Originally created 12 September 2020
Updated 31 January 2022
I am going to describe four types of Phelan-McDermid syndrome (PMS). By type, I mean four different genetic arrangements that can result in PMS. These are technically called “genotypes”. The four genotypes do not address the mechanisms that create each genotype. For example, my son, David, has Type 1 (Genotype 1) from an unbalanced translocation, but others have PMS Type 1 from de novo deletions or ring chromosomes. The types can be used by parents as a very simple short-hand to share information about their child.
Phelan McDermid syndrome Type 1, terminal microdeletion
This is the original 22q13.3 microdeletion syndrome described by Katy Phelan and Heather McDermid. It is also the most common type among people identified with PMS.
A microdeletion occurs when multiple genes on a chromosome are removed. Most microdeletions are too small to see under a microscope, but Katy Phelan has described some microdeletions that are large enough to be visible. Deletion sizes range from about 0.2 Mb to 9.3 Mb, with an average of 4.5 Mb. Nearly all of the microdeletions observed are terminal deletions (continue to the end of the chromosome). Terminal deletions much smaller than 0.2 Mb do not include SHANK3 and do not produce a syndrome.
Phelan McDermid syndrome Type 2, interstitial microdeletion
An interstitial microdeletion is a deletion that removes multiple genes, but does not extend to the end of the chromosome. For PMS Type 2, the deletion does not reach SHANK3, which is near the end of the chromosome.
Interstitial deletions that produce PMS, but do not disrupt SHANK3 are relatively rare. Some scientist have argued against including them in the definition of PMS. However, a recent scientific consensus paper (https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02180-5) justifies the strong reasoning for including Type 2 in the definition of PMS.
Phelan McDermid syndrome Type 3, single SHANK3 rare variant
A rare variant is an atypical version of a single gene. PMS caused by a rare variant of SHANK3 is called Type 3. Sometimes this has been called a “mutation” of SHANK3. That terminology is not always technically correct, so “variant” is preferred.
Type 3 is currently the second-most common example of PMS. However, rare variants of SHANK3 have been found in large collections of DNA from people with autism spectrum disorder (ASD). Although only 1 to 2% of people with ASD might have a rare variant of SHANK3, this still a potentially large population of people who might have PMS Type 3. More research is needed.
Phelan McDermid syndrome Type 4, heterozygous deleterious variants
You child does not have PMS Type 4. PMS Type 4 is included here for completeness. Individuals can inherit two copies of unusual variants of SHANK3, one from each parent. This can produce PMS as a recessive disorder. There may be cases of Type 4, but they would be very rare, indeed.
The consensus paper (see the link, above) has provided a clear statement about how the PMS diagnosis should be applied. This is the classification that geneticists and scientist should use.
PMS-SHANK3 related (Types 1, 3, 4)
PMS-SHANK3 unrelated (Type 2)
Note that most cases of PMS fit one of the four PMS types. However, the reality of genetics is that some cases can be very messy. The four genotypes of PMS are not always clearly segregated in any given individual. An individual can have an interstitial deletion, yet also have a pathological variant of SHANK3. This could be described as both PMS Type 2 and PMS Type 3. The classification system from the consensus group, PMS-SHANK3 related versus PMS-SHANK3 unrelated,covers all possible cases without any overlap.
Sometimes two different genotypes are actually very similar
Most PMS Type 1 and PMS Type 3 cases are very different from each other. An individual with a large terminal deletion is likely to have problems not shared by an individual with a SHANK3 variant. With Type 1 there are many important genes involved, some known to produce profound effects. In Type 2, any effect would only result from disturbing SHANK3. Yet, someone with a small terminal deletion (PMS Type 1) might be very similar to someone else with PMS Type 3. Although in different categories, they could end up being very similar.
PMS is a syndrome
PMS is defined by its genetics. However, central to all syndromes is that the individual must have a phenotype reflecting the syndrome. There are some individuals with interstitial deletions and other individuals with with SHANK3 variants who simply do not have significant features of Phelan-McDermid syndrome. These are very interesting cases, but they cannot be called PMS.
This simple system of PMS Types 1 to 4 can help parents quickly share the basic genetics of their children. PMS Types 1 and 2 have a deletion size associated with them. PMS Type 3 does not. Some manifestations of PMS, like lymphedema are not seen with Type 3. Sharing your child’s PMS Type can be an ice breaker during introductions and help a parent share key information without having to be a genetics expert.
