but critical effect on learning. Mutation of rodent Celsr1 disrupts the orientation of these new neurons in the hippocampus. This disruption interferes with building proper connections (Schafer et al, 2015). The human hippocampus may not have exactly the same mechanism for new memories. However, children with deletions greater than 6 Mb (megabase) may have problems with “pattern separation,” the very subtle learning process that prevents new learning from interfering with old knowledge (Johnston et al, 2015). The concept of pattern separation has arisen through complex mathematical learning models and needs to be studied in children with PMS.
How can we take this information on CELSR1 and translate it into treatments? There are several paths. First, we look forward to studies of mice missing one complete copy of Celsr1 (heterozygous knockout mouse) to make sure the effects seen in the current mice are not simply mutation effects (see Gene deletion versus mutation). Second, we need to find out about outer hair cell loss and its potential impact on hearing. Perhaps someday we can arrange for a medical histologist to examine the cochlea (hearing organ) from a PMS organ donor. Third, we need genetic testing (sequencing is best) on all patients missing CELSR1 to identify cases where the remaining CELSR1 gene is mutated. A mutation on the remaining CELSR1 gene could unmask recessive traits in a way that may be very informative.
Finally, if we really want to understand our children’s learning problems, we need to: 1) engage people involved in computational models of learning, and 2) study patients with interstitial deletions. Interstitial deletions will allow us to study genes in better isolation. These patients may be higher functioning, which is ideal for careful testing (see How to fix SHANK3). As the new studies start to bear fruit, we can then use the results to target our teaching methods. Right now parents, teachers and our children are frustrated with how poorly our children learn. Imagine how much better it will be when we know how to maximize learning for each child based on their genetic report. I dream of seeing the next generation of children with 22q13 deletion syndrome having all the benefits we never had for David. Let’s take lesson planning into the 21st century!
There have been a number of press releases and feel-good articles circulating among my 22q13 deletion syndrome Facebook friends celebrating the advancement of mouse models of “Phelan McDermid syndrome”. I am all for enthusiasm! However, cheering is more fun if you know how the game is played and what to cheer for. With that in mind, I would like to look carefully at models. What is a good model and what might it tell us?
I started out in engineering, where modeling is very important. Let’s imagine modeling an airplane. The first issue of modeling is, what aspects of the plane are motivating us to build a model? In this case we might want to learn about how the airplane will perform if the tail is damaged in flight. We can construct a scaled-down miniature with wings, tail, etc. and omit the inside furnishing (cockpit, storage compartments, etc.). If the miniature has the exact same shape and moving wing/tail parts as the real airplane, we would say our model has construct validity. That is, it is constructed in a way that reflects the original plane. The next step is to put our model into a wind tunnel and see if it flies. The model is held on a wire. We can adjust the wing flaps and other control surfaces. If the model tries to rise at the same wind speed as the real plane, and tries to bank left or right with the same amount of wing flap adjustment as the real plane, we can say this model has face validity. That is, with regard to what we are testing, the model behaves much like the real plane. We are finally ready to benefit from all our work. Let’s take the model for a test flight and then poke a hole in the tail. What settings of the flaps and other control surfaces allow us to keep control of the plane? We may struggle with this for weeks or months hoping we can learn to control our crippled model plane. If we find a solution, maybe we have found a way for pilots to rescue their plane in the event of a similar emergency. If this scheme works, our model has predictive validity. Thus, we measure a model’s worth by:
does it model what we want?
is it constructed in a way that tests what is important to us? (construct validity)
does it perform in a way that mimics what we already know? (face validity)
will model manipulations tell us how the real thing will respond? (predictive validity)
I hope you are getting a picture of what an animal model should do. Let’s look at a mouse model of “Phelan McDermid syndrome” or “PMS”. I use quotes because different scientists have different definitions of “PMS”. See Introduction. For this blog, I will omit the quotes, but remember that there are numerous definitions floating around.
