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 (de novo 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.
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.
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References
Verhoeven et al 2019
https://www.ncbi.nlm.nih.gov/pubmed/31465867
Kolevzen et al 2019
https://www.ncbi.nlm.nih.gov/pubmed/31879555
Reierson et al 2017
https://www.ncbi.nlm.nih.gov/pubmed/?term=28346892
Guilherme et al 2014
https://www.ncbi.nlm.nih.gov/pubmed/24700634
Some selected earlier blogs
22q13: a hotbed for autism and intellectual disability genes?
PMS for Dummies
Which genes cause brain abnormalities in Phelan McDermid syndrome?
PMS, IQ and why interstitial deletions matter
MAPK8IP2 (IB2) may explain the major problems with walking and hand use
TCF20 may explain why some big deletions are worse than others
Current trends in SHANK3 research
Which PMS genes are most associated with Autism?
Does SHANK3 cause Autism?
We need to study interstitial deletions to cure PMS
What do we know about PMS genes?
Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse models
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
22q13 deletion syndrome – an introduction
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