Phelan McDermid syndrome (22q13.3 deletion syndrome, PMS) comes in three flavors. By far, the most common variety of PMS that has been observed is a terminal microdeletion. A terminal deletion occurs when from three to 108 genes are chopped off the end of chromosome 22. There is a growing group of identified patients who have structural changes restricted to the SHANK3 gene, a gene very near the end of the chromosome. These changes can be minimal (e.g. single nucleotide polymorphism (SNP)) or substantial, with large parts of the gene duplicated or missing. The least studied form of PMS is found among those deletions that damage the same general region of chromosome 22 without affecting the very end of the chromosome where SHANK3 resides. These are often called interstitial deletions.
Genes of PMS
The SHANK3 gene is an elephant. It is a large, complicated gene and its disruption often (but not always) has severe consequences for its owner (the person harboring the mutation). Numerous studies show that the many genes of 22q13.3 contribute to intellectual disability, muscle tone and movement disorders, hearing problems, lymphedema, autism, schizophrenia and other problems. But, the penetrance of SHANK3 mutations, that is the likelihood that a pathological variant of the gene affects the owner, is high. So, it garners a lot of attention. Especially for people with the second flavor of PMS, fixing SHANK3 could ameliorate many of the symptoms associated with its disruption. For terminal deletions, the most common form of PMS, fixing SHANK3 should have at least a very helpful impact.
There are at least 18 genes that may need repair to fully restore normal function in a child with a large terminal deletion. Average size deletions (about 4.5 Mbase) would benefit from the repair of 10 genes. This blog discusses what we hope will be the future of PMS treatment: genetic repair. While regular medical treatments have been helpful for some problems, no experimental drugs have had an impact any better than physical therapy, speech therapy, ABA or other standard treatments for children with developmental disabilities. Although drug companies are sponsoring testing on children with PMS, these have traditionally been drugs looking for an application rather than targeted treatment for PMS.
We are in the early days
Excitement over gene editing, especially in stem cells (cells typical of a very early embryo) has led to giant research efforts and early attempts to fix diseases by editing. The same excitement has led to the promotion of unproven and occasionally dangerous therapies by entrepreneurs who provide services like stem cell infusion. So, let’s be clear. Gene therapy for PMS is well off into the future. There are many reasons for the delay. Some will be discussed below.
Obviously, we are at the earliest stages of gene therapy. Research and initial attempts at gene therapy target diseases that are the safest and most likely to work. This means that the disease most likely to be cured first may be a rather obscure one. It may also be a lethal disease, since the risks of side effects are no worse than letting the disease take its course.
One relatively safe way to test gene therapy is to modify blood products and then infuse them back into the body. This has safety advantages in a few different ways. First, the genetic modification occurs outside the body. The target cells can be modified without risking other cells of the body. Second, the target cells can be tested and evaluated for successful gene targeting (editing the right spot and not accidentally damaging another gene) outside the body. Third, the product can be infused a little at a time to test the benefits/impact gradually. Fourth, blood products usually have a limited lifetime in the body, so if the test begins having problems, the problems will likely go away with time. Thus, gene editing for diseases of the blood are good early candidates.
Another target for early genetics testing is the eye. It is a squeamish thought, but making injections into the eye are relatively easy. (I have had eye injections, so no need to educate me on the downsides.) The inner parts of the eye are well isolated from the rest of the body, which affords safety. Also, only very small injections are needed to bathe the retina. There is little likelihood of impacting the rest of the body. The amazing thing about eye therapy is that modern cameras and computers can take images of the eye with spectacular resolution. These images can track changes. Combined with vision testing, any progress associated with the therapy is easy to assess. As gross as it sounds, if something goes wrong with gene editing of the eye, the eye can be removed. Gene therapy for the eye would be to save vision. If vision will be lost with no intervention, the risks of trying a new therapy may be acceptable. Thus, genetic defects of the retina are high on the list of early therapeutic trials.
The human brain is not well isolated from the rest of the body and is not easily observed from the outside. There is a barrier between the bloodstream and the brain. The so called blood-brain-barrier can make treatment more difficult. Drugs injected into the bloodstream (systemic injections) may or may not reach the brain. Direct brain injection of genetic altering “vectors” may be an approach used in the future, but it is not ideal. Systemic injections would be a simpler way to reach all parts of the brain and to allow repeat injections to gradually reach the desired effect while watching for side effects. So, genetic editing in the brain is not going to be as simple as other targets.