The definition of PMS is important for modeling. The definition of PMS tells us what people claim to be modeling. Some scientists define PMS as a deletion or mutation on chromosome 22 that involves SHANK3. That is fine with me, but that omits the rest of 22q13 deletion syndrome, since there are numerous cases of “interstitial deletions” that don’t affect SHANK3. So, SHANK3 might not be a good choice of model for many families. It depends on the deletion and it depends on what is causing your child the greatest difficulties. There are currently mouse models for 11 different PMS genes for deletions of 1 Mbase or larger. Every gene on this list is relevant to 95% of patients (See Understanding deletion size.) The 11 genes are BRD1, CHKB, CPT1B, MAPK8IP2, MAPK11, MAPK12, NCAPH2, PANX2, PIM3, SHANK3, TYMP. Most of these mouse models are very well studied. If you go further up the chromosome you find other well studied genes with mouse models, like ATXN10. So, the choice of gene is all about what aspect of a disease or syndrome you wish to study.
SHANK3 is popular not because of PMS. It is popular because is has been associated with autism. There are under 1,000 identified people in the USA with PMS, but there are an estimated 36,500 children born each year in the USA with autism. Parents of 22q13 deletion syndrome children should appreciate that researchers who study Shank3 mice are tapping into the national (and world) autism crisis. Our children are a convenient source of subjects, which is why the big national study officially excludes PMS families with interstitial deletions that do not affect SHANK3. Children with SHANK3 mutations are of greatest interest even though they technically do not have 22q13 deletion syndrome (that is why the name PMS was created). Note that only 1/3 of children with PMS have autism, so patients with SHANK3 mutation and autism are the most valuable research subjects.
Although SHANK3 is of great current interest, autism is caused by hundreds of genes. Most parents don’t realize that many 22q13 genes are autism-related or suspected to contribute to autism. Some of the autism genes on chromosome 22 are BRD1, CELSR1, CHKB, MAPK12, PANX2, BRD1. Further up the chromosome (associated with somewhat larger deletions) you can find CELSR1, WNT7B, TCF20, EP300 and others.
Now we understand that Shank3 mice need to be models of something. From the above lists of genes, it is pretty clear that a mouse missing only one gene is not a universal models of either 22q13 deletion syndrome or autism. Both conditions involve a large number of genes. The Shank3 mice are single gene models. The mice are fashioned after super-rare cases of people with specific SHANK3 mutations. Let’s see how these models stack up in terms of construct, face and predictive validities.
All of the published papers so far describe Shank3 mutations and microdeletions, not deletion. I am not going to cite the specific papers here. I have written brief reviews on most of these papers. Contact me if you would like specifics. Some of the mouse Shank3 models use deletions that reflect mutations found in actual patients. For those specific patients (often just one or two), the genetic manipulations have construct validity. That is, the mouse gene has been changed in a way very similar to the human gene. As for the rest of us PMS parents, 95% of our children are missing the SHANK3 gene altogether, along with 30 to 100 more genes. So, these mice do not have very strong construct validity for our children. It is well known that mutations can be very different from deletions. (see Gene deletion versus mutation.) Of course, mutating a single gene may not be very helpful to understanding your child when so many other important genes may be involved. (see How do we know which genes are important?) There is also the problem of using a mouse to model a human. The gene is mutated in an animal that lacks brain areas that are crucial to human behavior, like the granular prefrontal cortex. If these brain areas are important to autism, then the construct validity is weaker.
To be fair, a lot of work goes into to creating a knockout mouse. I don’t have first-hand experience, but I work down the hall from a colleague who is an expert. He works hard and I can read the frustration in his brow on tough days. Just making a mouse is not good enough, you have to prove you have modified the right gene in the right place without messing up the rest of the genome. Then you cross-breed, back breed and then do more validations. My hat is off to those people who make a living this way. When done, the mouse has construct validity in that the targeted gene has been modified.
