Myotonic dystrophy type 1 (DM1 or MMD1) is an autosomal dominant neuromuscular disorder caused by mutations in the DMPK gene, located on chromosome 19. The gene in a healthy individual contains 5-34 copies of a CTG trinucleotide repeat. Any number of repeats beyond this number is classified as DM1. There is a statistically significant correlation–albeit no perfect correlation–between number of superfluous repeats and severity of symptoms: 35-49 repeats mean that the individual never gets any symptoms but their children can inherit it with an increased number of repeats; 50-150 repeats typically result in mild symptoms; 150-1000 repeats are usually classified as the classic (adult onset) version; >1000 repeats do often result in the congenital version of the disorder.
DM1 is progressive and cannot be cured. It primarily affects muscles but also other body systems. From mda.org:
The muscle-related symptoms include myotonia, for which the disease is named, and weakness, particularly of the face, neck, and limb muscles that are furthest from the center of the body (the distal muscles), such as the forearms, hands, lower legs and feet. Over time, all limb muscles can become weak.
Among the most serious effects of MMD1 are weakness of the breathing and swallowing muscles and dysfunction of the heart muscle, particularly the tissue in the heart that conducts electrical impulses from one part of the heart to another.
The so-called “smooth” muscles of the gastrointestinal tract can be affected, causing diarrhea, constipation and abdominal pain. Other smooth muscles that line the hollow organs of the body, such as the uterus and gallbladder, can be affected as well, leading to obstetric complications and gallstones.
The lenses in the eyes almost always develop cataracts, which can be surgically removed when they interfere with vision. […]
And then there are the effects on the brain, causing a range of symptoms, including learning disabilities, difficulty with decision-making, and what some psychologists have called an “avoidant” or “apathetic” personality type.
Excessive daytime sleepiness and chronic fatigue are among the most puzzling and troublesome of MMD1 symptoms, and their origin appears to be complex and probably related to the effects of the disease on the brain, limb muscles, respiratory system, heart and perhaps to altered levels of testosterone and insulin.
I am personally affected by the DM1 mutation with about 300 repeats, which means that I have the classic version of the disorder. I’ve been aware of this since I was 16 and got myself tested. I inherited the mutation from my father who passed away 57 years old in 2006 (primarily due to brain damage from alcohol abuse; it is however likely that DM1 played at least some role in shortening his life). My grandmother passed away from DM1 when she was 62, then weighing around 30 kg, similar to her own mother’s weight when she passed from DM1 around the age of 50.
I am 39 years old and I certainly hope to live a longer life than the previous generations with DM1 did, and I have made sure that I am the last in my family to carry the mutation. During the last two years, I have gained at least one size in clothes, but my weight has decreased with several kilos: muscles weigh more than fat and I am nowadays loosing muscles steadily. It becomes increasingly difficult to take long walks and I wake up during nights from a burning pain in the legs. My jaws get stuck ever so often and my articulation has already seen its best days–especially in English, a language that makes use of other facial muscles than my native language. My ability to swallow solid food is worsening; raw vegetables like carrots is nowadays a no-no, as is my favorite candy, and I need to cut green leaves like spinach and kale into small pieces to avoid choking. It gets increasingly difficult to clear the airways through coughing during common colds. My neck muscles are too weak to hold my head in place, and my appearance continues to change due to increased facial weakness. While I have lived with fatigue for several years already, that too is getting worse. Today I would never be able to keep a 9-5 full-time job; even 15-20 hours would likely had been over my current capacity. (Want to know how I despite this manage to engage in a full-time job as the founding director of IGDORE? Then stay tuned for a future blog post.)
Why do researchers choose an academic career? Some do because they have a very strong need and interest in finding out how the world functions; they become researchers out of pure curiosity. Others might primarily choose the science profession due to a wish for a good career and a high societal status. I personally became a researcher to help do something good for the world. I had got very interested in forensic psychology and wanted to do my part in improving criminal investigations by making interrogations with suspects more useful, adequate and ethical. I was therefore very disappointed to find that much research in this area was plagued by questionable research practices such as p-hacking and post hoc hypothesizing (also called HARKing). In addition were the studies severely underpowered, which does not only make them a waste of time and money, but also produces a high number of false positives (see e.g. Button et al., 2013, for a good explanation of why small sample sizes can increase the risk of false positive results).
It is today established that questionable research practices (QRPs), such as outcome switching, are common in randomised controlled trials (Chan et al, 2004; Dwan et al, 2011; Dwan et al, 2013), oral health (Pandis et al, 2015), psychology (Claesen et al, 2019; John et al, 2012), ecology (Fraser et al, 2018), and other fields and disciplines. Chan et al, 2004:
The reporting of [randomised controlled] trial outcomes is not only frequently incomplete but also biased and inconsistent with protocols. Published articles, as well as reviews that incorporate them, may therefore be unreliable and overestimate the benefits of an intervention.
Outcome switching in favor of variables that reached statistical significance are common in healthcare research (Page et al, 2014), surgery research (e.g. Killeen et al, 2014; Rosenthal & Dwan, 2013), cystic fibrosis research (Dwan et al, 2013), to name only a few. There is absolutely no reason to expect that the field of DM1 research is any less affected than these other medical areas. It is just that the prevalence of QRPs in DM1 research has not yet been properly investigated.