Once we start thinking about genetic manipulations in the body, we need to remember that nearly every cell in the body has the same 20,000 genes. Given that all cells in the body could be the same, what makes heart and lungs different from kidney and brain? The answer is gene expression. Heart cells know they are heart cells because only heart cell genes are turned on, making the proper heart cell proteins in the proper proportions. We hope that injecting a vector into the body will improve brain function, but we must worry about what else may change. We worry in two ways. First, we could modify our target gene in such a way that the brain improves, but the heart (or some other organ) suffers. Second, we could accidentally modify other genes (so called, off target effects) that have no adverse impact on brain cells, but might be bad for the heart. I used the heart as an example, but there are so many different tissues in the body we cannot know which might be adversely affected.
One more consideration is important in choosing a target for the early tests of genetic therapy. The complexity of the organ and the importance of early development in creating its detailed structure influence the age at which therapy may be effective. The brain is complex almost beyond comprehension and its early patterning during development is critical to adult function. Repair of a gene after early development may have limited benefit, and except for the most deadly of disorders, we dare not test interventions on fetuses or babies until we are confident of our methodology. Additionally, the complexity of the brain poses another risk. Increasing the production of a gene may be beneficial for one part of the brain, but could be detrimental elsewhere in the brain.
The challenges of PMS
The opening of this blog hinted at some of the challenges of PMS. Together with the subsequent discussion, we can now list the major challenges of applying early genetic methods to PMS: 1) the overwhelming majority of people diagnosed with PMS are missing many genes and modern methods are still struggling for success with single genes, 2) the gene of greatest interest is large and complex, neither of which is good for gene editing, 3) the brain is a challenging target for genetic manipulation, and 4) PMS is a developmental disorder and we have insufficient information on whether treatment in older children or adults will be beneficial.
Given the many hurdles, it may be a very long time before a comprehensive treatment for PMS emerges. To be sure, there are people working on strategies to manage the disadvantages. One approach is to target only one gene in the hopes that at least some subset of patients might benefit. Likewise, there are model (rodent) experiments that suggest some of the deficits of PMS can be mitigated by treating adults. Genetic treatments for other diseases are addressing the problem of reaching the brain without adversely impacting other organs. Both animal and early clinical trials are creating improved toolboxes for genetic therapies. We hope these technologies converge on better opportunities for PMS.
Progress in the field
Techniques like CRISPR/Cas9 grew out of studies in bacteria and other science far afield from human clinical work. Recent work in E. Coli and other bacteria, as well as work on yeasts and viruses have moved genetic editing towards more precise targeting, the possibility of replacing whole deleted sections of chromosome, and the ability to enhance the activity of the remaining gene after one has been deleted. There are new methods of turning on and off a newly inserted gene, so the proper dose of a gene can be safely titrated to avoid overdose. This blog has not addressed the different methods of gene editing and which ones might apply to PMS. Rather, it provides a framework to understand why one approach or another might be more suitable. Perhaps a future blog will cover the different tools and which ones are likely to provide the first clinical tests.
A strategy for PMS
After reading the scientific literature and talking with scientists, I have a policy suggestion for how we should approach PMS. Currently, the only genetic intervention being pursued for PMS is targeted at the SHANK3 gene. There are historical and logical reasons for targeting this gene. It is highly associated with several developmental disorders. That work should continue, but from a technical perspective, SHANK3 is not an easy gene to treat. The SHANK3 gene can produce from 20 to 100 isoforms (versions) of the shank3 protein, up to 1731 amino acids in size. (By comparison, the UBE3A gene associated with Angelman syndrome produces a maximum of 12 ube3a isoforms, with 875 amino acids being the largest. The MECP2 gene associated with Rett Syndrome, has two isoforms, with 486 amino acids being the largest.) Manipulating a large, complex gene like SHANK3 has consequences, at least some of which will likely be negative consequences. Like all early genetic clinical studies, initial trials will be on a few hand-picked cases. Unfortunately, even among people with SHANK3 mutations, there are many flavors and early treatment methods might not generalize to many patients.
If we are serious about a long-term solution for PMS we need to work on a smaller and more simple gene. Solving problems caused by SHANK3 is going to be a very slow process. We should choose a gene much easier to fix, and yet still has a serious impact in our children with PMS. The idea is to bring relief sooner, and to begin the important task of treating the full spectrum of PMS. There are 17 possible genes, three or four of which are among the best candidates. One possible target is BRD1. This is a regulatory gene that has been very well characterized. It is smaller than SHANK3 and one copy is missing in about 90% of the PMS population. Evidence so far supports the importance of missing only one copy of BRD1.