Face validity is a huge problem with mouse models. Our model airplane ascends and descends, banks and aerodynamically behaves much like its real-life big brother. We know the flight behaviors that are important and we can directly (although not perfectly) compare our model plane to the real thing. How do we compare our model disease to the real disease? Generally, the first step is to compare normal mice to our genetically modified mouse. We note what is different between the two. Then, we compare normal human subjects (“developmentally typical”) to those with the syndrome or disorder. The question then becomes, do the mouse differences seem to reflect the human differences? Mouse models of kidney function and cancer have been very successful with face validity. Urine output and tumor size are easier to measure than social behavior and eye contact in mice. Biopsies of human kidney and many tumors are also much easier than brain biopsies. It is no surprise, then, that mouse models of neuropsychiatric disorders are hard to validate.
The differences between normal and mutated mice can be observed in brain structure, chemical signatures, cellular changes and gene expression. For the most part, there is very little human data for comparison. There are studies with human post mortem tissue that can be helpful, but most of that tissue is from normal human brain. As you might guess, screening for gene expression and other changes in a donated brain from a PMS patient will have issues. Most patients have too many genes involved. One helpful approach is induced pluripotential stem cells (iPScs), grown from skin samples or hair follicles. One might even be fortunate enough to find a donor who’s genetic mutation matches the mouse (or vise versa). However, iPScs do not undergo normal development, so developmental studies are impossible at the moment. They also don’t produce circuits like an intact brain. These are all limitations that impact face validity.
The one common feature you can examine between mice and humans is behavior. There are two extreme viewpoints in this regard. At one extreme, some scientists argue that any behavioral difference between the normal mouse and the genetically modified mouse is “autism-associated” because of the construct validity. At the other extreme, a few scientists argue that the mouse behavioral difference should reflect the standard manual that defines neuropsychiatric disease (DSM-5). The remaining scientists are in the middle until it comes to publishing a paper. Then, they make the argument that their animals’ behavior somehow reflects the behavior of a person with autism. It is my observation that the more popular or prestigious the journal, the more their mouse sounds like a miniature human.
A major problem with Shank3 mice is that, almost universally, they don’t have a significant aberrant behavior. How can you study behavior when it seems normal? There are two solutions, but both have problems. With one approach, researchers find a mutation spot on the gene that is extra good at producing a pathological behavior (e.g., ignoring other mice, not learning, rubbing its fur until the skin is damaged). Another approach is to mutate both copies of the gene. Each of these solutions creates a new problem. In the first case, we are no longer modeling PMS or autism, because this behavior only shows up in very specific mutations. In the second case, we have lost construct validity. We were never trying to model mutation or loss of both copies of SHANK3. That would likely be a different syndrome (just as mutation is different from deletion).
In the end, current models of SHANK3 mutation (autism and SHANK3 mutation aspect of PMS) provide information about molecules and neurons, but are very limited models of the human diseases. They don’t necessarily say much about 22q13 deletion syndrome in general. It is interesting to note that mouse models of other genes of 22q13 deletion syndrome may be more promising. Several mouse models have clear consequences with only one gene mutated or deleted. For example, the Cpt1b mouse model is used to study cold tolerance and insulin sensitivity, and the autism and schizophrenia-associated gene, BRD1, is under intense research right now by a group in Denmark. In both cases the behavioral effects are clear when only one copy of the gene is affected.
We are not done yet, because the most important and most difficult type of validity is predictive validity. That is, does your mouse model tell you what will happen in your human subjects? Given all the problems with making a mouse model of a neuropsychiatric disorder, it is no surprise that the models have not lead to translational (treatment) gains. (See Hope for autism treatment dims as more drug trials fail).