Aiming to offer at least some empirically based thoughts on DM1 research, I took a (very) quick look at DM1 research conducted in my own field (psychology). The first article I found seems to be the most recent meta-analysis of cognitive deficits in DM1 patients, published 2017 in Cortex. From this article do I preliminary conclude that there seem to be problems with at least statistical power, measurement practices, and a lack of direct replications.
For example, the average number of patients included in the 40 studies is 22 (Md; M = 28); number of healthy controls were 20 (Md; M = 24). This implies that there might be quite an issue with power, unless the true effects for a majority of the tests actually are as large as the meta-analysis suggests.
The total number of neuropsychological tests employed by at least one study was 95, covering “all cognitive domains” (p. 13 in manuscript version). The number of cognitive domains was 12. The effect sizes for 7 of the domains (namely, global cognition; intelligence; visual memory; visuospatial perception; visuoconstruction; psychomotor speed; social cognition) were classified as large. That is, the meta-analysis suggests that patients with DM1 do significantly worse than healthy individuals in these 7 cognitive domains.
How about the other cognitive domains? Well, all other domains were also negatively affected by DM1, with effect sizes ranging from small to medium. That is, there was not one single investigated area that seemed unaffected by DM1, which may be a sign of publication bias.
Furthermore, out of 128 studies deemed relevant to include in the meta-analysis, 88 were excluded: 19 due to lack of access to the full-text, 7 due to double-reporting, and 14 due to lack of sufficient details in the methods and/or results section.
The publisher’s website suggested to me another meta-analysis, published in 2019, which investigated affective disorders in patients with DM1. In the included 36 studies, no less than 22 different measures of depression were employed. The two most frequently used measures were HAM-D and BDI, which were used in 10 studies each. And again are we looking at small samples and no direct replications.
As a patient living with DM1, I am interested in learning how the disorder is affecting me or potentially will affect me in the future. In particular am I interested in learning how symptoms of the disorder can be reduced. As a researcher myself do I also understand that research is not only conducted with the primary purpose of improving the situation for patients currently living with a certain disorder. We need to–and want to–understand how the world functions and we never know when or where research will give rise to an idea that fundamentally changes everything, for example by generating a cure to a disorder.
As a patient AND researcher, I would suggest an immediate end to public funding of DM1 research that lacks statistical power because (1) it is a severe waste of time for those of us living with the disorder, and (2) it is not good science (learn why in the Button et al, 2013 article referred to above).
Further do I propose–at least for now–to not do any new investigations into the prevalence of e.g. cognitive and affective deficits in DM1 patients. By now we do seem to know that many–but not all–DM1 patients have issues in these areas, but due to the extensive heterogeneity in the DM1 population, in combination with the general limitations of psychological research, will we not be able to draw any solid conclusions about the prevalence or exactly what it is that is prevalent and not. So it is time to stop and look for more fruitful approaches, clinically and/or methodologically.
As psychologists do we already know a thing or two about more or less successful interventions to help people cope with affective disorders, and I therefore find it superfluous to get into research on how to specifically help patients with DM1 with their affective disorders. For sure could it be a viable approach to get another publication on your CV, but please don’t take that route. Instead do I suggest much more focus on the broader areas of symptoms that seem to affect most of us and to which there do not yet seem to be any really successful interventions, for example muscle loss and fatigue / daytime sleepiness.
I want to end this post with a plea to all DM1 researchers, from a DM1 patient and a fellow researcher:
Please don’t waste our time, our lives, by not reporting everything you found. Don’t omit or hide statistical tests that “didn’t show anything”. Got a feeling your results won’t hold if you do this or that with the data or tests? Please report it explicitly in the paper; be transparent about your doubts and the uncertainty of the results.
Please don’t waste our time by having unexplained deviations between your preregistration (protocol) and the scientific report. Please make sure to make the materials you used and the anonymised data publicly available in an online repository so that other researchers can build upon your work; don’t waste our lives by keeping these crucial components of the research to yourself and your closest colleagues. Same goes for the scientific report: please make it publicly available online for us all to learn from and build upon.
Please show us respect by not engaging in underpowered research. If you can’t get enough data for your study, try collaborations with other teams or to make your study design more straightforward to increase its statistical power. Other ways to solve the problem may sometimes be to employ Bayesian instead of frequentist statistics.
Have you yourself been involved in research on DM1–or research otherwise highly relevant to DM1–that you today have lost confidence in? Please write a retroactive disclosure statement, or contact me for further advise on how to disclose previously unmentioned details about the research.
This all said, I hereby want to offer myself as a research subject to well-planned DM1 research that I may or may not be a co-author of. I am willing to provide high-quality data continuously during extended time periods.
Research that I myself might be interested in co-authoring includes
- (how) can muscle strength be improved (in patient[s] with DM1)?
- can extrinsic motivation increase level of regular physical activity (in patient[s] with DM1)?
- (how) can day time sleepiness and fatigue be decreased (in patient[s] with DM1)?
- systematic meta-analytic review(s) of outcome switching, publication bias and/or other questionable research practices in DM1 research
Further, I would be interested in being a research subject (including providing data continuously during extended time periods) in areas where I lack relevant competence to be a co-author:
- other promising approaches to cure DM1 or to decrease symptoms of the disorder
Want to contact me about research on DM1? Please use the contact details provided on my website.