Titrating expectations, but not hope
There is always a balance between the enthusiasm for research into effective treatments and maintaining a realistic view of scientific progress. Young parents have so many compromises to make in their hope for the future when they receive a diagnosis of PMS. Placing the disorder into perspective takes years. We grow into a life consumed by a child with a major developmental disability. Hope requires embracing the possibilities, maintaining enthusiasm about the future, yet titrating our expectations to match today’s realities. We are a long way off. Our own children will likely be adults, perhaps old ones, before effective genetic treatments are ready for widespread application. We need to be realistic about our expectations without diminishing our hopes. Indeed, this is what raising a child with PMS is all about.
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.
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.
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.
Brain structure and functional abnormalities have been reported in Phelan McDermid syndrome (PMS) by a number of different investigators, including a a recent study associated with the Developmental Synaptopathies Consortium natural history study of PMS (Srivastava et al 2019). Prior studies have found abnormal formation of the cerebellum (Aldinger et al 2013), abnormal function of the cortex and amygdala (Philippe et al 2008), micropolygyria (Kurtas et al 2018), as well as commonly observed thinning of the corpus callosum and the presence of arachnoid cysts.
Brain abnormalities can provide important clues to understanding what goes wrong in PMS. They also could serve as “biomarkers”, biological measurements for early indicators of severity or evidence for treatment effectiveness. Readers of my blog will recognize that I spend a lot of time identifying which genes are most important in PMS. You need to know which genes are causing what problems to have any hope of finding effective treatments. My son, David (see picture), is waiting for new treatments.
So, what do the brain structural studies tell us?
SHANK3 variants can impact the proper development of white matter, but have minimal impact on the gray matter of the brain (Jesse et al 2020). Gray matter is where the neurons and their synapses reside. White matter is made up of the long, thin “axons” that travel together connecting one region of the brain with another region.
Aldinger and colleagues (Aldinger et al 2013) studied 10 subjects with PMS using x-ray images. Eight of the 10 subjects showed abnormality of the cerebellum (mostly gray matter) in addition to thinning of the corpus callosum (white matter) and enlargement of the cerebral ventricles (fluid space of the brain). Although there was no clear effect of deletion size, mutation of SHANK3 was not sufficient to cause cerebellar problems. They identified MAPK8IP2 and PLXNB2 as the more likely candidates for cerebellar malformation based on preclinical mouse studies.
The study by Philippe (Philippe et al 2008) had similar results from 8 PMS subjects. Three of the 4 subjects with small deletions (150 Kb or less) had no cerebellar or other major magnetic resonance imaging (MRI) results. The 4th subject with a small deletion had the least impressive positive finding. Thus, using MRI, there was a clear effect of deletion size, with small deletions have little or no effect. Four deletions of 1 to 9.3 Mb in size had stronger effects. Like the Aldinger study, SHANK3 did not seem to be a good candidate for most of their findings. In addition to cerebellar malformation, the group studied brain function using positron emission tomography (PET). They showed a group effect of amygdala dysfunction. Importantly, they used children with intellectual disability as their control group, a much stricter standard than other PMS studies.
The Srivastava study (Srivastava et al 2019) showed reduced size of the dorsal striatum, which is the opposite effect that loss of SHANK3 has in mouse models of PMS. Together, the results suggest that genes other than SHANK3 are driving brain malformation. SHANK3 can contribute to thinning of white matter, but is not the cause of other brain malformations.
Which genes might be driving the observed effects? Is there a smoking gun? To be a smoking gun, a gene that drives malformation should meet most, or all, of these criteria:
is strongly associated with a human neuropsychiatric or neurodevelopmental condition
causes reduced brain size in the striatum
impacts the amygdala
There are 6 genes on chromosome 22 that meet criteria 1 and 2. They have a high pLI score and are very frequently lost in PMS. They are located within 1 Mb of the chromosome terminus, which accounts for 95% of patients with a 22q13.3 deletion (see my blog Understanding deletion size). Those genes are: MAPK8IP2, PLXNB2, TRABD, PIM3, ZBED4 and BRD1. Of these, 4 genes meet criterion 3, being highly expressed in the cerebellum: MAPK8IP2, PLXNB2, ZBED4 and BRD1. Of these, 3 genes are associated with neuropsychiatric disorders. BRD1 is strongly associated with and schizophrenia. MAPK8IP2 is weakly associated with ASD (see my blog Which PMS genes are most associated with Autism?), and ZBED4 is weakly associated with schizophrenia. This leaves BRD1 as the strongest candidate gene for brain abnormalities/malformation in PMS.