I have heard many people in the research field try to sound hopeful to parents. I believe that hope, when anchored in reality, is very helpful and important. But, too many people have alternative reasons for fanning the flames of hope by knowingly or unknowingly misrepresenting the size of strides in research. My recent blog (How can the same deletion have such different consequences?) touches on why so many parents are mislead by researchers, writers and support organizations. The subsequent blog (22q13 deletion syndrome and science leadership) explains that it does not have to be this way if we bite the bullet and hire qualified leaders.
As a parent, my heartstrings feel the tug of hope every day. The urge to follow those feelings is managed by having a deeper understanding of the research world, and remembering that too many people are eager to give those strings an extra tug.
Although non-verbal, David is clearly in charge of this trip.
David does not talk, but he does know how to express himself. In this photograph we are taking a ride to his brother’s apartment. As soon as I arrived at David’s house, he grabbed my hand and walked me back to the car. He pulled on the door leading to the back seat. “Take me for a ride! The usual place, of course!” He communicates very well considering all his disabilities, but I would love to have a medication to help him talk, or walk better, or toilet easier, or not overheat in the summer. In fact, what I really want is a custom pill made for David. Different patients with different size deletions have different needs. Although intellectual disability affects 100% of our kids and ASD affects up to 30%, the reality is that our children can have many different problems. Except for a few confusing cases, kids with larger deletions have more problems and often more severe problems.
If you read my earlier blog on deletion size (Understanding deletion size), you will know that over 95% of patients with 22q13 deletion syndrome are missing from 10 to over 100 genes. The genes near the end of the chromosome are the first ones to be deleted by a terminal deletion (the most common type). These genes are tightly packed together. In this region, you cannot simply say “a small deletion”. You must know the exact deletion size to know how many genes are affected.
Precision medicine
According to the National Institutes of Health, “precision medicine” is “… an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person” (from: NIH Precision Medicine Initiative). The promise of precision medicine has not reached most people because the average patient does not know which genes are most important to his/her health. For patients with 22q13 deletion syndrome, however, the genes that cause the syndrome are obviously the genes of greatest clinical importance. The primary goal of 22q13 deletion syndrome research should be to maximize the benefit of knowing the exact genes involved on a patient-by-patient basis. Think: “I want a pill optimized for my child”. Of course, it is an oversimplification to think about a custom pill, but the NIH definition of precision medicine helps guide us toward more practical thinking.
In my last blog (How do we know which genes are important?) I listed the genes that are likely to contribute to hypotonia. Categorizing the genes into clinically meaningful categories provided us with insight into treatment. Each gene in the list has a known effect on the brain and rest of the body. Some genes interfere with normal brain function. Other genes can affect peripheral myelin, a insulator that is needed to transmit information back and forth between the spinal cord and the muscles. Still other genes can disrupt a muscle’s ability to tolerate sustained work. Each of these categories provide important information to the physical therapist. A child with poor sensory feedback from the muscles might be handled differently from a child with poor muscle stamina. Precision medicine is in its infancy, used mostly in cancer treatment. However, precision medicine for 22q13 deletion syndrome could start today. Physicians and therapists could readily benefit from a report for each person that brings together an individual’s genetics with the known functions of the missing 22q13 genes.
One might wonder how far this precision medicine idea can be taken. Well, for next year the White House reports a 215 million dollar initiative for government supported research and promotion of precision medicine (White House Fact Sheet). Businesses have already invested billions of dollars into electronic health records, the backbone of precision medicine. There is no question that precision medicine will bring major changes to medical practice and patient choices.