Animal studies of BRD1 agree with the results from PMS imaging studies. Per Qvist and his colleagues in Denmark have been studying the BRD1 gene for some time. They have shown that loss of one copy of Brd1 in mice is sufficient to reduce cerebellum size, reduce striatum size and reduce the size of the amygdala (Qvist et al 2018). BRD1 is by far the strongest candidate gene for causing altered brain development, especially in gray matter.
The importance of BRD1 in PMS goes much further than structural brain anomalies. It has been known for some time that BRD1 impacts 100s of other genes through gene regulation (epigenetics), and the role of BRD1 shifts from development in utero (fetus) to a different role after birth (Dyrvig et al 2017). Now, a new epigenetics study of people with PMS Type 1 (terminal deletions) confirms that loss of BRD1 produces widespread changes in the human genome. BRD1 is a crucial gene lost in people with deletions greater than 1 Mb.
There is little doubt at this point that BRD1 plays a crucial role in PMS.
PMS is a contiguous chromosomal deletion syndrome, meaning that larger deletions interrupt more genes of importance. BRD1 is a critical gene for brain development. If we want to understand PMS, we need detailed studies that explore more genes like BRD1. One great way to study the impact of different genes is to look more deeply at the phenotypes and genotypes of people with interstitial deletions (PMS Type 2). A treasure trove of new information awaits these studies. Not exploring these candidate genes of PMS is a waste precious time. My son, David, and so many others, are waiting for these studies. We need to do the best possible science if we are ever going to find effective treatments.
Technical description: The evidence from recording of cerebellar granular cells indicate that NMDA receptors at synapses are dysfunctional in the Ib2 knockout mouse. The receptors are overstimulated, which disrupts the excitation/inhibition (E/I) balance of the neurons. Computer models show that the dysfunction of the NMDA receptors can explain the severe synaptopathy in the mouse’s cerebellum.
The practical result is poor cerebellar function. What does the cerebellum do? Wikipedia explains: “The human cerebellum…contributes to coordination, precision, and accurate timing…Cerebellar damage produces disorders in fine movement, equilibrium, posture, and motor learning in humans.” Sound familiar? To me, this sounds like David (pictured, above). He has problems learning any new motor task. He has problems retaining skills he has learned. His balance problems undoubtedly come from problems with his cerebellum.
Why is this problem so common among PMS children? That is easy to answer. Aside from SHANK3, MAPK8IP2 is the most frequently lost important gene of PMS. The two genes are very near each other on the chromosome and the vast majority of terminal deletions impact both genes.
It is possible that loss of SHANK3 contributes, to some degree, to the problem in the cerebellum. Shank3 is present in one cell type of the cerebellum. However, the new research shows that the major dysfunction produced by loss of Mapk8ip2 occurs independently of Shank3.
It is nice to start getting some answers. MAPK8IP2 is likely the most important PMS gene for balance and fine motor control. Even more exciting is that earlier work showed an already-approved FDA medication, memantine, improved behavior in Ib2 knockout mice. I wonder if this medication could help David now?
What the new study shows is, regardless how a person gets autism or schizophrenia, the same networks of genes become dysregulated. Let’s first discuss what gene regulation means. DNA is like a well-stocked bakery. A good cook can prepare many different kinds of breads or desserts by choosing how much of each ingredient to use, and when. Just about every cell in the body has the same DNA. What makes one part of the body different from another is how much, and when, each gene is used. DNA cooking is called gene regulation. In autism and schizophrenia, the proportions of ingredients have gone awry.
The green diagram at the top of this blog maps the results of the new study. The researchers found certain critical “modules” (functional groups) of genes that are dysregulated in the brains of individuals with these two disorders. Once, again, these genes are dysregulated regardless of how one acquires autism or schizophrenia. The map identifies the 20 most dysregulated genes in each module (140 total) and how they interact in the brain.
What does this diagram tell us? It says some things we already knew. Autism (and schizophrenia) cause problems in neurons, the brain cells responsible for sensation, thinking and action. Less obvious, autism seems to be related to two other cell types, astrocytes and microglia. Astrocytes nourish neurons. Microglia, which also come in contact with neurons, are known to regulate the formation and removal of synapses. There are other important cell types, as well.
What is the news for PMS? We learn that two PMS genes are core genes of the dysregulated neuron networks. I have circled these genes in RED. There are about 20,000 genes in the human genome. The paper identifies the top 140 dysregulated genes. Obviously, they are quite important for psychiatric disorders. The two PMS genes are MAPK8IP2 and SULT4A1. Not surprisingly, MAPK8IP2 and SULT4A1 have already been identified as two of the 18 most important genes of PMS (see Which PMS genes are most important?).
Which individuals with PMS are missing these genes? Nearly all (over 95%) of people with PMS are missing MAPK8IP2. About 30% of people with PMS are missing both MAPK8IP2 and SULT4A1. If your child has a typical (terminal) deletion, you can look up which important PMS genes are missing in this blog: Which PMS genes are most important?
At this point, it seems pretty likely that deletions of 22q13.3 do more than raise the risk of autism. Deletions can directly impact MAPK8IP2 and SULT4A1, two core genes dysregulated in autism, schizophrenia and other neuropsychiatric disorders. Perhaps the good news is that people who study autism and schizophrenia have a new impetus to study MAPK8IP2 and SULT4A1. It is up to PMS parents to lobby, cajole and otherwise let everyone know that studying these genes is very important to us.
Two very recent studies of Phelan McDermid syndrome (PMS) drew exactly the same conclusion: We need to recruit and study more PMS patients with interstitial deletions if we are going to understand the syndrome (see references 1 and 2, below). This blog explains why that is a critical need. In some ways, this blog is an update to an earlier blog (Why don’t we have better drugs for 22q13 deletion syndrome?).
PMS can be broken down into a few obvious classes. The original disorder, 22q13.3 deletion syndrome, has terminal deletions and interstitial deletions. Later, SHANK3 variants (often called “mutations”) were added. As I have discussed before (Gene deletion versus mutation: sometimes missing a gene is better), mutations are a mixed bag. Some mutations produce symptoms like 22q13.3 deletion syndrome, but other mutations produce other disorders (like ASD or Aspergers), or no disorder at all.
PMS research started out with SHANK3, but somehow it got stuck there. Being stuck has led to some serious deficiencies in our understanding of PMS. First, very little is being done for the future of children with interstitial deletions. Their SHANK3 gene is intact, so SHANK3 research does them no good. Second, drug studies that use PMS patients to study SHANK3 are likely to fail without accounting for the important genes in each PMS patient. This was discussed in the recent paper on PMS genes (reference 2). PMS patients have such a mix of deleted genes that the benefits of a drug for SHANK3 loss might not be detectable. Third, certain serious problems seen in PMS are unlikely a result of SHANK3. These issues, like poor thermoregulation (body temperature control), lymphedema, cerebellar malformation, mitochondrial problems, and certain developmental problems, impact a large proportion of children with PMS. Every year children and adults with PMS die. We need to know which genes are associated with lethality. These issues will remain serious problems for people with PMS as long as SHANK3 remains the narrow focus of PMS research. Even our understanding of SHANK3, itself, is incomplete without a much better understanding of the other important genes of PMS.
The best way to understand the many genes of PMS is to study people with interstitial deletions. They are the only PMS patients where we can safely say that SHANK3 deletion does not play a role. My last two blogs show that we actually know a lot about PMS genes that are most likely to cause problems. However, we need to know much more about how each of these genes affect people. That requires people with different size interstitial deletions.
There was one research study of people with interstitial deletions published in 2014 (Disciglio et al.). It covered 12 patients. Since that paper, there has been only one additional (single) case study of an interstitial deletion. By comparison, PubMed shows 164 papers with SHANK3 in the title. Most PMS families are probably not aware that the current major studies of PMS specifically exclude interstitial patients: Natural History of Phelan McDermid Syndrome and the Electrophysiological Biomarkers of Phelan-McDermid Syndrome. Some of the sites in these multisite studies have not excluded participants with interstitial deletions, recognizing the scientific importance of these cases. Scientifically, excluding interstitial deletion patients makes no sense. We should be seeking them out, recruiting them. As a parent, excluding interstitial deletions seems unfair to both those families, and to the rest of us. We need to get unstuck. We need the best science possible to help our children.
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.
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?