Clearing up some misconceptions
It is amusing at times to hear well-meaning parents talk about the barriers to using genetic information to guide treatment. One common misconception is that too little is known about the genes. Actually, many of the genes have been studied for decades and the research has obvious clinical implications. For example, at the Society for Neurosciences meeting earlier this month I talked to a young researcher from California who was working on CELSR1 (missing in about 50% of our kids). He showed that neurons in the hippocampus essential for learning new relationships between events and places (e.g., learning to navigate a new school building or deal with a change in classroom schedule) are disrupted when CELSR1 is deleted. What he told me next was even bigger news. A researcher in Belgium has been studying mice lacking CELSR1 for years. It took only one email to that scientist to net a trove of information about CELSR1. Apparently, CELSR1 is not only important for brain wiring, but also the flow of cerebrospinal fluid (CSF) in the brain. Read that: enlarged ventricles. A radiologist who evaluates the MRI of a 22q13 deletion syndrome child will someday associate his/her findings with deletion size based on studies like these. After enough MRI reports are collected from enough patients, the association of CELSR1 with ventricle size can be confirmed. The beauty of precision medicine is that you collect new data for the next generation each time you treat patients in this generation. Taking your child to the doctor actually helps other patients with 22q13 deletion syndrome. Is that great, or what? For people with 22q13 deletion syndrome, it is knowing the detailed genetic information that will make it work.
Another misconception is that there is no clear relationship between deletion size and the severity of 22q13 deletion syndrome. Actually, even if there was no clear relationship, it would still be of great value to use our knowledge of which genes are involved in each person. But, we are sometimes faced with the confusing observation that a few kids with big deletions are more functional than others with smaller deletions. These apparent exceptions to the rule are examples of how genetics can fool us. Let’s use two examples to show how important knowing the basics can be. Reading the scientific literature you can find one or two kids with tiny SHANK3 mutations/microdeletions who are more affected than one or two other kids missing a whole group of genes. As I discussed in my earlier blog (Sometimes missing a gene is better) a gene mutation is often more damaging than deleting that gene. Such is the case for specific mutations of SHANK3, ATXN10, CELSR1 and other genes on 22q13. That is part of the reason I use the term “22q13 deletion syndrome”, which distinguishes deletions from mutations. The second example is the clumping of important genes on the distal part of the chromosome. Because the genes are not evenly distributed on the chromosome, someone with a 1.5 Mbase deletion and someone with a 2.5 Mbase are actually missing the same genes. Deletion size is not a measure of gene loss. It simply provides a map to the list of genes that are deleted. Comparisons have to be made after making a list of genes.
There are other reasons for a conflict between deletion size and severity of 22q13 deletion syndrome. One recent study has shown that de novo chromosomal deletions (the most common type) often include mutations and other deletions elsewhere on the chromosome or on other chromosomes. This more widespread occurrence of genetic errors does not tend to show up in the parents or siblings of a child with a de novo deletion. That is, a diagnosis is 22q13 deletion syndrome raises the possibility that there are more genetic errors elsewhere in the DNA. Precision medicine will someday not only include the deletion size, but a list of other genes that show potential issues. There are other reasons for the unusual cases that I won’t go into, but larger deletions affect more genes and generally cause more problems. Of course, individual differences do matter. That is why it is called precision medicine.
The future is now
My posting on hypotonia landed me an opportunity to give a guest lecture to a graduate physical therapy class. The lecture was on the genetics of infant hypotonia. I ended the lecture with a “hopeful warning” that all of medicine is about to change. It was a warning, because all clinical practitioners will need to understand the implications of genetics in their practice, and it was hopeful because the lives of patients are about to get better. It may be a while before we can go to an apothecary for a customized pill, but we can reap benefits today. Your physicians, nurses and therapists could begin receiving guidance curated from the currently available literature on genes. Of course, someone has to compile the information. Perhaps we need to convene a conference that brings together experts on each gene with medical practitioners who would use the information. I have seen a number of conferences for 22q13 deletion syndrome, but none like that.
I should probably get a detailed genetic report for David and combine that with my own readings on his genes so that he can benefit from the promise of precision medicine. I am torn by a moral dilemma. I don’t want to be biased in my pursuit of 22q13 genetics. Whether we like it or not, we are always biased by what our own child needs. Not knowing David’s details is, in a way, liberating. I am hanging out with David as I write this. We are watching the Graceland video with Paul Simon. If you know the history behind that video, it is a reminder that everyone matters, regardless of their skin color, which is to say, regardless of their genetics.
Although he is a bit unsteady at times, David loves to walk. David began a day program after high school and he was assigned an aid new to the program. After one month the aid nearly quit! Keeping up with David’s constant motion — usually walking — forced the aid to become an athlete. After working with David for twelve years, she looks back at the experience in an appreciative way. David brought fitness into her life and the two of them developed a deep affection for each other. They enriched each other’s lives in many ways. Health from walking was an important one.
David has 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome (PMS). David, like many others with PMS, was born a “floppy baby”: A general medical reference to an abnormal condition of newborns and infants manifested by inadequate tone of the muscles. It can be due to a multitude of different neurologic and muscle problems. See also Hypotonia. At age one, after daily work-outs and multiple physical therapy sessions each week, David developed the strength to lift his head and arms. He gradually learned to sit up, drag himself by his arms, and then crawl. Countless hours of therapy in a clinic and at home went into each milestone. We pushed him constantly for six years. Each time he improved, we “raised the bar”. Once David gained strength and basic skills, his mom, Carol, would exercise David at the grocery store by having him hold onto the side of the shopping cart as she pushed. One day, fascinated by a stack of bright red apples in the produce section, David let go of the cart and walked eight steps on his own to reach the stack of applies. Carol was caught completely by surprise. David reached the apples and everything ended up on the floor. The store staff came running and found Carol holding David, crying tears of joy. After six very long years, David had learned to walk on his own. Now, David I go on weekend walks together (see photo). Every time I walk with David, it warms my heart to watch him
Hypotonia
Having very low muscle tone interferes with normal growth and development in many ways. Muscle tone is important for breathing in newborns (Lopes et al., 1981). David was born prematurely and he was on a ventilator for weeks. Low muscle tone slowed his recovery. Muscle tone is important for normal cognitive development and function (e.g., Jongsma et al., 2015). Gastroesophageal reflux plagues many children with PMS (including David) and is likely caused by low tone of the esophageal sphincter (Hershcovici et al., 2011). Other gastrointestinal problems likely result from muscle tone problems of smooth muscles. The most obvious problem with low muscle tone, however, is delayed or absent walking. Walking requires stable standing, which requires sufficient tone to hold the body erect. Building strength in David’s abdominal, back and leg muscles took years of work.
What is muscle tone and what interferes with normal tone? For skeletal muscle, “Muscle tone refers to the resistance that an examiner perceives when moving someone’s limb in a passive manner” (Mitz and Winstein, in Neuroscience for Rehabilitation, 1993). Normal muscle tone disappears when someone is knocked unconscious, or when the muscle itself is unable to support contractions. Diagnosing the cause of hypotonia in infants can be complex, especially in the presence of a genetic syndrome (Bodensteiner, 2008). In genetic syndromes that include both hypotonia and intellectual disability, the hypotonia is often diagnosed as “central hypotonia”: hypotonia caused by problems with the brain or spinal cord. However, the hypotonia associated with PMS may be from multiple causes. Certainly, it is not caused by any one gene. No single gene deletion or mutation has been identified that always causes hypotonia, and no one gene is essential for hypotonia. There is also no doubt that infant hypotonia is far more common in children with somewhat larger deletions (Sarasua et al., 2014, figure S1).
The severe hypotonia so often seen in infants with PMS may arise from multiple sources. Since finding ways to treat hypotonia could help children with PMS, understanding the causes will open the door to improving their lives.
Genes that directly affect synapses
If your child with PMS was seen by a pediatrician or pediatric neurologist, it is likely the physician concluded that the hypotonia was of central origin (see, Bodensteiner, 2008). Although the conclusion would be based on accepted clinical practice, it would actually require a battery of tests to rule out other sources. Without other signs of major muscle or metabolic problems, the physician may be wise to avoid the additional tests that would be necessary. Right now, such testing is best done as part of a research study.
Which genes might contribute to low muscle tone of central origin? One obvious source of central hypotonia is a problem with synaptic proteins. For chromosomal deletions of 22q13.3, two proteins coding genes are nearly always deleted together: SHANK3 and MAPK8IP2. I have found only one published clear case where MAPK8IP2 and more proximal genes were deleted without impacting SHANK3 (Vondráčková et al., 2014). That patient had hypotonia. Thus, hypotonia can be caused without impacting SHANK3. What is lacking in PMS research are more studies of children with so called interstitial deletions. (See my blog: PMS, IQ and why interstitial deletions matter). Generally, hypotonia created by the deletion of SHANK3 is less than with deletions of any larger size. If we include pathogenic variants of SHANK3, we know that hypotonia with a SHANK3 variant is much less prevalent (33%) than hypotonia in patients with terminal deletions of 22q13.3 (65% to 75%), whether or not SHANK3 is involved in the deletion (Vondráčková et al., 2014).
Genes that affect brain development
In PMS, hypotonia of central origin is likely caused by the genes essential to normal to brain development. A review of PMS genes showed that 18 genes that are deleted in PMS patients are associated with brain development (Mitz et al., 2018). Of these, 10 genes are associated with reproductive fitness (e.g., necessary for normal health) based on their “pLI” scores: SHANK3, MAPK8IP2, PLXNB2, TUBGCP6, BRD1, TBC1D22A, CELSR1, SULT4A1, TCF20 (see Supplementary Table S2 of Mitz et al.). Since that study, The gene PHF21B has been added to the list as an epigenetic regulator of development (Basu et al., 2020). Thus, genes across the nearly entire 22q13.3 region associated with PMS are critical genes that participate in normal brain development. Any, and likely all, contribute to both the intellectual disability and the hypotonia of PMS.
Genes that may affect the environment of the central nervous system
We sometimes forget that the brain must have lot of things working properly for synapses to operate. For example, the brain is about 2% of our total body weight, but it uses up 20% of the oxygen we breathe (Rolfe and Brown, 1997). So, the blood flow from the heart, nutrition from the gut and oxygen from the lungs are of critical importance to human brain function. Any missing gene that might affect the brain’s ability to process energy in the mitochondria may impact synaptic function. Note that studies of rats and mice might be misleading. The rat brain, for example, uses only 3% of the oxygen they breathe for brain function. These mammals are not nearly as sensitive to the “energetics” of brain function as humans. The genes of 22q13.3 used by mitochondria appear to have a mixed impact on people with PMS (Frye et al., 2016). Beyond hypotonia of central origin, the same genes that affect the energy supply for the central nervous system can affect muscles directly. Muscles come in three flavors, skeletal, cardiac and smooth. They are all major users of energy.
SCO2 and TYMP are two mitochondrial PMS genes that are lost with relatively small deletions of 22q13.3. Individuals missing one copy of SCO2 and/or one copy of TYMP seem to do fine (Pronicka et al., 2013). However, if the remaining copy of either SCO or TYMP has an unusual variant, the results can be profound (Vondráčková et al., 2014). Of greater concern for most people with terminal deletions of 22q13.3 is the SULT4A1 gene. SULT4A1 is one of the few genes that has been implicated in intellectual disability and hypotonia based on a study of interstitial deletions. Recently, it has been shown the SULT4A1 protein is crucial for mitochondria function in the brain.
Conclusions
Most clinicians will conclude that hypotonia in children with PMS is of central origin. This is a good assumption, but further research is needed to look for more direct effects on muscle. There is strong evidence that many PMS genes contribute to central hypotonia, and central hypotonia occurs with all genotypes of PMS (see The four types of Phelan McDermid syndrome). On average, larger deletions lead to greater hypotonia. Developing broad and effective treatment for hypotonia will require understanding more about each gene’s contribution to maintaining healthy muscle tone (see 22q13 deletion syndrome: the hope of precision medicine).
arm22q13 